RU2812706C2 - Compositions and methods of treatment of cancer with braf atypical mutations - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: invention relates to methods, pharmaceutical compositions and sets for treating or mitigating the effects of a cancer in an individual that has an atypical BRAF mutation (i.e., a BRAF non-V600E/K mutation) comprising an ERK inhibitor. Also the methods of identifying an individual having a cancer with an atypical BRAF mutation who would benefit from a therapy comprising an ERK inhibitor are provided.

EFFECT: obtaining compositions and methods of treatment of cancer with BRAF atypical mutations.

68 cl, 4 dwg, 3 tbl, 1 ex

Description

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit from U.S. Provisional Patent Application No. 62/506995, filed May 16, 2017, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to methods, kits and pharmaceutical compositions for treating or mitigating the effects of cancer with atypical genetic mutations using one or more anti-cancer agents.

INCLUDING A LIST OF SEQUENCES AS A REFERENCE

[0003] This application contains references to amino acid sequences and/or nucleic acid sequences that were provided herewith as a sequence listing text file "2391211.txt", file size 246 kB, created on May 15, 2018. The above sequence listing is incorporated herein by reference in its entirety in accordance with 37 C.F.R. § 1.52(e)(5).

BACKGROUND OF THE INVENTION

[0004] Mitogen-activated protein kinase (MAPK) or RAS/RAF/MEK/ERK signaling is responsible for several cellular signal transduction cascades involved in the control of proliferation, differentiation and apoptosis. The MAPK cellular signaling cascade has been found to be disrupted in human malignancies, often due to activating mutations in the KRAS, NRAS, or BRAF genes. Selective BRAF inhibitors, such as vemurafenib and dabrafenib, have been developed to target tumors with BRAF mutations. For example, vemurafenib is approved for unresectable or metastatic melanomas with the BRAF V600E mutation, and detection of the BRAF V600E mutation has become a standard procedure for predicting response to treatment with vemurafenib, dabrafenib, and trametinib.

[0005] While the V600E mutation is the most common BRAF mutation seen in many tumor types, more than 100 other mutations in exons 11 and 15 of the BRAF gene have been described in the Catolog of Somatic Mutations in Cancer (COSMIC) database. The clinical significance of BRAF mutations not at codon V600 is largely unknown.

[0006] In view of the above, there is a need for new drugs that target the MAPK cascade in cell types containing BRAF mutations other than V600E. This application addresses these and other needs.

SUMMARY OF THE INVENTION

[0007] In accordance with one aspect, the present invention provides a method of treating or mitigating the effects of a cancer in an individual having a BRAF mutation other than V600E/K, the method comprising administering to the individual an effective amount of an ERK inhibitor or a pharmaceutically acceptable salt thereof.

[0008] In accordance with some embodiments, the ERK inhibitor is selected from the group consisting of BVD-523, SCH-722984 (Merck & Co.), SCH-772984 (Merck & Co.), SCH-900353 (MK-8353) ( Merck & Co.), LY3214996 (Lilly), AEZS-140 (Aeterna Zentaris), AEZS-131 (Aeterna Zentaris), AEZS-136 (Aeterna Zentaris), LTT-462 (Novartis), RG-7842 (Genentech), CC -90003 (Celgene), KIN-4050 (Kinentia) and combinations thereof.

[0009] In some embodiments, the ERK inhibitor is BVD-523.

[0010] In some embodiments, the non-V600E/K BRAF mutation is a kinase-activating mutation, a kinase-disrupting mutation, or a mutation with an unknown effect on the kinase, and combinations thereof.

[0011] In some embodiments, the kinase activating mutation is selected from the group consisting of R462I, I463S, G464E, G464R, G464V, G466A, G469A, N581S, E586K, F595L, L597Q, L597R, L597S, L597V, A598V, T599E, V 600R, K601E, S602D, A728V and their combinations.

[0012] In some embodiments, the kinase-impairing mutation is selected from the group consisting of G466E, G466R, G466V, Y472C, K483M, D594A, D594E, D594G, D594H, D594N, D594V, G596R, T599A, S602A, and combinations thereof.

[0013] In some embodiments, the mutation with an unknown effect on the kinase is selected from the group consisting of T440I, S467L, G469E, G469R, G469S, G469V, L584F, L588F, V600_K601delinsE, S605I, Q609L, E611Q, and combinations thereof.

[0014] In some embodiments, the non-V600E/K BRAF mutation is selected from the group consisting of D594, G469, K601E, L597, T599 duplication, L485W, F247L, G466V, BRAF fusion, BRAF-AGAP3 rearrangement, BRAF exon 15 splice variant, and their combinations.

[0015] In some embodiments, the individual is a mammal.

[0016] In some embodiments, the mammal is selected from the group consisting of humans, primates, farm animals, and domestic animals.

[0017] In some embodiments, the mammal is a human.

[0018] In some embodiments, the cancer is a solid malignancy or a hematologic malignancy.

[0019] In some embodiments, the cancer is selected from the group consisting of glioblastoma, melanoma, cholangiocarcinoma, small cell lung cancer, colorectal cancer, prostate cancer, vaginal cancer, angiosarcoma, non-small cell lung cancer, appendix cancer, squamous cell carcinoma, salivary gland ductal carcinoma, adenoid cystic carcinoma, small intestinal cancer and gallbladder cancer.

[0020] In some embodiments, the cancer is selected from the group consisting of small intestinal cancer, non-small cell lung cancer, gallbladder cancer, and squamous cell carcinoma.

[0021] In some embodiments, the method further includes administering to the individual at least one additional drug selected from the group consisting of a MEK inhibitor, a RAF inhibitor, an HDAC inhibitor, and combinations thereof.

[0022] In some embodiments, the MEK inhibitor is selected from the group consisting of anthrax toxin, anthroquinolol (Golden Biotechnology), ARRY-142886 ((2-hydroxyethoxy)amide 6-(4-bromo-2-chloro-phenylamino)-7 -fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid) (Array BioPharma), ARRY-438162 (Array BioPharma) binimetinib (MEK162, ARRY-1662), AS-1940477 (Astellas), AS-703988 (Merck KGaA ), bentamapimod (Merck KGaA), BI-847325 (Boehringer Ingelheim), E-6201 (Eisai), GDC-0623 (Hoffmann-La Roche), GDC-0973 (cobimetinib) (Hoffmann-La Roche), L783277 (Merck) , part of the lethal anthrax toxin, MEK162 (Array BioPharma), PD 098059 (2-(2'-amino-3'-methoxphenyl)oxanaphthalene-4-one) (Pfizer), PD 184352 (CI-1040) ( Pfizer), PD-0325901 (Pfizer), PD318088 (Pfizer), PD334581 (Pfizer), 6-methoxy-7-(3-morpholin-4-ylpropoxy)-4-(4-phenoxyphenylamino)quinoline-3-carbonitrile, 4 -[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-3-carbonitrile, pimasertib (Santhera Pharmaceuticals) , RDEA119 (Ardea Biosciences/Bayer), refametinib (AstraZeneca), RG422 (Chugai Pharmaceutical Co.), R0092210 (Roche), R04987655 (Hoffmann-La Roche), R05126766 (Hoffmann-La Roche), selumetinib (AZD6244) (AstraZeneca) , SL327 (Sigma), TAK-733 (Takeda), trametinib (Japan Tobacco), U0126 (1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene) (Sigma), WX -554 (Wilex), YopJ polypeptide (Mittal et al., 2010), pharmaceutically acceptable salts thereof, and combinations thereof.

[0023] In some embodiments, the RAF inhibitor is selected from the group consisting of AAL881 (Novartis), AB-024 (Ambit Biosciences), ARQ-736 (ArQule), ARQ-761 (ArQule), AZ628 (Axon Medchem BV), BAY 43-9006 sorafenib, BeiGene-283 (BeiGene), BUB-024 (MLN 2480) (Sunesis & Takeda), b-raf inhibitor (Sareum), BRAF kinase inhibitor (Selexagen Therapeutics), anti-BRAF siRNA 313 (tacaccagcaagctagatgca) and 523 (cctatcgttagagtcttcctg) (Liu et al., 2007), CHIR-265 (Novartis), CTT239065 (Institute of Cancer Research), dabrafenib (GSK2118436), DP-4978 (Deciphera Pharmaceuticals), HM-95573 (Hanmi), GDC-0879 (Genentech), GW-5074 (Sigma Aldrich), ISIS 5132 (Novartis), L779450 (Merck), LBT613 (Novartis), LXH254 (Novartis), LErafAON (NeoPharm, Inc.), LGX-818 (Novartis), pazopanib ( GlaxoSmithKline), PLX3202 (Plexxikon), PLX4720 (Plexxikon), PLX5568 (Plexxikon), PLX3603 (Daiichi Sankyo), PLX8394 (Daiichi Sankyo), RAF-265 (Novartis), RAF-365 (Novartis), REDX0535 (RedX Pharma Plc) , regorafenib (Bayer Healthcare Pharmaceuticals, Inc.), RO 5126766 (Hoffmann-La Roche), SB-590885 (GlaxoSmithKline), SB699393 (GlaxoSmithKline), sorafenib (Onyx Pharmaceuticals), TAK 632 (Takeda), TL-241 (Teligene) , vemurafenib (RG7204 or PLX4032) (Daiichi Sankyo), XL-281 (Exelixis), ZM-336372 (AstraZeneca), pharmaceutically acceptable salts thereof, and combinations thereof.

[0024] In some embodiments, the HDAC inhibitor is selected from the group consisting of Abexinostat (PCI-24781), Givinostat, Entinostat, Vorinostat, CI-994, CUDC-101, Entinostat, BML-210, M344, NVP-LAQ824, Panobinostat, Pracinosate (SB939), Mocetinostat, Resminostat, Romidepsin, Belinostat, pharmaceutically acceptable salts thereof and combinations thereof.

[0025] In some embodiments, the method further includes administering to the individual at least one additional drug selected from the group consisting of an antibody, antibody fragment, antibody conjugate, cytotoxic agent, toxin, radionuclide, immunomodulator, photoactive drug, radiosensitizing agent, hormone, antiangiogenic agent and combinations thereof.

[0026] In some embodiments, the antibody, fragment thereof, or conjugate thereof is selected from the group consisting of rituximab (Rituxan), Brentuximab Vedotin (Adcetriz), Adotrastuzumab emtansine (Kadcyla), Cetuximab (Erbitux), bevacizumab (Avastin), Ibritumomab (Zevalin) ), vedolizumab (Entyvio), Ipilimumab (Yervoy), Nivolumab (Opdivo), pembrolizumab (Keytruda), Alemtuzumab atezolizumab (Tecentriq), avelumab (Bavenzio), durvalumab (Imfinzi), B-701, Ofatumumab, Obinutuzumab (Gaziva), Panitumumab , plosalizumab, BI-754091, OREG-103, COM-701, BI-754111 and combinations thereof.

[0027] In some embodiments, the cytotoxic agent is selected from the group consisting of cyclophosphamide, mechlorethamine, uramustine, melphalan, chlorambucil, ifosfamide, carmustine, lomustine, streptozocin, busulfan, temozolomide, cisplatin, carboplatin, oxaliplatin, nedaplatin, satraplatin, triplatin tetranitrate a, doxorubicin, daunorubicin, idarubicin, mitoxantrone, methotrexate, pemetrexed, 6-mercaptopurine, dacarbazine, fludarabine, 5-fluorouracil, arabinosylcytosine, capecitabine, gemcitabine, decitabine, vinca alkaloids, paclitaxel (Taxol), docetaxel (Taxotere), Ixa bepilona (Ixempra), actinomycin, anthracyclines, valrubicin, epirubicin, bleomycin, plicamycin, mitomycin, pharmaceutically acceptable salts thereof, prodrugs and combinations thereof.

[0028] In some embodiments, the toxin is diphtheria toxin or parts thereof.

[0029] In some embodiments, the radionuclide is selected from the group consisting of I-125, At-211, Lu-177, Cu-67, I-131, Sm-153, Re-186, P-32, Re-188, In-114m, Y-90 and their combinations.

[0030] In some embodiments, the immunomodulator is selected from the group consisting of granulocyte colony stimulating factor (G-CSF), LAG-3, IMP-321, JCAR-014, ASLAN-002 (BMS-777607), interferons, imiquimod, and cell membrane fractions from bacteria, IL-2, IL-7, IL-12, CCL3, CCL26, CXCL7, synthetic cytosine phosphate-guanosine (CpG), immune checkpoint inhibitors and combinations thereof.

[0031] In some embodiments, the radiosensitizing agent is selected from the group consisting of misonidazole, metronidazole, tirapazamine, sodium trans-crocetinate, and combinations thereof.

[0032] In some embodiments, the hormone is selected from the group consisting of prostaglandins, leukotrienes, prostacyclin, thromboxane, amylin, anti-Mullerian hormone, adiponectin, adrenocorticotropic hormone, angiotensinogen, angiotensin, vasopressin, atriopeptin, brain natriuretic peptide, calcitonin, cholicystokinin, corticotrope in -releasing hormone, encephalin, endothelin, erythropoietin, follicle-stimulating hormone, galanin, gastrin, ghrelin, glucagon, gonadotropin-releasing hormone, growth hormone releasing factor, human chorionic gonadotropin, human placental lactogen, growth hormone, inhibin, insulin, somatomedin, leptin , lipotropin, luteinizing hormone, melanocyte-stimulating hormone, motilin, orexin, oxytocin, pancreatic polypeptide, parathyroid hormone, prolactin, prolactin-releasing hormone, relaxin, renin, secretin, somatostatin, thrombopoietin, thyroid-stimulating hormone, testosterone, dehydroepiandrosterone, androstend ion, dihydrotestosterone , aldosterone, estradiol, estrone, estriol, cortisol, progesterone, calcitriol, calcidiol, tamoxifen (Nolvadex), anastrozole (Arimidex), lectrozole (Femara), fulvestrant (Faslodex) and combinations thereof.

[0033] In some embodiments, the antiangiogenic agent is selected from the group consisting of 2-methoxyestradiol, angiostatin, bevacizumab, cartilage angiogenesis inhibitory factor, endostatin, IFN-alpha, IL-12, itraconazole, linomide, platelet-derived factor-4, prolactin, SU5416 , suramin, tasquinimod, tecogalane, tetrathiomolybdate, thalidomide, thrombospondin, thrombospondin, TNP-470, ziv-aflibercept, pharmaceutically acceptable salts, prodrugs and combinations thereof.

[0034] In some embodiments, the additional drug is an inhibitor of the PI3K/Akt cascade.

[0035] In some embodiments, the PI3K/Akt cascade inhibitor is selected from the group consisting of A-674563 (CAS No. 552325-73-2), AGL 2263, AMG-319 (Amgen, Thousand Oaks, CA), AS-041164 ( 5-benzo[1,3]dioxol-5-ylmethylenethiazolidin-2,4-dione), AS-604850 (5-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethylene)thiazolidin-2, 4-dione), AS-605240 (5-quinoxylin-6-methylene-1,3-thiazolidine-2,4-dione), AT7867 (CAS No. 857531-00-1), benzimidazoles series, Genentech (Roche Holdings Inc. , South San Francisco, CA), BML-257 (CAS No. 32387-96-5), BVD-723, CAL-120 (Gilead Sciences, Foster City, CA), CAL-129 (Gilead Sciences), CAL-130 ( Gilead Sciences), CAL-253 (Gilead Sciences), CAL-263 (Gilead Sciences), CAS No. 612847-09-3, CAS No. 681281-88-9, CAS No. 75747-14-7, CAS No. 925681-41- 0, CAS No. 98510-80-6, CCT128930 (CAS No. 885499-61-6), CH5132799 (CAS No. 1007207-67-1), CHR-4432 (Chroma Therapeutics, Ltd., Abingdon, UK), FPA 124 ( CAS No. 902779-59-3), GS-1101 (CAL-101) (Gilead Sciences), GSK 690693 (CAS No. 937174-76-0), H-89 (CAS No. 127243-85-0), Honokiola, IC87114 (Gilead Science), IPI-145 (Intellikine Inc.), KAR-4139 (Karus Therapeutics, Chilworth, UK), KAR-4141 (Karus Therapeutics), KIN-1 (Karus Therapeutics), KT 5720 (CAS No. 108068-98 -0), Miltefosine, MK-2206 dihydrochloride (CAS No. 1032350-13-2), ML-9 (CAS No. 105637-50-1), Naltrindole hydrochloride, OXY-111A (NormOxys Inc., Brighton, MA), perifosine , PHT-427 (CAS No. 1191951-57-1), PI3-kinase delta inhibitor, Merck KGaA (Merck & Co., Whitehouse Station, NJ), PI3-kinase delta inhibitors, Genentech (Roche Holdings Inc.), PI3 inhibitors -kinase delta, Incozen (Incozen Therapeutics, Pvt. Ltd., Hydrabad, India), PI3-kinase inhibitor-2 delta, Incozen (Incozen Therapeutics), PI3-kinase inhibitor, Roche-4 (Roche Holdings Inc.), PI3-kinase inhibitors, Roche (Roche Holdings Inc.), PI3-kinase inhibitors, Roche-5 (Roche Holdings Inc.), PI3-alpha/delta inhibitors, Pathway Therapeutics (Pathway Therapeutics Ltd., South San Francisco, CA), PI3-delta inhibitors, Cellzome (Cellzome AG, Heidelberg, Germany ), PI3-delta inhibitors, Intellikine (Intellikine Inc., La Jolla, CA), PI3-delta inhibitors, Pathway Therapeutics-1 (Pathway Therapeutics Ltd.), PI3-delta inhibitors, Pathway Therapeutics-2 (Pathway Therapeutics Ltd.) , PI3-delta/gamma inhibitors, Cellzome (Cellzome AG), PI3-delta/gamma inhibitors, Cellzome (Cellzome AG), PI3-delta/gamma inhibitors, Intellikine (Intellikine Inc.), PI3-delta/gamma inhibitors, Intellikine ( Intellikine Inc.), PI3-delta/gamma inhibitors, Pathway Therapeutics (Pathway Therapeutics Ltd.), PI3-delta/gamma inhibitors, Pathway Therapeutics (Pathway Therapeutics Ltd.), PI3-gamma inhibitor Evotec (Evotec), PI3-gamma inhibitor , Cellzome (Cellzome AG), PI3-gamma inhibitors, Pathway Therapeutics (Pathway Therapeutics Ltd.), PI3K-delta/gamma inhibitors, Intellikine-1 (Intellikine Inc.), PI3K-delta/gamma inhibitors, Intellikine-1 (Intellikine Inc. .), pictilisib (Roche Holdings Inc.), PIK-90 (CAS No. 677338-12-4), SC-103980 (Pfizer, New York, NY), SF-1126 (Semafore Pharmaceuticals, Indianapolis, IN), SH -5, SH-6, tetrahydrocurcumin, TG100-115 (Targegen Inc., San Diego, CA), Triciribine, X-339 (Xcovery, West Palm Beach, FL), XL-499 (Evotech, Hamburg, Germany) , their pharmaceutically acceptable salts and combinations thereof.

[0036] In accordance with one aspect, the present invention provides a method of treating or mitigating the effects of a cancer in an individual, comprising: (a) identifying an individual with a cancer having a non-V600E/K BRAF mutation; and (b) administering to the individual an effective amount of an ERK inhibitor or a pharmaceutically acceptable salt thereof.

[0037] In some embodiments, the ERK inhibitor is selected from the group consisting of BVD-523, SCH-722984 (Merck & Co.), SCH-772984 (Merck & Co.), SCH-900353 (MK-8353) (Merck & Co.), Co.), LY3214996 (Lilly), AEZS-140 (Aeterna Zentaris), AEZS-131 (Aeterna Zentaris), AEZS-136 (Aeterna Zentaris), LTT-462 (Novartis), RG-7842 (Genentech), CC-90003 (Celgene), KIN-4050 (Kinentia) and combinations thereof.

[0038] In some embodiments, the ERK inhibitor is BVD-523.

[0039] In some embodiments, the non-V600E/K BRAF mutation is a kinase-activating mutation, a kinase-disrupting mutation, or a mutation with an unknown effect on the kinase, and combinations thereof.

[0040] In some embodiments, the kinase activating mutation is selected from the group consisting of R462I, I463S, G464E, G464R, G464V, G466A, G469A, N581S, E586K, F595L, L597Q, L597R, L597S, L597V, A598V, T599E, V 600R, K601E, S602D, A728V and their combinations.

[0041] In some embodiments, the kinase-impairing mutation is selected from the group consisting of G466E, G466R, G466V, Y472C, K483M, D594A, D594E, D594G, D594H, D594N, D594V, G596R, T599A, S602A, and combinations thereof.

[0042] In some embodiments, the mutation with an unknown effect on the kinase is selected from the group consisting of T440I, S467L, G469E, G469R, G469S, G469V, L584F, L588F, V600_K601delinsE, S605I, Q609L, E611Q, and combinations thereof.

[0043] In some embodiments, the individual is a mammal.

[0044] In some embodiments, the mammal is selected from the group consisting of humans, primates, farm animals, and pets.

[0045] In some embodiments, the mammal is a human.

[0046] In some embodiments, the cancer is a solid cancer or a hematologic malignancy.

[0047] In some embodiments, the cancer is selected from the group consisting of glioblastoma, melanoma, cholangiocarcinoma, small cell lung cancer, colorectal cancer, prostate cancer, vaginal cancer, angiosarcoma, non-small cell lung cancer, appendix cancer, squamous cell carcinoma, salivary gland ductal carcinoma, adenoid cystic carcinoma, small intestinal cancer and gallbladder cancer.

[0048] In some embodiments, the cancer is selected from the group consisting of small intestinal cancer, non-small cell lung cancer, gallbladder cancer, and squamous cell carcinoma.

[0049] In some embodiments, the method further includes (i) obtaining a biological sample from an individual; and (ii) screening the sample to determine whether the individual has a BRAF mutation other than V600E/K.

[0050] In some embodiments, the method further includes administering to the individual at least one additional drug selected from the group consisting of a MEK inhibitor, a RAF inhibitor, an HDAC inhibitor, and combinations thereof.

[0051] In some embodiments, the MEK inhibitor is selected from the group consisting of anthrax toxin, anthroquinonol (Golden Biotechnology), ARRY-142886 ((2-hydroxyethoxy)amide) 6-(4-bromo-2-chlorophenylamino)-7- fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (Array BioPharma), ARRY-438162 (Array BioPharma), binimetinib (MEK162, ARRY-1662), AS-1940477 (Astellas), AS-703988 (Merck KGaA), bentamapimod (Merck KGaA), BI-847325 (Boehringer Ingelheim), E-6201 (Eisai), GDC-0623 (Hoffmann-La Roche), GDC-0973 (cobimetinib) (Hoffmann-La Roche), L783277 (Merck), parts lethal anthrax toxin MEK162 (Array BioPharma), PD 098059 (2-(2'-amino-3'-methoxphenyl)oxanaphthalene-4-one) (Pfizer), PD 184352 (CI-1040) (Pfizer) , PD-0325901 (Pfizer), PD318088 (Pfizer), PD334581 (Pfizer), 6-methoxy-7-(3-morpholin-4-ylpropoxy)-4-(4-phenoxyphenylamino)quinoline-3-carbonitrile, 4-[ 3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-3-carbonitrile, pimasertib (Santhera Pharmaceuticals), RDEA119 (Ardea Biosciences/Bayer), refametinib (AstraZeneca), RG422 (Chugai Pharmaceutical Co.), R0092210 (Roche), R04987655 (Hoffmann-La Roche), R05126766 (Hoffmann-La Roche), selumetinib (AZD6244) (AstraZeneca), SL327 (Sigma), TAK-733 (Takeda), trametinib (Japan Tobacco), U0126 (1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene) (Sigma), WX-554 (Wilex), YopJ polypeptide (Mittal et al., 2010), pharmaceutically acceptable salts thereof and combinations thereof.

[0052] In some embodiments, the RAF inhibitor is selected from the group consisting of AAL881 (Novartis), AB-024 (Ambit Biosciences), ARQ-736 (ArQule), ARQ-761 (ArQule), AZ628 (Axon Medchem BV), BAY 43-9006 sorafenib, BeiGene-283 (BeiGene), BUB-024 (MLN 2480) (Sunesis & Takeda), b-raf inhibitor (Sareum), BRAF kinase inhibitor (Selexagen Therapeutics), anti-BRAF siRNA 313 (tacaccagcaagctagatgca) and 523 (cctatcgttagagtcttcctg) (Liu et al., 2007), CHIR-265 (Novartis), CTT239065 (Institute of Cancer Research), dabrafenib (GSK2118436), DP-4978 (Deciphera Pharmaceuticals), HM-95573 (Hanmi), GDC-0879 (Genentech), GW-5074 (Sigma Aldrich), ISIS 5132 (Novartis), L779450 (Merck), LBT613 (Novartis), LXH254 (Novartis), LErafAON (NeoPharm, Inc.), LGX-818 (Novartis), pazopanib ( GlaxoSmithKline), PLX3202 (Plexxikon), PLX4720 (Plexxikon), PLX5568 (Plexxikon), PLX3603 (Daiichi Sankyo), PLX8394 (Daiichi Sankyo), RAF-265 (Novartis), RAF-365 (Novartis), REDX0535 (RedX Pharma Plc) , regorafenib (Bayer Healthcare Pharmaceuticals, Inc.), RO 5126766 (Hoffmann-La Roche), SB-590885 (GlaxoSmithKline), SB699393 (GlaxoSmithKline), sorafenib (Onyx Pharmaceuticals), TAK 632 (Takeda), TL-241 (Teligene) , vemurafenib (RG7204 or PLX4032) (Daiichi Sankyo), XL-281 (Exelixis), ZM-336372 (AstraZeneca), pharmaceutically acceptable salts thereof, and combinations thereof.

[0053] In some embodiments, the HDAC inhibitor is selected from the group consisting of Abexinostat (PCI-24781), Givinostat, Entinostat, Vorinostat, CI-994, CUDC-101, Entinostat, BML-210, M344, NVP-LAQ824, Panobinostat, Pracinosate (SB939), Mocetinostat, Resminostat, Romidepsin, Belinostat, pharmaceutically acceptable salts thereof and combinations thereof.

[0054] In some embodiments, the method further includes administering to the individual at least one additional drug selected from the group consisting of an antibody, antibody fragment, antibody conjugate, cytotoxic agent, toxin, radionuclide, immunomodulator, photoactive drug, radiosensitizing agent, hormone, antiangiogenic agent and combinations thereof.

[0055] In some embodiments, the antibody, fragment thereof, or conjugate thereof is selected from the group consisting of rituximab (Rituxan), Brentuximab Vedotin (Adcetriz), Adotrastuzumab emtansine (Kadcyla), Cetuximab (Erbitux), bevacizumab (Avastin), Ibritumomab (Zevalin) ), vedolizumab (Entyvio), Ipilimumab (Yervoy), Nivolumab (Opdivo), pembrolizumab (Keytruda), Alemtuzumab atezolizumab (Tecentriq), avelumab (Bavenzio), durvalumab (Imfinzi), B-701, Ofatumumab, Obinutuzumab (Gaziva), Panitumumab , plosalizumab, BI-754091, OREG-103, COM-701, BI-754111 and combinations thereof.

[0056] In some embodiments, the cytotoxic agent is selected from the group consisting of cyclophosphamide, mechlorethamine, uramustine, melphalan, chlorambucil, ifosfamide, carmustine, lomustine, streptozocin, busulfan, temozolomide, cisplatin, carboplatin, oxaliplatin, nedaplatin, satraplatin, triplatin tetranitrate a, doxorubicin, daunorubicin, idarubicin, mitoxantrone, methotrexate, pemetrexed, 6-mercaptopurine, dacarbazine, fludarabine, 5-fluorouracil, arabinosylcytosine, capecitabine, gemcitabine, decitabine, vinca alkaloids, paclitaxel (Taxol), docetaxel (Taxotere), Ixa bepilona (Ixempra), actinomycin, anthracyclines, valrubicin, epirubicin, bleomycin, plicamycin, mitomycin, pharmaceutically acceptable salts thereof, prodrugs and combinations thereof.

[0057] In some embodiments, the toxin is diphtheria toxin or parts thereof.

[0058] In some embodiments, the radionuclide is selected from the group consisting of I-125, At-211, Lu-177, Cu-67, I-131, Sm-153, Re-186, P-32, Re-188, In-114m, Y-90 and their combinations.

[0059] In some embodiments, the immunomodulator is selected from the group consisting of granulocyte colony stimulating factor (G-CSF), LAG-3, IMP-321, JCAR-014, ASLAN-002 (BMS-777607), interferons, imiquimod, and cell membrane fractions from bacteria, IL-2, IL-7, IL-12, CCL3, CCL26, CXCL7, synthetic cytosine phosphate-guanosine (CpG), immune checkpoint inhibitors and combinations thereof.

[0060] In some embodiments, the radiosensitizing agent is selected from the group consisting of misonidazole, metronidazole, tirapazamine, sodium trans-crocetinate, and combinations thereof.

[0061] In some embodiments, the hormone is selected from the group consisting of prostaglandins, leukotrienes, prostacyclin, thromboxane, amylin, anti-Mullerian hormone, adiponectin, adrenocorticotropic hormone, angiotensinogen, angiotensin, vasopressin, atriopeptin, brain natriuretic peptide, calcitonin, cholicystokinin, corticotrope in -releasing hormone, encephalin, endothelin, erythropoietin, follicle-stimulating hormone, galanin, gastrin, ghrelin, glucagon, gonadotropin-releasing hormone, growth hormone releasing factor, human chorionic gonadotropin, human placental lactogen, growth hormone, inhibin, insulin, somatomedin, leptin , lipotropin, luteinizing hormone, melanocyte-stimulating hormone, motilin, orexin, oxytocin, pancreatic polypeptide, parathyroid hormone, prolactin, prolactin-releasing hormone, relaxin, renin, secretin, somatostatin, thrombopoietin, thyroid-stimulating hormone, testosterone, dehydroepiandrosterone, androstend ion, dihydrotestosterone , aldosterone, estradiol, estrone, estriol, cortisol, progesterone, calcitriol, calcidiol, tamoxifen (Nolvadex), anastrozole (Arimidex), lectrozole (Femara), fulvestrant (Faslodex) and combinations thereof.

[0062] In some embodiments, the antiangiogenic agent is selected from the group consisting of 2-methoxyestradiol, angiostatin, bevacizumab, cartilage angiogenesis inhibitory factor, endostatin, IFN-alpha, IL-12, itraconazole, linomide, platelet-derived factor-4, prolactin, SU5416 , suramin, tasquinimod, tecogalane, tetrathiomolybdate, thalidomide, thrombospondin, thrombospondin, TNP-470, ziv-aflibercept, pharmaceutically acceptable salts, prodrugs and combinations thereof.

[0063] In some embodiments, the additional drug is an inhibitor of the PI3K/Akt cascade.

[0064] In some embodiments, the PI3K/Akt cascade inhibitor is selected from the group consisting of A-674563 (CAS No. 552325-73-2), AGL 2263, AMG-319 (Amgen, Thousand Oaks, CA), AS-041164 ( 5-benzo[1,3]dioxol-5-ylmethylenethiazolidin-2,4-dione), AS-604850 (5-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethylene)thiazolidin-2, 4-dione), AS-605240 (5-quinoxylin-6-methylene-1,3-thiazolidine-2,4-dione), AT7867 (CAS No. 857531-00-1), benzimidazoles series, Genentech (Roche Holdings Inc. , South San Francisco, CA), BML-257 (CAS No. 32387-96-5), BVD-723, CAL-120 (Gilead Sciences, Foster City, CA), CAL-129 (Gilead Sciences), CAL-130 ( Gilead Sciences), CAL-253 (Gilead Sciences), CAL-263 (Gilead Sciences), CAS No. 612847-09-3, CAS No. 681281-88-9, CAS No. 75747-14-7, CAS No. 925681-41- 0, CAS No. 98510-80-6, CCT128930 (CAS No. 885499-61-6), CH5132799 (CAS No. 1007207-67-1), CHR-4432 (Chroma Therapeutics, Ltd., Abingdon, UK), FPA 124 ( CAS No. 902779-59-3), GS-1101 (CAL-101) (Gilead Sciences), GSK 690693 (CAS No. 937174-76-0), H-89 (CAS No. 127243-85-0), Honokiola, IC87114 (Gilead Science), IPI-145 (Intellikine Inc.), KAR-4139 (Karus Therapeutics, Chilworth, UK), KAR-4141 (Karus Therapeutics), KIN-1 (Karus Therapeutics), KT 5720 (CAS No. 108068-98 -0), Miltefosine, MK-2206 dihydrochloride (CAS No. 1032350-13-2), ML-9 (CAS No. 105637-50-1), Naltrindole hydrochloride, OXY-111A (NormOxys Inc., Brighton, MA), perifosine , PHT-427 (CAS No. 1191951-57-1), PI3-kinase delta inhibitor, Merck KGaA (Merck & Co., Whitehouse Station, NJ), PI3-kinase delta inhibitors, Genentech (Roche Holdings Inc.), PI3 inhibitors -kinase delta, Incozen (Incozen Therapeutics, Pvt. Ltd., Hydrabad, India), PI3-kinase inhibitor-2 delta, Incozen (Incozen Therapeutics), PI3-kinase inhibitor, Roche-4 (Roche Holdings Inc.), PI3-kinase inhibitors, Roche (Roche Holdings Inc.), PI3-kinase inhibitors, Roche-5 (Roche Holdings Inc.), PI3-alpha/delta inhibitors, Pathway Therapeutics (Pathway Therapeutics Ltd., South San Francisco, CA), PI3-delta inhibitors, Cellzome (Cellzome AG, Heidelberg, Germany ), PI3-delta inhibitors, Intellikine (Intellikine Inc., La Jolla, CA), PI3-delta inhibitors, Pathway Therapeutics-1 (Pathway Therapeutics Ltd.), PI3-delta inhibitors, Pathway Therapeutics-2 (Pathway Therapeutics Ltd.) , PI3-delta/gamma inhibitors, Cellzome (Cellzome AG), PI3-delta/gamma inhibitors, Cellzome (Cellzome AG), PI3-delta/gamma inhibitors, Intellikine (Intellikine Inc.), PI3-delta/gamma inhibitors, Intellikine ( Intellikine Inc.), PI3-delta/gamma inhibitors, Pathway Therapeutics (Pathway Therapeutics Ltd.), PI3-delta/gamma inhibitors, Pathway Therapeutics (Pathway Therapeutics Ltd.), PI3-gamma inhibitor Evotec (Evotec), PI3-gamma inhibitor , Cellzome (Cellzome AG), PI3-gamma inhibitors, Pathway Therapeutics (Pathway Therapeutics Ltd.), PI3K-delta/gamma inhibitors, Intellikine-1 (Intellikine Inc.), PI3K-delta/gamma inhibitors, Intellikine-1 (Intellikine Inc. .), pictilisib (Roche Holdings Inc.), PIK-90 (CAS No. 677338-12-4), SC-103980 (Pfizer, New York, NY), SF-1126 (Semafore Pharmaceuticals, Indianapolis, IN), SH -5, SH-6, tetrahydrocurcumin, TG100-115 (Targegen Inc., San Diego, CA), Triciribine, X-339 (Xcovery, West Palm Beach, FL), XL-499 (Evotech, Hamburg, Germany) , their pharmaceutically acceptable salts and combinations thereof.

[0065] In accordance with one aspect, the present invention provides a method for identifying an individual having a cancer that would benefit from therapy with an ERK inhibitor or a pharmaceutically acceptable salt thereof, the method comprising: (a) obtaining a biological sample from the individual; and (b) screening the sample to determine whether the individual has a non-V600E/K BRAF mutation, wherein the presence of a non-V600E/K BRAF mutation confirms that the individual will benefit from therapy with an ERK inhibitor or a pharmaceutically acceptable salt thereof.

[0066] In some embodiments, the ERK inhibitor is selected from the group consisting of BVD-523, SCH-722984 (Merck & Co.), SCH-772984 (Merck & Co.), SCH-900353 (MK-8353) (Merck & Co.), Co.), LY3214996 (Lilly), AEZS-140 (Aeterna Zentaris), AEZS-131 (Aeterna Zentaris), AEZS-136 (Aeterna Zentaris), LTT-462 (Novartis), RG-7842 (Genentech), CC-90003 (Celgene), KIN-4050 (Kinentia) and combinations thereof.

[0067] In some embodiments, the ERK inhibitor is BVD-523.

[0068] In some embodiments, the non-V600E/K BRAF mutation is a kinase-activating mutation, a kinase-disrupting mutation, or a mutation with an unknown effect on the kinase, and combinations thereof.

[0069] In some embodiments, the kinase activating mutation is selected from the group consisting of R462I, I463S, G464E, G464R, G464V, G466A, G469A, N581S, E586K, F595L, L597Q, L597R, L597S, L597V, A598V, T599E, V 600R, K601E, S602D, A728V and their combinations.

[0070] In some embodiments, the kinase-impairing mutation is selected from the group consisting of G466E, G466R, G466V, Y472C, K483M, D594A, D594E, D594G, D594H, D594N, D594V, G596R, T599A, S602A, and combinations thereof.

[0071] In some embodiments, the mutation with an unknown effect on the kinase is selected from the group consisting of T440I, S467L, G469E, G469R, G469S, G469V, L584F, L588F, V600_K601delinsE, S605I, Q609L, E611Q, and combinations thereof.

[0072] In some embodiments, the individual is a mammal.

[0073] In some embodiments, the mammal is selected from the group consisting of humans, primates, farm animals, and domestic animals.

[0074] In some embodiments, the mammal is a human.

[0075] In some embodiments, the cancer is a solid malignancy or a hematologic malignancy.

[0076] In some embodiments, the cancer is selected from the group consisting of glioblastoma, melanoma, cholangiocarcinoma, small cell lung cancer, colorectal cancer, prostate cancer, vaginal cancer, angiosarcoma, non-small cell lung cancer, appendix cancer, squamous cell carcinoma, salivary gland ductal carcinoma, adenoid cystic carcinoma, small intestinal cancer and gallbladder cancer.

[0077] In some embodiments, the cancer is selected from the group consisting of small intestinal cancer, non-small cell lung cancer, gallbladder cancer, and squamous cell carcinoma.

[0078] In some embodiments, the method further comprises administering an ERK inhibitor or a pharmaceutically acceptable salt thereof to an individual having a non-V600E/K BRAF mutation.

[0079] In some embodiments, the method further includes administering to the individual at least one additional drug selected from the group consisting of a MEK inhibitor, a RAF inhibitor, an HDAC inhibitor, and combinations thereof.

[0080] In some embodiments, the MEK inhibitor is selected from the group consisting of anthrax toxin, anthroquinolol (Golden Biotechnology), ARRY-142886 ((2-hydroxyethoxy)amide 6-(4-bromo-2-chloro-phenylamino)-7 -fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid) (Array BioPharma), ARRY-438162 (Array BioPharma) binimetinib (MEK162, ARRY-1662), AS-1940477 (Astellas), AS-703988 (Merck KGaA ), bentamapimod (Merck KGaA), BI-847325 (Boehringer Ingelheim), E-6201 (Eisai), GDC-0623 (Hoffmann-La Roche), GDC-0973 (cobimetinib) (Hoffmann-La Roche), L783277 (Merck) , part of the lethal anthrax toxin, MEK162 (Array BioPharma), PD 098059 (2-(2'-amino-3'-methoxphenyl)oxanaphthalene-4-one) (Pfizer), PD 184352 (CI-1040) ( Pfizer), PD-0325901 (Pfizer), PD318088 (Pfizer), PD334581 (Pfizer), 6-methoxy-7-(3-morpholin-4-ylpropoxy)-4-(4-phenoxyphenylamino)quinoline-3-carbonitrile, 4 -[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-3-carbonitrile, pimasertib (Santhera Pharmaceuticals) , RDEA119 (Ardea Biosciences/Bayer), refametinib (AstraZeneca), RG422 (Chugai Pharmaceutical Co.), R0092210 (Roche), R04987655 (Hoffmann-La Roche), R05126766 (Hoffmann-La Roche), selumetinib (AZD6244) (AstraZeneca) , SL327 (Sigma), TAK-733 (Takeda), trametinib (Japan Tobacco), U0126 (1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene) (Sigma), WX -554 (Wilex), YopJ polypeptide (Mittal et al., 2010), pharmaceutically acceptable salts thereof, and combinations thereof.

[0081] In some embodiments, the RAF inhibitor is selected from the group consisting of AAL881 (Novartis), AB-024 (Ambit Biosciences), ARQ-736 (ArQule), ARQ-761 (ArQule), AZ628 (Axon Medchem BV), BAY 43-9006 sorafenib, BeiGene-283 (BeiGene), BUB-024 (MLN 2480) (Sunesis & Takeda), b-raf inhibitor (Sareum), BRAF kinase inhibitor (Selexagen Therapeutics), anti-BRAF siRNA 313 (tacaccagcaagctagatgca) and 523 (cctatcgttagagtcttcctg) (Liu et al., 2007), CHIR-265 (Novartis), CTT239065 (Institute of Cancer Research), dabrafenib (GSK2118436), DP-4978 (Deciphera Pharmaceuticals), HM-95573 (Hanmi), GDC-0879 (Genentech), GW-5074 (Sigma Aldrich), ISIS 5132 (Novartis), L779450 (Merck), LBT613 (Novartis), LXH254 (Novartis), LErafAON (NeoPharm, Inc.), LGX-818 (Novartis), pazopanib ( GlaxoSmithKline), PLX3202 (Plexxikon), PLX4720 (Plexxikon), PLX5568 (Plexxikon), PLX3603 (Daiichi Sankyo), PLX8394 (Daiichi Sankyo), RAF-265 (Novartis), RAF-365 (Novartis), REDX0535 (RedX Pharma Plc) , regorafenib (Bayer Healthcare Pharmaceuticals, Inc.), RO 5126766 (Hoffmann-La Roche), SB-590885 (GlaxoSmithKline), SB699393 (GlaxoSmithKline), sorafenib (Onyx Pharmaceuticals), TAK 632 (Takeda), TL-241 (Teligene) , vemurafenib (RG7204 or PLX4032) (Daiichi Sankyo), XL-281 (Exelixis), ZM-336372 (AstraZeneca), pharmaceutically acceptable salts thereof, and combinations thereof.

[0082] In some embodiments, the HDAC inhibitor is selected from the group consisting of Abexinostat (PCI-24781), Givinostat, Entinostat, Vorinostat, CI-994, CUDC-101, Entinostat, BML-210, M344, NVP-LAQ824, Panobinostat, Pracinosate (SB939), Mocetinostat, Resminostat, Romidepsin, Belinostat, pharmaceutically acceptable salts thereof and combinations thereof.

[0083] In some embodiments, the method further comprises administering to an individual having a non-V600E/K BRAF mutation at least one additional drug selected from the group consisting of an antibody, antibody fragment, antibody conjugate, cytotoxic agent, toxin, radionuclide, an immunomodulator, a photoactive drug, a radiosensitizing agent, a hormone, an antiangiogenic agent, and combinations thereof.

[0084] In some embodiments, the antibody, fragment thereof, or conjugate thereof is selected from the group consisting of rituximab (Rituxan), Brentuximab Vedotin (Adcetriz), Adotrastuzumab emtansine (Kadcyla), Cetuximab (Erbitux), bevacizumab (Avastin), Ibritumomab (Zevalin) ), vedolizumab (Entyvio), Ipilimumab (Yervoy), Nivolumab (Opdivo), pembrolizumab (Keytruda), Alemtuzumab atezolizumab (Tecentriq), avelumab (Bavenzio), durvalumab (Imfinzi), B-701, Ofatumumab, Obinutuzumab (Gaziva), Panitumumab , plosalizumab, BI-754091, OREG-103, COM-701, BI-754111 and combinations thereof.

[0085] In some embodiments, the cytotoxic agent is selected from the group consisting of cyclophosphamide, mechlorethamine, uramustine, melphalan, chlorambucil, ifosfamide, carmustine, lomustine, streptozocin, busulfan, temozolomide, cisplatin, carboplatin, oxaliplatin, nedaplatin, satraplatin, triplatin tetranitrate a, doxorubicin, daunorubicin, idarubicin, mitoxantrone, methotrexate, pemetrexed, 6-mercaptopurine, dacarbazine, fludarabine, 5-fluorouracil, arabinosylcytosine, capecitabine, gemcitabine, decitabine, vinca alkaloids, paclitaxel (Taxol), docetaxel (Taxotere), Ixa bepilona (Ixempra), actinomycin, anthracyclines, valrubicin, epirubicin, bleomycin, plicamycin, mitomycin, pharmaceutically acceptable salts thereof, prodrugs and combinations thereof.

[0086] In some embodiments, the toxin is diphtheria toxin or parts thereof.

[0087] In some embodiments, the radionuclide is selected from the group consisting of I-125, At-211, Lu-177, Cu-67, I-131, Sm-153, Re-186, P-32, Re-188, In-114m, Y-90 and their combinations.

[0088] In some embodiments, the immunomodulator is selected from the group consisting of granulocyte colony stimulating factor (G-CSF), LAG-3, IMP-321, JCAR-014, ASLAN-002 (BMS-777607), interferons, imiquimod, and cell membrane fractions from bacteria, IL-2, IL-7, IL-12, CCL3, CCL26, CXCL7, synthetic cytosine phosphate-guanosine (CpG), immune checkpoint inhibitors and combinations thereof.

[0089] In some embodiments, the radiosensitizing agent is selected from the group consisting of misonidazole, metronidazole, tirapazamine, sodium trans-crocetinate, and combinations thereof.

[0090] In some embodiments, the hormone is selected from the group consisting of prostaglandins, leukotrienes, prostacyclin, thromboxane, amylin, anti-Mullerian hormone, adiponectin, adrenocorticotropic hormone, angiotensinogen, angiotensin, vasopressin, atriopeptin, brain natriuretic peptide, calcitonin, cholicystokinin, corticotrope in -releasing hormone, encephalin, endothelin, erythropoietin, follicle-stimulating hormone, galanin, gastrin, ghrelin, glucagon, gonadotropin-releasing hormone, growth hormone releasing factor, human chorionic gonadotropin, human placental lactogen, growth hormone, inhibin, insulin, somatomedin, leptin , lipotropin, luteinizing hormone, melanocyte-stimulating hormone, motilin, orexin, oxytocin, pancreatic polypeptide, parathyroid hormone, prolactin, prolactin-releasing hormone, relaxin, renin, secretin, somatostatin, thrombopoietin, thyroid-stimulating hormone, testosterone, dehydroepiandrosterone, androstend ion, dihydrotestosterone , aldosterone, estradiol, estrone, estriol, cortisol, progesterone, calcitriol, calcidiol, tamoxifen (Nolvadex), anastrozole (Arimidex), lectrozole (Femara), fulvestrant (Faslodex) and combinations thereof.

[0091] In some embodiments, the antiangiogenic agent is selected from the group consisting of 2-methoxyestradiol, angiostatin, bevacizumab, cartilage angiogenesis inhibitory factor, endostatin, IFN-alpha, IL-12, itraconazole, linomide, platelet-derived factor-4, prolactin, SU5416 , suramin, tasquinimod, tecogalane, tetrathiomolybdate, thalidomide, thrombospondin, thrombospondin, TNP-470, ziv-aflibercept, pharmaceutically acceptable salts, prodrugs and combinations thereof.

[0092] In some embodiments, the additional drug is an inhibitor of the PI3K/Akt cascade.

[0093] In some embodiments, the PI3K/Akt cascade inhibitor is selected from the group consisting of A-674563 (CAS No. 552325-73-2), AGL 2263, AMG-319 (Amgen, Thousand Oaks, CA), AS-041164 ( 5-benzo[1,3]dioxol-5-ylmethylenethiazolidin-2,4-dione), AS-604850 (5-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethylene)thiazolidin-2, 4-dione), AS-605240 (5-quinoxylin-6-methylene-1,3-thiazolidine-2,4-dione), AT7867 (CAS No. 857531-00-1), benzimidazoles series, Genentech (Roche Holdings Inc. , South San Francisco, CA), BML-257 (CAS No. 32387-96-5), BVD-723, CAL-120 (Gilead Sciences, Foster City, CA), CAL-129 (Gilead Sciences), CAL-130 ( Gilead Sciences), CAL-253 (Gilead Sciences), CAL-263 (Gilead Sciences), CAS No. 612847-09-3, CAS No. 681281-88-9, CAS No. 75747-14-7, CAS No. 925681-41- 0, CAS No. 98510-80-6, CCT128930 (CAS No. 885499-61-6), CH5132799 (CAS No. 1007207-67-1), CHR-4432 (Chroma Therapeutics, Ltd., Abingdon, UK), FPA 124 ( CAS No. 902779-59-3), GS-1101 (CAL-101) (Gilead Sciences), GSK 690693 (CAS No. 937174-76-0), H-89 (CAS No. 127243-85-0), Honokiola, IC87114 (Gilead Science), IPI-145 (Intellikine Inc.), KAR-4139 (Karus Therapeutics, Chilworth, UK), KAR-4141 (Karus Therapeutics), KIN-1 (Karus Therapeutics), KT 5720 (CAS No. 108068-98 -0), Miltefosine, MK-2206 dihydrochloride (CAS No. 1032350-13-2), ML-9 (CAS No. 105637-50-1), Naltrindole hydrochloride, OXY-111A (NormOxys Inc., Brighton, MA), perifosine , PHT-427 (CAS No. 1191951-57-1), PI3-kinase delta inhibitor, Merck KGaA (Merck & Co., Whitehouse Station, NJ), PI3-kinase delta inhibitors, Genentech (Roche Holdings Inc.), PI3 inhibitors -kinase delta, Incozen (Incozen Therapeutics, Pvt. Ltd., Hydrabad, India), PI3-kinase inhibitor-2 delta, Incozen (Incozen Therapeutics), PI3-kinase inhibitor, Roche-4 (Roche Holdings Inc.), PI3-kinase inhibitors, Roche (Roche Holdings Inc.), PI3-kinase inhibitors, Roche-5 (Roche Holdings Inc.), PI3-alpha/delta inhibitors, Pathway Therapeutics (Pathway Therapeutics Ltd., South San Francisco, CA), PI3-delta inhibitors, Cellzome (Cellzome AG, Heidelberg, Germany ), PI3-delta inhibitors, Intellikine (Intellikine Inc., La Jolla, CA), PI3-delta inhibitors, Pathway Therapeutics-1 (Pathway Therapeutics Ltd.), PI3-delta inhibitors, Pathway Therapeutics-2 (Pathway Therapeutics Ltd.) , PI3-delta/gamma inhibitors, Cellzome (Cellzome AG), PI3-delta/gamma inhibitors, Cellzome (Cellzome AG), PI3-delta/gamma inhibitors, Intellikine (Intellikine Inc.), PI3-delta/gamma inhibitors, Intellikine ( Intellikine Inc.), PI3-delta/gamma inhibitors, Pathway Therapeutics (Pathway Therapeutics Ltd.), PI3-delta/gamma inhibitors, Pathway Therapeutics (Pathway Therapeutics Ltd.), PI3-gamma inhibitor Evotec (Evotec), PI3-gamma inhibitor , Cellzome (Cellzome AG), PI3-gamma inhibitors, Pathway Therapeutics (Pathway Therapeutics Ltd.), PI3K-delta/gamma inhibitors, Intellikine-1 (Intellikine Inc.), PI3K-delta/gamma inhibitors, Intellikine-1 (Intellikine Inc. .), pictilisib (Roche Holdings Inc.), PIK-90 (CAS No. 677338-12-4), SC-103980 (Pfizer, New York, NY), SF-1126 (Semafore Pharmaceuticals, Indianapolis, IN), SH -5, SH-6, tetrahydrocurcumin, TG100-115 (Targegen Inc., San Diego, CA), Triciribine, X-339 (Xcovery, West Palm Beach, FL), XL-499 (Evotech, Hamburg, Germany) , their pharmaceutically acceptable salts and combinations thereof.

[0094] In accordance with one aspect, the present invention provides a pharmaceutical composition for treating or mitigating the effects of a cancer in an individual having a BRAF mutation other than V600E/K, the composition comprising a pharmaceutically acceptable carrier or diluent and an effective amount of an ERK inhibitor or a pharmaceutically acceptable drug thereof. salt.

[0095] In some embodiments, the ERK inhibitor is selected from the group consisting of BVD-523, SCH-722984 (Merck & Co.), SCH-772984 (Merck & Co.), SCH-900353 (MK-8353) (Merck & Co.) Co.), LY3214996 (Lilly), AEZS-140 (Aeterna Zentaris), AEZS-131 (Aeterna Zentaris), AEZS-136 (Aeterna Zentaris), LTT-462 (Novartis), RG-7842 (Genentech), CC-90003 (Celgene), KIN-4050 (Kinentia) and combinations thereof.

[0096] In some embodiments, the ERK inhibitor is BVD-523.

[0097] In some embodiments, the non-V600E/K BRAF mutation is a kinase-activating mutation, a kinase-disrupting mutation, or a mutation with an unknown effect on the kinase, and combinations thereof.

[0098] In some embodiments, the kinase activating mutation is selected from the group consisting of R462I, I463S, G464E, G464R, G464V, G466A, G469A, N581S, E586K, F595L, L597Q, L597R, L597S, L597V, A598V, T599E, V 600R, K601E, S602D, A728V and their combinations.

[0099] In some embodiments, the kinase-impairing mutation is selected from the group consisting of G466E, G466R, G466V, Y472C, K483M, D594A, D594E, D594G, D594H, D594N, D594V, G596R, T599A, S602A, and combinations thereof.

[0100] In some embodiments, the mutation with an unknown effect on the kinase is selected from the group consisting of T440I, S467L, G469E, G469R, G469S, G469V, L584F, L588F, V600_K601delinsE, S605I, Q609L, E611Q, and combinations thereof.

[0101] In some embodiments, the individual is a mammal.

[0102] In some embodiments, the mammal is selected from the group consisting of humans, primates, farm animals, and domestic animals.

[0103] In some embodiments, the mammal is a human.

[0104] In some embodiments, the cancer is a solid cancer or a hematologic malignancy.

[0105] In some embodiments, the cancer is selected from the group consisting of glioblastoma, melanoma, cholangiocarcinoma, small cell lung cancer, colorectal cancer, prostate cancer, vaginal cancer, angiosarcoma, non-small cell lung cancer, appendix cancer, squamous cell carcinoma, salivary gland ductal carcinoma, adenoid cystic carcinoma, small intestinal cancer and gallbladder cancer.

[0106] In some embodiments, the cancer is selected from the group consisting of small intestinal cancer, non-small cell lung cancer, gallbladder cancer, and squamous cell carcinoma.

[0107] In some embodiments, the composition is administered to an individual orally or by injection.

[0108] In some embodiments, the composition is administered to an individual as a tablet.

[0109] In some embodiments, the pharmaceutical composition contains at least one additional drug selected from the group consisting of a MEK inhibitor, a RAF inhibitor, an HDAC inhibitor, and combinations thereof.

[0110] In some embodiments, the MEK inhibitor is selected from the group consisting of anthrax toxin, anthroquinonol (Golden Biotechnology), ARRY-142886 ((2-hydroxyethoxy)amide) 6-(4-bromo-2-chlorophenylamino)-7- fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (Array BioPharma), ARRY-438162 (Array BioPharma), binimetinib (MEK162, ARRY-1662), AS-1940477 (Astellas), AS-703988 (Merck KGaA), bentamapimod (Merck KGaA), BI-847325 (Boehringer Ingelheim), E-6201 (Eisai), GDC-0623 (Hoffmann-La Roche), GDC-0973 (cobimetinib) (Hoffmann-La Roche), L783277 (Merck), parts lethal anthrax toxin MEK162 (Array BioPharma), PD 098059 (2-(2'-amino-3'-methoxphenyl)oxanaphthalene-4-one) (Pfizer), PD 184352 (CI-1040) (Pfizer) , PD-0325901 (Pfizer), PD318088 (Pfizer), PD334581 (Pfizer), 6-methoxy-7-(3-morpholin-4-ylpropoxy)-4-(4-phenoxyphenylamino)quinoline-3-carbonitrile, 4-[ 3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-3-carbonitrile, pimasertib (Santhera Pharmaceuticals), RDEA119 (Ardea Biosciences/Bayer), refametinib (AstraZeneca), RG422 (Chugai Pharmaceutical Co.), R0092210 (Roche), R04987655 (Hoffmann-La Roche), R05126766 (Hoffmann-La Roche), selumetinib (AZD6244) (AstraZeneca), SL327 (Sigma), TAK-733 (Takeda), trametinib (Japan Tobacco), U0126 (1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene) (Sigma), WX-554 (Wilex), YopJ polypeptide (Mittal et al., 2010), pharmaceutically acceptable salts thereof and combinations thereof.

[0111] In some embodiments, the RAF inhibitor is selected from the group consisting of AAL881 (Novartis), AB-024 (Ambit Biosciences), ARQ-736 (ArQule), ARQ-761 (ArQule), AZ628 (Axon Medchem BV), BAY 43-9006 sorafenib, BeiGene-283 (BeiGene), BUB-024 (MLN 2480) (Sunesis & Takeda), b-raf inhibitor (Sareum), BRAF kinase inhibitor (Selexagen Therapeutics), anti-BRAF siRNA 313 (tacaccagcaagctagatgca) and 523 (cctatcgttagagtcttcctg) (Liu et al., 2007), CHIR-265 (Novartis), CTT239065 (Institute of Cancer Research), dabrafenib (GSK2118436), DP-4978 (Deciphera Pharmaceuticals), HM-95573 (Hanmi), GDC-0879 (Genentech), GW-5074 (Sigma Aldrich), ISIS 5132 (Novartis), L779450 (Merck), LBT613 (Novartis), LXH254 (Novartis), LErafAON (NeoPharm, Inc.), LGX-818 (Novartis), pazopanib ( GlaxoSmithKline), PLX3202 (Plexxikon), PLX4720 (Plexxikon), PLX5568 (Plexxikon), PLX3603 (Daiichi Sankyo), PLX8394 (Daiichi Sankyo), RAF-265 (Novartis), RAF-365 (Novartis), REDX0535 (RedX Pharma Plc) , regorafenib (Bayer Healthcare Pharmaceuticals, Inc.), RO 5126766 (Hoffmann-La Roche), SB-590885 (GlaxoSmithKline), SB699393 (GlaxoSmithKline), sorafenib (Onyx Pharmaceuticals), TAK 632 (Takeda), TL-241 (Teligene) , vemurafenib (RG7204 or PLX4032) (Daiichi Sankyo), XL-281 (Exelixis), ZM-336372 (AstraZeneca), pharmaceutically acceptable salts thereof, and combinations thereof.

[0112] In some embodiments, the HDAC inhibitor is selected from the group consisting of Abexinostat (PCI-24781), Givinostat, Entinostat, Vorinostat, CI-994, CUDC-101, Entinostat, BML-210, M344, NVP-LAQ824, Panobinostat, Pracinosate (SB939), Mocetinostat, Resminostat, Romidepsin, Belinostat, pharmaceutically acceptable salts thereof and combinations thereof.

[0113] In some embodiments, the method further includes administering to the individual at least one additional drug selected from the group consisting of an antibody, antibody fragment, antibody conjugate, cytotoxic agent, toxin, radionuclide, immunomodulator, photoactive drug, radiosensitizing agent, hormone, antiangiogenic agent and combinations thereof.

[0114] In some embodiments, the antibody, fragment thereof, or conjugate thereof is selected from the group consisting of rituximab (Rituxan), Brentuximab Vedotin (Adcetriz), Adotrastuzumab emtansine (Kadcyla), Cetuximab (Erbitux), bevacizumab (Avastin), Ibritumomab (Zevalin) ), vedolizumab (Entyvio), Ipilimumab (Yervoy), Nivolumab (Opdivo), pembrolizumab (Keytruda), Alemtuzumab atezolizumab (Tecentriq), avelumab (Bavenzio), durvalumab (Imfinzi), B-701, Ofatumumab, Obinutuzumab (Gaziva), Panitumumab , plosalizumab, BI-754091, OREG-103, COM-701, BI-754111 and combinations thereof.

[0115] In some embodiments, the cytotoxic agent is selected from the group consisting of cyclophosphamide, mechlorethamine, uramustine, melphalan, chlorambucil, ifosfamide, carmustine, lomustine, streptozocin, busulfan, temozolomide, cisplatin, carboplatin, oxaliplatin, nedaplatin, satraplatin, triplatin tetranitrate a, doxorubicin, daunorubicin, idarubicin, mitoxantrone, methotrexate, pemetrexed, 6-mercaptopurine, dacarbazine, fludarabine, 5-fluorouracil, arabinosylcytosine, capecitabine, gemcitabine, decitabine, vinca alkaloids, paclitaxel (Taxol), docetaxel (Taxotere), Ixa bepilona (Ixempra), actinomycin, anthracyclines, valrubicin, epirubicin, bleomycin, plicamycin, mitomycin, pharmaceutically acceptable salts thereof, prodrugs and combinations thereof.

[0116] In some embodiments, the toxin is diphtheria toxin or parts thereof.

[0117] In some embodiments, the radionuclide is selected from the group consisting of I-125, At-211, Lu-177, Cu-67, I-131, Sm-153, Re-186, P-32, Re-188, In-114m, Y-90 and their combinations.

[0118] In some embodiments, the immunomodulator is selected from the group consisting of granulocyte colony stimulating factor (G-CSF), LAG-3, IMP-321, JCAR-014, ASLAN-002 (BMS-777607), interferons, imiquimod, and cell membrane fractions from bacteria, IL-2, IL-7, IL-12, CCL3, CCL26, CXCL7, synthetic cytosine phosphate-guanosine (CpG), immune checkpoint inhibitors and combinations thereof.

[0119] In some embodiments, the radiosensitizing agent is selected from the group consisting of misonidazole, metronidazole, tirapazamine, sodium trans-crocetinate, and combinations thereof.

[0120] In some embodiments, the hormone is selected from the group consisting of prostaglandins, leukotrienes, prostacyclin, thromboxane, amylin, anti-Mullerian hormone, adiponectin, adrenocorticotropic hormone, angiotensinogen, angiotensin, vasopressin, atriopeptin, brain natriuretic peptide, calcitonin, cholicystokinin, corticotrope in -releasing hormone, encephalin, endothelin, erythropoietin, follicle-stimulating hormone, galanin, gastrin, ghrelin, glucagon, gonadotropin-releasing hormone, growth hormone releasing factor, human chorionic gonadotropin, human placental lactogen, growth hormone, inhibin, insulin, somatomedin, leptin , lipotropin, luteinizing hormone, melanocyte-stimulating hormone, motilin, orexin, oxytocin, pancreatic polypeptide, parathyroid hormone, prolactin, prolactin-releasing hormone, relaxin, renin, secretin, somatostatin, thrombopoietin, thyroid-stimulating hormone, testosterone, dehydroepiandrosterone, androstend ion, dihydrotestosterone , aldosterone, estradiol, estrone, estriol, cortisol, progesterone, calcitriol, calcidiol, tamoxifen (Nolvadex), anastrozole (Arimidex), lectrozole (Femara), fulvestrant (Faslodex), and combinations thereof.

[0121] In some embodiments, the antiangiogenic agent is selected from the group consisting of 2-methoxyestradiol, angiostatin, bevacizumab, cartilage angiogenesis inhibitory factor, endostatin, IFN-alpha, IL-12, itraconazole, linomide, platelet-derived factor-4, prolactin, SU5416 , suramin, tasquinimod, tecogalane, tetrathiomolybdate, thalidomide, thrombospondin, thrombospondin, TNP-470, ziv-aflibercept, pharmaceutically acceptable salts, prodrugs and combinations thereof.

[0122] In some embodiments, the additional drug is an inhibitor of the PI3K/Akt cascade.

[0123] In some embodiments, the PI3K/Akt cascade inhibitor is selected from the group consisting of A-674563 (CAS No. 552325-73-2), AGL 2263, AMG-319 (Amgen, Thousand Oaks, CA), AS-041164 ( 5-benzo[1,3]dioxol-5-ylmethylenethiazolidin-2,4-dione), AS-604850 (5-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethylene)thiazolidin-2, 4-dione), AS-605240 (5-quinoxylin-6-methylene-1,3-thiazolidine-2,4-dione), AT7867 (CAS No. 857531-00-1), benzimidazoles series, Genentech (Roche Holdings Inc. , South San Francisco, CA), BML-257 (CAS No. 32387-96-5), BVD-723, CAL-120 (Gilead Sciences, Foster City, CA), CAL-129 (Gilead Sciences), CAL-130 ( Gilead Sciences), CAL-253 (Gilead Sciences), CAL-263 (Gilead Sciences), CAS No. 612847-09-3, CAS No. 681281-88-9, CAS No. 75747-14-7, CAS No. 925681-41- 0, CAS No. 98510-80-6, CCT128930 (CAS No. 885499-61-6), CH5132799 (CAS No. 1007207-67-1), CHR-4432 (Chroma Therapeutics, Ltd., Abingdon, UK), FPA 124 ( CAS No. 902779-59-3), GS-1101 (CAL-101) (Gilead Sciences), GSK 690693 (CAS No. 937174-76-0), H-89 (CAS No. 127243-85-0), Honokiola, IC87114 (Gilead Science), IPI-145 (Intellikine Inc.), KAR-4139 (Karus Therapeutics, Chilworth, UK), KAR-4141 (Karus Therapeutics), KIN-1 (Karus Therapeutics), KT 5720 (CAS No. 108068-98 -0), Miltefosine, MK-2206 dihydrochloride (CAS No. 1032350-13-2), ML-9 (CAS No. 105637-50-1), Naltrindole hydrochloride, OXY-111A (NormOxys Inc., Brighton, MA), perifosine , PHT-427 (CAS No. 1191951-57-1), PI3-kinase delta inhibitor, Merck KGaA (Merck & Co., Whitehouse Station, NJ), PI3-kinase delta inhibitors, Genentech (Roche Holdings Inc.), PI3 inhibitors -kinase delta, Incozen (Incozen Therapeutics, Pvt. Ltd., Hydrabad, India), PI3-kinase inhibitor-2 delta, Incozen (Incozen Therapeutics), PI3-kinase inhibitor, Roche-4 (Roche Holdings Inc.), PI3-kinase inhibitors, Roche (Roche Holdings Inc.), PI3-kinase inhibitors, Roche-5 (Roche Holdings Inc.), PI3-alpha/delta inhibitors, Pathway Therapeutics (Pathway Therapeutics Ltd., South San Francisco, CA), PI3-delta inhibitors, Cellzome (Cellzome AG, Heidelberg, Germany ), PI3-delta inhibitors, Intellikine (Intellikine Inc., La Jolla, CA), PI3-delta inhibitors, Pathway Therapeutics-1 (Pathway Therapeutics Ltd.), PI3-delta inhibitors, Pathway Therapeutics-2 (Pathway Therapeutics Ltd.) , PI3-delta/gamma inhibitors, Cellzome (Cellzome AG), PI3-delta/gamma inhibitors, Cellzome (Cellzome AG), PI3-delta/gamma inhibitors, Intellikine (Intellikine Inc.), PI3-delta/gamma inhibitors, Intellikine ( Intellikine Inc.), PI3-delta/gamma inhibitors, Pathway Therapeutics (Pathway Therapeutics Ltd.), PI3-delta/gamma inhibitors, Pathway Therapeutics (Pathway Therapeutics Ltd.), PI3-gamma inhibitor Evotec (Evotec), PI3-gamma inhibitor , Cellzome (Cellzome AG), PI3-gamma inhibitors, Pathway Therapeutics (Pathway Therapeutics Ltd.), PI3K-delta/gamma inhibitors, Intellikine-1 (Intellikine Inc.), PI3K-delta/gamma inhibitors, Intellikine-1 (Intellikine Inc. .), pictilisib (Roche Holdings Inc.), PIK-90 (CAS No. 677338-12-4), SC-103980 (Pfizer, New York, NY), SF-1126 (Semafore Pharmaceuticals, Indianapolis, IN), SH -5, SH-6, tetrahydrocurcumin, TG100-115 (Targegen Inc., San Diego, CA), Triciribine, X-339 (Xcovery, West Palm Beach, FL), XL-499 (Evotech, Hamburg, Germany) , their pharmaceutically acceptable salts and combinations thereof.

[0124] In some embodiments, the pharmaceutical composition is in a unit dosage form containing both an ERK inhibitor and an additional drug.

[0125] In some embodiments, the ERK inhibitor pharmaceutical composition is in a first unit dosage form and the additional drug is in a second unit dosage form separate from the first.

[0126] In some embodiments, the ERK inhibitor and the additional drug are co-administered to a subject.

[0127] In some embodiments, the ERK inhibitor and the additional drug are administered to an individual sequentially.

[0128] In some embodiments, the ERK inhibitor is administered to the individual before or after administration of the additional drug.

[0129] In accordance with one aspect, the present invention provides a method of treating or mitigating the effects of a cancer having a BRAF mutation other than V600E/K, the method comprising administering to an individual an effective amount of BVD-523 or a pharmaceutically acceptable salt thereof.

[0130] In accordance with one aspect, the present invention provides a method of treating or mitigating the effects of a cancer in an individual, comprising: (a) identifying an individual with a cancer having a non-V600E/K BRAF mutation; and (b) administering to the individual an effective amount of BVD-523 or a pharmaceutically acceptable salt thereof.

[0131] In accordance with one aspect, the present invention provides a method for identifying an individual having a cancer that would benefit from therapy with BVD-523 or a pharmaceutically acceptable salt thereof, the method comprising: (a) obtaining a biological sample from the individual; and (b) screening the sample to determine whether the individual has a non-V600E/K BRAF mutation, wherein the presence of a non-V600E/K BRAF mutation confirms that the individual would benefit from therapy with BVD-523 or a pharmaceutically acceptable salt thereof.

[0132] In accordance with one aspect, the present invention provides a pharmaceutical composition for treating or mitigating the effects of cancer in an individual having a BRAF mutation other than V600E/K, the composition comprising a pharmaceutically acceptable carrier or diluent and an effective amount of BVD-523 or a pharmaceutically acceptable drug thereof. salt.

[0133] In accordance with one aspect, the present invention provides a kit for treating or mitigating the effects of a cancer in an individual having a BRAF mutation other than V600E/K, the kit comprising the pharmaceutical composition of any one of claims 88, 103 and 107, packaged along with instructions for use.

[0134] In some embodiments, the RAF inhibitor is selected from the group consisting of erlotinib (Tarceva), gefitinib (Iressa), imatinib mesylate (Gleevec), lapatinib (Tyverb), sunitinib malate (Sutent), pharmaceutically acceptable salts thereof, and combinations thereof.

[0135] In some embodiments, the RAF inhibitor is selected from the group consisting of LXH254 (Novartis), PLX3603 (Daiichi Sankyo), PLX8394 (Daiichi Sankyo), REDX0535 (RedX Pharma Plc), pharmaceutically acceptable salts thereof, and combinations thereof.

[0136] In some embodiments, the HDAC inhibitor is selected from the group consisting of Vorinostat, Panobinostat, Romidepsin, Belinostat, pharmaceutically acceptable salts thereof, and combinations thereof.

[0137] In some embodiments, the antibody, fragment thereof, or conjugate thereof is selected from the group consisting of rituximab (Rituxan), Brentuximab Vedotin (Adcetriz), Adotrastuzumab emtansine (Kadcyla), Ipilimumab (Yervoy), Nivolumab (Opdivo), pembrolizumab (Keytruda ), Alemtuzumab atezolizumab (Tecentriq), durvalumab (Imfinzi), Ofatumumab, Obinutuzumab (Gazyva), Panitumumab and combinations thereof.

[0138] In some embodiments, the inhibitor of the PI3K/Akt cascade is BVD-723.

BRIEF DESCRIPTION OF THE DRAWINGS

[0139] Figure 1 is a diagram of the mitogen-activated protein kinase (MAPK) cascade.

[0140] Figure 2 shows the response in patients administered BVD-523. All patients with RECIST v1.1-defined disease who received one or more doses of study drug and more than 1 tumor evaluation during treatment were included. Response was defined as the change from baseline in the sum of the largest diameters of each target lesion. The solid line indicates the threshold for partial response according to RECIST v1.1. Abbreviations: GBM, glioblastoma; NSCLC, non-small cell lung cancer; CRC, colorectal cancer. The atypical BRAF mutation associated with each patient's malignancy is indicated.

[0141] Figure 3 shows the duration of treatment on the pool lane graph, divided into groups. Group 1 members are any patients with any BRAF mutation in any tumor type other than colorectal cancer (CRC) and non-small cell lung carcinoma (NSCLC) and who have been previously treated with a MAPK cascade inhibitor. Members of group 2 represent patients with any BRAF mutation in CRC who have not previously been treated with a MAPK cascade inhibitor. Members of group 3 are patients with the BRAF V600E/K mutation who are refractory to a MAPK inhibitor. Group 6 members represent patients with any BRAF mutation present in NSCLC. As shown in Figure 3, all 28 patients are included, as shown by the horizontal bars, one for each individual. The duration of treatment for each individual in each group is illustrated from top (longest treatment duration) to bottom (shortest treatment duration) by group. The horizontal axis represents the duration in days of an individual's stay in the study. Figure 3 also shows the type of response achieved by each patient according to RECIST v1.1 (diamond=partial response; circle=stable disease; vertical bar=progressive disease; triangle=not assessed).

[0142] Figure 4 shows the duration of treatment on a pool lane graph according to BRAF mutation. All 28 patients meeting RECIST v1.1 response criteria were included, plus additional patients not assessed by RECIST v1.1 (diamond=partial response; circle=stable disease; vertical bar=progressive disease; triangle=not assessed) .

DETAILED DESCRIPTION OF THE INVENTION

[0143] In accordance with one aspect, the present invention provides a method of treating or mitigating the effects of a cancer in an individual having a non-V600E/K BRAF mutation, comprising administering to the individual an effective amount of an ERK inhibitor or a pharmaceutically acceptable salt thereof.

[0144] As used herein, the terms "BRAF V600E/K mutation" referring to a cancer in an individual, and grammatical variants thereof, mean a cancer cell that contains a non-synonymous substitution mutation in the gene encoding human BRAF (SEQ ID NO: 2), which causes the amino acid valine (V) at amino acid position 600 of BRAF to be replaced by glutamic acid (E) or lysine (K). As used herein, the terms "containing a non-V600E/K BRAF mutation" referring to a cancer in an individual, and grammatical variations thereof, mean that the cancer cell contains a somatic cell mutation that is not a BRAF V600E/K mutation. As used herein, all BRAF mutations are based on the human wild type sequence (SEQ ID NO: 2). Also contemplated herein are their orthologs from other species.

[0145] As used herein, the terms “treat,” “treating,” “treatment,” and grammatical variations thereof mean subjecting an individual to a protocol, regimen, process, or method of treatment in which it is desired to achieve a physiological response or outcome in that individual, for example, a patient. In particular, the methods and compositions of the present invention can be used to slow the development of symptoms of a disease or delay the onset of a disease or condition, and stop the progression of disease development. However, since each individual treated may not respond to a particular treatment protocol, regimen, process, or method of treatment, the treatment does not require that the desired physiological response or outcome be achieved in each individual or in each population of individuals, such as a population of patients. Thus, a given individual or population of individuals, eg a population of patients, may not respond or insufficiently respond to treatment.

[0146] As used herein, the terms “alleviate,” “mitigate,” and grammatical variations thereof mean a reduction in the severity of symptoms of a disease in an individual.

[0147] As used herein, an "individual" is a mammal, preferably a human. In addition to humans, categories of mammals included in the scope of the present invention include, for example, farm animals, pets, laboratory animals, etc. Some examples of farm animals include cows, pigs, horses, goats, etc. Some examples of pets include dogs, cats, etc. Some examples of laboratory animals include primates, rats, mice, rabbits, guinea pigs, etc.

[0148] As used herein, the term "effective amount" or "therapeutically effective amount" of a compound or composition described herein is an amount of such compound or composition that is insufficient to provide the beneficial or desired results as described in herein, when administered to humans. Effective dosage forms, routes of administration, and dosage may be determined empirically, and making such determinations is within the scope of skill in the art. Those skilled in the art will appreciate that dosage will vary depending on the route of administration, rate of excretion, duration of treatment, type of any other drugs administered, age, size and species of the mammal, e.g., human patient, and similar factors well known. in the field of medicine and veterinary medicine. Generally, a suitable dose of a compound or composition of the invention will be the amount of the composition that is the lowest dose effective to produce the desired effect. An effective dose of a compound or composition of the present invention can be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day.

[0149] In some embodiments, the ERK inhibitor is selected from the group consisting of BVD-523, SCH-722984 (Merck & Co.), SCH-772984 (Merck & Co.), SCH-900353 (MK-8353) (Merck & Co.), Co.), LY3214996 (Lilly), AEZS-140 (Aeterna Zentaris), AEZS-131 (Aeterna Zentaris), AEZS-136 (Aeterna Zentaris), LTT-462 (Novartis), RG-7842 (Genentech), CC-90003 (Celgene), KIN-4050 (Kinentia) and combinations thereof. In some embodiments, the ERK inhibitor is BVD-523.

[0150] For the purposes of the present invention, BVD-523 is a compound of formula (I):

[0151] and pharmaceutically acceptable salts thereof. BVD-523 is a highly potent, selective, reversible, ATP-competitive inhibitor of ERK1/2. BVD-523 can be synthesized by methods described, for example, in US patent No. 7354939, which is incorporated herein by reference. Also included within the scope of the present invention are enantiomers and racemic mixtures of both enantiomers of BVD-523. BVD-523 is an ERK1/2 inhibitor with a mechanism of action that is believed to be, for example, unique and different from certain other ERK1/2 inhibitors, such as SCH772984. For example, other ERK1/2 inhibitors such as SCH772984 inhibit ERK autophosphorylation (Morris et al., 2013), while BVD-523 allows ERK autophosphorylation while inhibiting ERK.

[0152] In some embodiments, the individual's cancer has a somatic mutation in the BRAF gene. As used herein, "somatic mutation" means a change occurring in any cell that is not intended to become a germ cell. The mutation may be, for example, a substitution, deletion, insertion or fusion. Table 1 below provides an overview of the distribution of BRAF mutations as shown in the Sanger database.

TABLE 1

Overview of BRAF mutation distributions Mutation type Samples with mutations Percent Nonsense replacement 23 0.07 Missense substitution 32955 99.07 Synonymous replacement 80 0.24 Insertion in reading frame 25 0.08 Frameshift insertion 1 0.00 In-frame deletion 13 0.04 Frameshift deletion 5 0.02 Complex 39 0.12 Other 172 0.52 Total 33263 100

[0153] BRAF mutations occur in approximately 66% of melanomas (Davies et al., 2002; Brose et al., 2002; Hocket et al., 2007) and in a relatively lower percentage of other malignancies: 36% of thyroid tumors and in 10% of colon cancer cases (Xu et al., 2003; Fransen et al., 2004). The most common BRAF mutation occurs at amino acid position 600 of human wild-type protein kinase (SEQ ID NO: 2) by substituting glutamic acid for valine, resulting in the B-RafV600E mutant, and accounts for approximately 80% of BRAF mutations (Davies et al., 2002 ; Hocker et al., 2007). The kinase domain of B-RafV600E has 500-fold higher kinase activity compared to the basal activity of wild-type B-Raf (Wan et al., 2004). Among other BRAF mutations identified in melanoma, V600K and V600D/R are also common and account for 16% and 3% of all BRAF mutations, respectively (Long et al., 2011). In addition to melanoma, BRAF mutations are also common in many other malignancies, including papillary thyroid carcinoma, ovarian carcinoma, and colorectal carcinoma. (Wellbrock et al., 2004). In one study, BRAF splice variants (excision by splicing exons 14 and 15) were found in 5/24 (21%) of colorectal cancer cell lines (Seth et al., 2009).

[0154] Table 2 below from the Sanger database presents the distribution and frequency of BRAF mutations in human tumors.

TABLE 2

Primary tissue Unique mutant samples Total unique samples % Mutant N.S. 1071 1788 59.90 Adrenal 3 155 1.94 Autonomic ganglia 3 703 0.43 Biliary tract 36 684 5.26 Bone 5 284 1.76 Breast 27 2297 1.18 central nervous system 206 3297 6.25 Cervix 6 473 1.27 Endometrium 40 2510 1.59 Eye 70 732 9.56 Fallopian tube 0 2 0 Gastrointestinal tract (unspecified area) 5 514 0.97 Genital tract 4 54 7.41 Hematopoietic and lymphoid tissue 507 5388 9.41 Bud 34 959 3.55 Colon 8301 67530 12.29 Liver 18 618 2.91 Lung 293 11249 2.60 Meningeal membrane 0 74 0 Esophagus 5 927 0.54 Ovary 312 3922 7.96 Pancreas 16 1089 1.47 Epithelial body 0 20 0 Penis 0 28 0 Peritoneum 0 37 0 Pituitary 1 115 0.87 Placenta 0 2 0 Pleura 3 148 2.03 Prostate 25 1483 1.69 Salivary gland 1 131 0.76 Leather 7245 16943 42.76 Small intestine 12 251 4.78 Soft fabric 45 2160 2.08 Stomach eleven 1473 0.75 Testicle 7 251 2.79 Thymus 0 50 0 Thyroid 14929 38002 39.28 upper gastrointestinal and respiratory tract 14 1352 1.04 Urinary tract 8 612 1.31 Vagina 0 1 0 Vulva 0 3 0 Total 33263 168311 19.76

[0155] Table 3 below presents the individual nucleic acid sequences and amino acid sequences of BRAF. These sequences can be used in methods for identifying individuals with a mutant BRAF genotype (as in the methods described below).

TABLE 3

SEQ ID NO Nucleic acid or polypeptide Organism Other information 1 nucleic acid Human 2 polypeptide Human 3 nucleic acid Rat (Rattus norvegicus) 4 polypeptide Rat (Rattus norvegicus) 5 nucleic acid Mouse, Mus musculus 6 polypeptide Mouse, Mus musculus 7 nucleic acid Rabbit, Oryctolagus cuniculus 8 polypeptide Rabbit, Oryctolagus cuniculus 9 nucleic acid Guinea pig, Cavia porcellus 10 polypeptide Guinea pig, Cavia porcellus eleven nucleic acid Dog, Canis lups familiaris option x1 12 polypeptide Dog, Canis lups familiaris option x1 13 nucleic acid Dog, Canis lups familiaris option x2 14 polypeptide Dog, Canis lups familiaris option x2 15 nucleic acid Cat, Felis catus 16 polypeptide Cat, Felis catus 17 nucleic acid Cow, Bos taurus option X1 18 polypeptide Cow, Bos taurus option X1 19 nucleic acid Cow, Bos taurus option X2 20 polypeptide Cow, Bos taurus option X2 21 nucleic acid Cow, Bos taurus option X3 22 polypeptide Cow, Bos taurus option X3 23 nucleic acid Cow, Bos taurus option X4 24 polypeptide Cow, Bos taurus option X4 25 nucleic acid Cow, Bos taurus variant X5 26 polypeptide Cow, Bos taurus variant X5 27 nucleic acid Cow, Bos taurus variant X6 28 polypeptide Cow, Bos taurus variant X6 29 nucleic acid Cow, Bos taurus variant X7 thirty polypeptide Cow, Bos taurus variant X7 31 nucleic acid Cow, Bos taurus variant X8 32 polypeptide Cow, Bos taurus variant X8 33 nucleic acid Cow, Bos taurus option X9 34 polypeptide Cow, Bos taurus option X9 35 nucleic acid Cow, Bos taurus option X10 36 polypeptide Cow, Bos taurus option X10 37 nucleic acid Cow, Bos taurus option X11 38 polypeptide Cow, Bos taurus option X11 39 nucleic acid Cow, Bos taurus option 2 40 polypeptide Cow, Bos taurus option 2 41 nucleic acid Horse, Equus caballus 42 polypeptide Horse, Equus caballus 43 nucleic acid Chicken, Gallus gallus 44 Polypeptide Chicken, Gallus gallus

[0156] Methods for identifying mutations in nucleic acids, such as the above BRAF genes, are known in the art. Nucleic acids can be obtained from biological samples. Within the scope of the present invention, biological samples include, but are not limited to, blood, plasma, urine, skin, saliva and biopsies. Biological samples are obtained from an individual using standard techniques and techniques that are known in the art.

[0157] Non-limiting examples of mutation identification methods include PCR, sequencing, hybrid trap, solution capture, invertible molecular probe, fluorescence in situ hybridization (FISH) assays, and combinations thereof.

[0158] Various sequencing methods are known in the art. These include, but are not limited to, Sanger sequencing (also called dideoxy sequencing) and various sequencing by synthesis (SBS) methods as described, for example, in Metzker 2005, sequencing by hybridization, ligation (eg WO 2005021786), degradation ( eg US Patents 5622824 and 6140053) and nanopore sequencing (which is commercially available from Oxford Nanopore Technologies, UK). In deep sequencing methods, a given nucleotide in the sequence is read more than once during sequencing. Deep sequencing methods are described, for example, in US Patent Publication No. 20120264632 and International Patent Publication No. WO2012125848.

[0159] PCR-based methods for detecting mutations are known in the art and use PCR amplification, where each target sequence in the sample has a corresponding pair of unique sequence-specific primers. For example, the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method allows rapid detection of mutations after amplification of genomic sequences by PCR. The mutation is detected by digestion with specific restriction endonucleases and identified by electrophoresis. See, for example, Ota et al., 2007. Mutations can also be detected using real-time PCR. See, for example, International Application Publication No. WO2012046981.

[0160] Hybrid decoy methods are known in the art and are described, for example, in US Patent Publication No. 20130203632 and US Patent Nos. 8389219 and 8288520. These methods rely on selective hybridization of genomic target regions with user-designed oligonucleotides. Hybridization can be accomplished with oligonucleotides immobilized on high- or low-density microarrays (on-chip capture), or through solution-phase hybridization with ligand-modified oligonucleotides (e.g., biotin), which can subsequently be immobilized on a solid surface such as a bead ( hybridization in solution).

[0161] Invertible molecular probe (MIP) methods are known in the art and are described, for example, in Absalan et al., 2008. Such methods use MIP molecules, which are specialized padlock-type probes (Nilsson et al., 1994), for genotyping. The MIP molecule is a linear oligonucleotide that contains specific regions, universal sequences, restriction sites and a tag (marker) sequence (16-22 bp). In such methods, the MIP hybridizes directly to the region of the genetic marker/SNP of interest. The MIP method can also use a series of padlock probe sets that hybridize to genomic DNA in parallel (Hardenbol et al., 2003). In the case of an absolute match, regions of genomic homology are ligated, undergoing an inversion of configuration (as indicated by the name of the technology) and creating a circular molecule. After the first restriction digestion, all molecules are amplified with universal primers. The amplicons are digested again, providing short fragments for hybridization on a microarray. The resulting short fragments are labeled and, through the tag sequence, hybridized with the cTag (complementary strand for the marker) on the chip. After the Tag-cTag duplex is formed, the signal is detected.

[0162] In some embodiments, the non-V600E/K BRAF mutation is a kinase-activating mutation, a kinase-disrupting mutation, or a mutation with an unknown effect on the kinase, and combinations thereof. As used herein, the term “kinase-activating mutation” and its grammatical variations mean that the mutation causes an increase in the kinase activity of the mutant kinase relative to the wild-type kinase. As used herein, the term “kinase disrupting mutation” and its grammatical variations mean that the mutation causes a decrease in the kinase activity of the mutant kinase relative to the wild-type kinase. As used herein, the term “mutation of unknown kinase effect” and its grammatical variants mean that the activity of the mutant kinase is unknown or that the activity of the mutant kinase is approximately equivalent to the kinase activity of the wild-type kinase (see Zheng, G., et al., Clinical detection and categorization of uncommon and concomitant mutations involving BRAF, BMC Cancer, (2015) 15:779, incorporated herein by reference in its entirety).

[0163] In some embodiments, the BRAF kinase activating mutation is selected from the group consisting of R462I, I463S, G464E, G464R, G464V, G466A, G469A, N581S, E586K, F595L, L597Q, L597R, L597S, L597V, A598V, T599E , V600R, K601E, S602D, A728V and their combinations. In some embodiments, the kinase-impairing BRAF mutation is selected from the group consisting of G466E, G466R, G466V, Y472C, K483M, D594A, D594E, D594G, D594H, D594N, D594V, G596R, T599A, S602A, and combinations thereof. In some embodiments, the mutation with an unknown effect on BRAF kinase is selected from the group consisting of T440I, S467L, G469E, G469R, G469S, G469V, L584F, L588F, V600_K601delinsE, S605I, Q609L, E611Q, and combinations thereof. As used herein, all BRAF mutations are based on the human wild type sequence (SEQ ID NO: 2). Also contemplated herein are their orthologs from other species.

[0164] Within the scope of the present invention, a method and composition for treating non-V600E/K BRAF mutations are effective against disease states that have a single mutation and one or more mutations. Indeed, any single mutation or any combination of mutations described herein (or set forth below) can be treated using the compositions or methods of the present invention (e.g., any combination of non-V600E/K mutations or any combination of non-V600E/K mutations with the V600E/K mutation).

[0165] In some embodiments, the BRAF non-V600E/K mutation is selected from the group consisting of D594, G469, K601E, L597, T599 duplication, L485W, F247L, G466V, BRAF fusion, BRAF-AGAP3 rearrangement, BRAF exon 15 splice variant, and their combinations.

[0166] As used herein, the designation of an amino acid substitution mutation includes the following complete format: wild-type amino acid; position; replacement amino acid (for example, K601E). As used herein, the designation of an amino acid substitution also includes the following open format: wild-type amino acid; position (eg G469). As used herein, the open designation includes substitutions for any amino acid. For example, the G469 mutation refers to the replacement of glycine at position 469 with any of the amino acids A, R, N, D, C, Q, E, H, I, L, K, M, F, P, S, T, W, Y, V. Also, as used within the scope of the invention, the closed designation includes substitutions for any amino acid and preferably for the specified replacement amino acid. For example, the K601E mutation refers to the replacement of lysine at position 601 with any of the amino acids A, R, N, D, C, Q, E, G, H, I, L, M, F, P, S, T, W, Y , V, and more preferably to amino acid E. The use of a closed designation as used herein should not be construed as limiting the description to the particular amino acid substitution specified.

[0167] In some embodiments, the individual having a cancer having a non-V600E/K BRAF mutation is a mammal. In some embodiments, the mammal is selected from the group consisting of humans, primates, farm animals, and pets. In some embodiments, the mammal is a human.

[0168] In accordance with some aspects, the present invention relates to both solid and hematological malignancies. Non-limiting examples of solid malignancies include adrenal carcinoma, anal cancer, bladder cancer, bone cancer (such as osteosarcoma), malignant brain tumor, breast cancer, carcinoid tumor, carcinoma, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, extrahepatic bile duct cancer, Ewing family of malignancies, extracranial germ cell cancer, eye cancer, gallbladder cancer, gastric cancer, germ cell tumor, gestational trophoblastic tumor, head and neck cancer, hypopharyngeal cancer, islet cell carcinoma, cancer kidney, colon cancer, laryngeal cancer, leukemia, lip and oral cavity cancer, liver tumor/cancer, lung tumor/cancer, lymphoma, malignant mesothelioma, Merkel cell carcinoma, mycosis fungoides, myelodysplastic syndrome, myeloproliferative disorders, nasopharyngeal cancer, neuroblastoma , oral cavity cancer, oropharyngeal cancer, osteosarcoma, epithelial ovarian cancer, ovarian germ cell cancer, pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pituitary cancer, plasma cell neoplasm, prostate cancer, rhabdomyosarcoma , rectal cancer, renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter, salivary gland cancer, Sézary syndrome, skin malignancies (such as cutaneous T-cell lymphoma, Kaposi's sarcoma, mast cell tumor and melanoma), cancer small intestine, soft tissue sarcoma, stomach cancer, testicular cancer, thymoma, thyroid cancer, urethral cancer, uterine cancer, vaginal cancer, vulvar cancer and Wilms tumor.

[0169] Examples of hematologic malignancies include, but are not limited to, leukemias such as adult/childhood acute lymphoblastic leukemia, adult/childhood acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia and hairy cell leukemia, lymphomas such as AIDS-related lymphoma, cutaneous T-cell lymphoma, adult/pediatric Hodgkin's lymphoma, mycosis fungoides, adult/pediatric non-Hodgkin's lymphoma, primary central nervous system lymphoma, Sézary syndrome, cutaneous T-cell lymphoma and Waldenström's macroglobulinemia, as well as other proliferative disorders such as chronic myeloproliferative disorders, Langerhans cell histiocytosis, multiple myeloma/plasmacyte neoplasms, myelodysplastic syndromes, and myelodysplastic/myeloproliferative neoplasms.

[0170] In some embodiments, the individual's cancer is selected from the group consisting of glioblastoma, melanoma, cholangiocarcinoma, small cell lung cancer, colorectal cancer, prostate cancer, vaginal cancer, angiosarcoma, non-small cell lung cancer, appendix cancer, squamous cell carcinoma , salivary gland ductal carcinoma, adenoid cystic carcinoma, small intestinal cancer and gallbladder cancer. Preferably, the malignant tumor is selected from the group consisting of small intestinal cancer, non-small cell lung cancer, gallbladder cancer and squamous cell carcinoma.

[0171] In accordance with some aspects, the present invention relates to the administration of at least one additional mitogen-activated protein kinase (MAPK) cascade inhibitor to an individual. In some embodiments, the at least one additional drug is selected from the group consisting of a MEK inhibitor, a RAF inhibitor, an HDAC inhibitor, an ERK inhibitor, and combinations thereof.

[0172] As used herein, a “mitogen-activated protein kinase (MAPK) cascade inhibitor” is any substance that modulates, for example, reduces, the activity, expression or phosphorylation of proteins in the MAPK cascade, resulting in decreased cell growth or increased cell death.

[0173] An overview of mammalian MAPK cascades is presented in Figure 1. Details of MAPK cascades are reviewed, for example, in Akinleye et al., 2013. Briefly, regarding the ERK1/2 module in Figure 1 (light purple box), the MAPK 1/2 signaling cascade is activated by ligand binding to receptor tyrosine kinases (RTK). Activated receptors attract and phosphorylate the adapter proteins Grb2 and SOS, which then interact with the membrane-bound GTPase Ras and cause its activation. In its activated GTP-bound form, Ras recruits and activates Raf kinases (A-Raf, B-Raf, and C-Raf/RaF-1). Activated Raf kinases activate MAPK 1/2 (MKK1/2), which in turn catalyzes the phosphorylation of threonine and tyrosine residues in the Thr-Glu-Tyr activating sequence of ERK1/2. Regarding the JNK/p38 module (yellow box in Figure 1), the upstream MAP3K kinases such as MEKK1/4, ASK1/2 and MLK1/2/3 activate MAP2K3/6 (MKK3/6), MAP2K4 (MKK4) and MAP2K7 (MKK7). These MAP2Ks then activate JNK protein kinases, including JNK1, JNK2, and JNK3, as well as p38 α/β/γ/Δ. To perform their functions, JNKs activate several transcription factors, including c-Jun, ATF-2, NF-ATc1, HSF-1, and STAT3. Regarding the ERK5 module (blue box in Figure 1), the kinases upstream of MAP2K5 (MKK5) are MEKK2 and MEKK3. The best characterized downstream target of MEK5 is ERK5, also known as large MAP kinase 1 (BMK1), as it is twice the size of other MAPKs.

[0174] Non-limiting examples of MAPK cascade inhibitors include RAS inhibitors, RAF inhibitors, MEK inhibitors, ERK1/2 inhibitors, pharmaceutically acceptable salts thereof, and combinations thereof.

[0175] As used herein, “RAS inhibitor” means substances that (i) directly interact with RAS, for example by binding to RAS, and (ii) reduce the expression or activity of RAS. Non-limiting exemplary RAS inhibitors include, but are not limited to, farnesyltransferase inhibitors (eg, such as tipifarnib and lonafarnib), small molecule compounds containing a farnesyl group (eg, such as salirasib and TLN-4601), DCAI as described by Maurer et al ., 2012), Kobe0065 and Kobe2602 as described by Shima (Shima et al., 2013), HBS 3 (Patgiri et al., 2011) and AIK-4 (Allinky).

[0176] As used herein, "RAF inhibitor" means substances that (i) directly interact with RAF, for example by binding to RAF and (ii) reduce the expression or activity of RAF, such as A-RAF, B -RAF and C-RAF (Raf-1). Non-limiting exemplary RAF inhibitors include:

Connection 7 (Li et al.)

Connection 9 (Ibid.)

Connection 10 (Ibid.)

Connection 13 (Ibid.)

Connection 14 (Ibid.)

Connection 15 (Ibid.)

Connection 16 (Ibid.)

Connection 18 (Ibid.)

Connection 19 (Ibid.)

Connection 20 (Ibid.)

Connection 21 (Ibid.)

Connection 22 (Ibid.)

Connection 23 (Ibid.)

Connection 24 (Ibid.)

Connection 25 (Ibid.)

Connection 26 (Ibid.)

Connection 27 (Ibid.)

Connection 28 (Ibid.)

Connection 30 (Ibid.)

Compound 31 (Ibid.)

Connection 32 (Ibid.)

Connection 33 (Ibid.)

Connection 34 (Ibid.)

Connection 35 (Ibid.)

Connection 36 (Ibid.)

Connection 37 (Ibid.)

Connection 38 (Ibid.)

Connection 39 (Ibid.)

Connection 40 (Ibid.)

[0177] AAL881 (Novartis); AB-024 (Ambit Biosciences), ARQ-736 (ArQule), ARQ-761 (ArQule), AZ628 (Axon Medchem BV), BAY 43-9006 sorafenib, BeiGene-283 (BeiGene), BUB-024 (MLN 2480) ( Sunesis & Takeda), b-raf inhibitor (Sareum), BRAF kinase inhibitor (Selexagen Therapeutics), BRAF siRNA 313 (tacaccagcaagctagatgca) and 523 (cctatcgttagagtcttcctg) (Liu et al., 2007), CHIR-265 (Novartis), CTT239065 (Institute of Cancer Research), dabrafenib (GSK2118436), DP-4978 (Deciphera Pharmaceuticals), HM-95573 (Hanmi), GDC-0879 (Genentech), GW-5074 (Sigma Aldrich), ISIS 5132 (Novartis), L779450 ( Merck), LBT613 (Novartis), LXH254 (Novartis), LErafAON (NeoPharm, Inc.), LGX-818 (Novartis), pazopanib (GlaxoSmithKline), PLX3202 (Plexxikon), PLX4720 (Plexxikon), PLX5568 (Plexxikon), PLX3603 ( Daiichi Sankyo), PLX8394 (Daiichi Sankyo), RAF-265 (Novartis), RAF-365 (Novartis), REDX0535 (RedX Pharma Plc), regorafenib (Bayer Healthcare Pharmaceuticals, Inc.), RO 5126766 (Hoffmann-La Roche), SB-590885 (GlaxoSmithKline), SB699393 (GlaxoSmithKline), sorafenib (Onyx Pharmaceuticals), TAK 632 (Takeda), TL-241 (Teligene), vemurafenib (RG7204 or PLX4032) (Daiichi Sankyo), XL-281 (Exelixis), ZM -336372 (AstraZeneca), pharmaceutically acceptable salts thereof and combinations thereof.

[0178] In some embodiments, RAF inhibitors include general inhibitors, non-limiting examples of which include erlotinib (Tarceva), gefitinib (Iressa), imatinib mesylate (Gleevec), lapatinib (Tyverb), sunitinib malate (Sutent), pharmaceutically acceptable salts thereof, and their combinations.

[0179] As used herein, “MEK inhibitor” means substances that (i) directly interact with MEK, for example by binding MEK, and (ii) reduce the expression or activity of MEK. Thus, inhibitors that act upstream of MEK, such as RAS inhibitors and RAF inhibitors, are not MEF inhibitors according to the present invention. Non-limiting examples of MEK inhibitors include anthrax toxin, anthroquinolol (Golden Biotechnology), ARRY-142886 ((2-hydroxyethoxy)amide 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole -5-carboxylic acid) (Array BioPharma), ARRY-438162 (Array BioPharma), binimetinib (MEK162, ARRY-1662), AS-1940477 (Astellas), AS-703988 (Merck KGaA), bentamapimod (Merck KGaA), BI- 847325 (Boehringer Ingelheim), E-6201 (Eisai), GDC-0623 (Hoffmann-La Roche), GDC-0973 (cobimetinib) (Hoffmann-La Roche), L783277 (Merck), the lethal portion of the anthrax toxin, MEK162 (Array BioPharma), PD 098059 (2-(2'-amino-3'-methoxphenyl)oxanaphthalene-4-one) (Pfizer), PD 184352 (CI-1040) (Pfizer), PD-0325901 (Pfizer), PD318088 (Pfizer), PD334581 (Pfizer), 6-methoxy-7-(3-morpholin-4-ylpropoxy)-4-(4-phenoxyphenylamino)quinoline-3-carbonitrile, 4-[3-chloro-4-(1 -methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinoline-3-carbonitrile, pimasertib (Santhera Pharmaceuticals), RDEA119 (Ardea Biosciences/Bayer), refametinib (AstraZeneca), RG422 (Chugai Pharmaceutical Co.), R0092210 (Roche), R04987655 (Hoffmann-La Roche), R05126766 (Hoffmann-La Roche), selumetinib (AZD6244) (AstraZeneca), SL327 (Sigma), TAK-733 ( Takeda), trametinib (Japan Tobacco), U0126 (1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene) (Sigma), WX-554 (Wilex), YopJ polypeptide (Mittal et al., 2010), a pharmaceutically acceptable salt thereof, and a combination thereof.

[0180] As used herein, “ERK1/2 inhibitor” means substances that (i) directly interact with ERK1 and/or ERK2, for example by binding to ERK1/2, and (ii) reduce the expression or activity of ERK1 protein kinases and/or ERK2. Thus, inhibitors that act upstream of ERK1/2, such as MEK inhibitors and RAF inhibitors, are not ERK1/2 inhibitors according to the present invention. Non-limiting examples of ERK1/2 inhibitor include AEZS-131 (Aeterna Zentaris), AEZS-136 (Aeterna Zentaris), BVD-523, SCH-722984 (Merck & Co.), SCH-772984 (Merck & Co.), SCH-900353 (MK-8353) (Merck & Co.), LY3214996 (Lilly), pharmaceutically acceptable salts thereof, and combinations thereof.

[0181] As used herein, “HDAC inhibitor” means substances that (i) directly interact with histone deacetylase (HDAC), for example, by binding to HDAC, and (ii) reduce HDAC expression or activity. Non-limiting examples of HDAC inhibitors include Abexinostat (PCI-24781), Givinostat, Entinostat, Vorinostat, CI-994, CUDC-101 Entinostat, BML-210, M344, NVP-LAQ824, Panobinostat, Pracinostat (SB939), Mocetinostat, Resminostat, Romidepsin, Belinostat, their pharmaceutically acceptable salts and combinations thereof.

[0182] In some embodiments, the HDAC inhibitor is selected from the group consisting of Vorinostat, Panobinostat, Romidepsin, Belinostat, pharmaceutically acceptable salts thereof, and combinations thereof.

[0183] In another aspect, the method further includes administering to the individual at least one additional drug effective to treat or mitigate the effects of the cancer. The additional drug may be selected from the group consisting of an antibody, antibody fragment, antibody conjugate, cytotoxic agent, toxin, radionuclide, immunomodulator, photoactive drug, radiosensitizer, hormone, antiangiogenic agent, and combinations thereof.

[0184] As used herein, "antibody" includes naturally occurring immunoglobulins as well as non-naturally occurring immunoglobulins, including, for example, single chain antibodies, chimeric antibodies (eg, humanized mouse antibodies), and antibody heteroconjugates (eg, bispecific antibodies ). Antibody fragments include fragments that bind antigen (eg, Fab', F(ab')2, Fab, Fv and rIgG). Also see, for example, Pierce Catalog and Handbook, 1994-1995 (Pierce Chemical Co., Rockford, Ill.); Kuby, J., Immunology, 3rd Ed., W.H. Freeman & Co., New York (1998). The term "antibody" also includes divalent or bispecific molecules, diantibodies, triantibodies and tetraantibodies. The term "antibody" further includes both polyclonal and monoclonal antibodies.

[0185] Examples of therapeutic antibodies that can be used within the scope of the present invention include rituximab (Rituxan), Brentuximab Vedotin (Adcetriz), Adotrastuzumab emtansine (Kadcyla), Cetuximab (Erbitux), bevacizumab (Avastin), Ibritumomab (Zevalin), vedolizumab ( Entyvio), Ipilimumab (Yervoy), Nivolumab (Opdivo), pembrolizumab (Keytruda), Alemtuzumab atezolizumab (Tecentriq), avelumab (Bavenzio), durvalumab (Imfinzi), B-701, Ofatumumab, Obinutuzumab (Gazyva), Panitumumab, plosalizumab, BI -754091, OREG-103, COM-701, BI-754111 and combinations thereof.

[0186] In some embodiments, the antibody, fragment thereof, or conjugate thereof is selected from the group consisting of rituximab (Rituxan), Brentuximab Vedotin (Adcetriz), Adotrastuzumab emtansine (Kadcyla), Ipilimumab (Yervoy), Nivolumab (Opdivo), pembrolizumab (Keytruda ), Alemtuzumab atezolizumab (Tecentriq), durvalumab (Imfinzi), Ofatumumab, Obinutuzumab (Gazyva), Panitumumab and combinations thereof.

[0187] Cytotoxic agents in accordance with the present invention include DNA damaging agents, antimetabolites, anti-microtubule agents, antibiotics, etc. DNA damaging agents include alkylating agents, platinum-based agents, intercalating agents, and DNA replication inhibitors. Non-limiting examples of DNA alkylating agents include cyclophosphamide, mechlorethamine, uramustine, melphalan, chlorambucil, ifosfamide, carmustine, lomustine, streptozocin, busulfan, temozolomide, pharmaceutically acceptable salts thereof, prodrugs and combinations thereof. Non-limiting examples of platinum-based agents include cisplatin, carboplatin, oxaliplatin, nedaplatin, satraplatin, triplatin tetranitrate, pharmaceutically acceptable salts, prodrugs and combinations thereof. Non-limiting examples of intercalating agents include doxorubicin, daunorubicin, idarubicin, mitoxantrone, pharmaceutically acceptable salts, prodrugs, and combinations thereof. Non-limiting examples of DNA replication inhibitors include irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, teniposide, pharmaceutically acceptable salts, prodrugs and combinations thereof. Antimetabolites include folate antagonists such as methotrexate and premetrexed, purine antagonists such as 6-mercaptopurine, dacarbazine and fludarabine, and pyrimidine antagonists such as 5-fluorouracil, arabinosylcytosine, capecitabine, gemcitabine, decitabine, their pharmaceutically acceptable salts, prodrugs and their combinations. Anti-microtubule agents include, but are not limited to, vinca alkaloids, paclitaxel (Taxol®), docetaxel (Taxotere®), and ixabepilone (Ixempra®). Antibiotics include, but are not limited to, actinomycin, anthracyclines, valrubicin, epirubicin, bleomycin, plicamycin, mitomycin, pharmaceutically acceptable salts, prodrugs and combinations thereof.

[0188] In some embodiments, the cytotoxic agent is selected from the group consisting of cyclophosphamide, mechlorethamine, uramustine, melphalan, chlorambucil, ifosfamide, carmustine, lomustine, streptozocin, busulfan, temozolomide, cisplatin, carboplatin, oxaliplatin, nedaplatin, satraplatin, triplatin tetranitrate a, doxorubicin, daunorubicin, idarubicin, mitoxantrone, methotrexate, pemetrexed, 6-mercaptopurine, dacarbazine, fludarabine, 5-fluorouracil, arabinosylcytosine, capecitabine, gemcitabine, decitabine, vinca alkaloids, paclitaxel (Taxol), docetaxel (Taxotere), Ixa bepilona (Ixempra), actinomycin, anthracyclines, valrubicin, epirubicin, bleomycin, plicamycin, mitomycin, pharmaceutically acceptable salts, prodrugs and combinations thereof.

[0189] Cytotoxic agents in accordance with the present invention also include an inhibitor of the PI3K/Akt cascade. Non-limiting examples of a PI3K/Akt cascade inhibitor include A-674563 (CAS No. 552325-73-2), AGL 2263, AMG-319 (Amgen, Thousand Oaks, Calif.), AS-041164 (5-benzo[1,3]dioxol -5-ylmethylenethiazolidin-2,4-dione), AS-604850 (5-(2,2-difluorobenzo[1,3]dioxol-5-ylmethylene)thiazolidin-2,4-dione), AS-605240 (5- quinoxylin-6-methylene-1,3-thiazolidine-2,4-dione), AT7867 (CAS No. 857531-00-1), benzimidazoles series, Genentech (Roche Holdings Inc., South San Francisco, Calif.), BML- 257 (CAS No. 32387-96-5), BVD-723, CAL-120 (Gilead Sciences, Foster City, Calif.), CAL-129 (Gilead Sciences), CAL-130 (Gilead Sciences), CAL-253 (Gilead Sciences), CAL-263 (Gilead Sciences), CAS No. 612847-09-3, CAS No. 681281-88-9, CAS No. 75747-14-7, CAS No. 925681-41-0, CAS No. 98510-80-6 , CCT128930 (CAS No. 885499-61-6), CH5132799 (CAS No. 1007207-67-1), CHR-4432 (Chroma Therapeutics, Ltd., Abingdon, UK), FPA 124 (CAS No. 902779-59-3), GS-1101 (CAL-101) (Gilead Sciences), GSK 690693 (CAS No. 937174-76-0), H-89 (CAS No. 127243-85-0), Honokiol, IC87114 (Gilead Science), IPI-145 ( Intellikine Inc.), KAR-4139 (Karus Therapeutics, Chilworth, UK), KAR-4141 (Karus Theryubapeutics), KIN-1 (Karus Therapeutics), KT 5720 (CAS No. 108068-98-0), Miltefosine, MK-2206 dihydrochloride (CAS No. 1032350-13-2), ML-9 (CAS No. 105637-50-1), Naltrindole hydrochloride, OXY-111A (NormOxys Inc., Brighton, Mass.), perifosine, PHT-427 (CAS No. 1191951 -57-1), PI3-kinase inhibitor delta, Merck KGaA (Merck & Co., Whitehouse Station, N.J.), PI3-kinase inhibitors delta, Genentech (Roche Holdings Inc.), PI3-kinase inhibitors delta, Incozen (Incozen Therapeutics , Pvt. Ltd., Hydrabad, India), PI3-kinase delta 2 inhibitors, Incozen (Incozen Therapeutics), PI3-kinase inhibitor, Roche-4 (Roche Holdings Inc.), PI3-kinase inhibitors, Roche (Roche Holdings Inc.), inhibitors PI3-kinases, Roche-5 (Roche Holdings Inc.), PI3-alpha/delta inhibitors, Pathway Therapeutics (Pathway Therapeutics Ltd., South San Francisco, Calif.), PI3-delta inhibitors, Cellzome (Cellzome AG, Heidelberg, Germany ), PI3-delta inhibitors, Intellikine (Intellikine Inc., La Jolla, Calif.), PI3-delta inhibitors, Pathway Therapeutics-1 (Pathway Therapeutics Ltd.), PI3-delta inhibitors, Pathway Therapeutics-2 (Pathway Therapeutics Ltd. ), PI3-delta/gamma inhibitors, Cellzome (Cellzome AG), PI3-delta/gamma inhibitors, Cellzome (Cellzome AG), PI3-delta/gamma inhibitors, Intellikine (Intellikine Inc.), PI3-delta/gamma inhibitors, Intellikine (Intellikine Inc.), PI3-delta/gamma inhibitors, Pathway Therapeutics (Pathway Therapeutics Ltd.), PI3-delta/gamma inhibitors, Pathway Therapeutics (Pathway Therapeutics Ltd.), PI3-gamma inhibitor Evotec (Evotec) and PI3- gamma, Cellzome (Cellzome AG), PI3-gamma inhibitors, Pathway Therapeutics (Pathway Therapeutics Ltd.), PI3K-delta/gamma inhibitors, Intellikine-1 (Intellikine Inc.), PI3-delta/gamma inhibitors, Intellikine-1 (Intellikine Inc.), pictilisib (Roche Holdings Inc.), PIK-90 (CAS No. 677338-12-4), SC-103980 (Pfizer, New York, N.Y.), SF-1126 (Semafore Pharmaceuticals, Indianapolis, Ind.) , SH-5, SH-6, Tetrahydrocurcumin, TG100-115 (Targegen Inc., San Diego, Calif.), Triciribine, X-339 (Xcovery, West Palm Beach, Fla.), XL-499 (Evotech, Hamburg, Germany), their pharmaceutically acceptable salts and combinations thereof.

[0190] For the purposes of the present invention, BVD-723 is a compound of formula (II):

[0191] and pharmaceutically acceptable salts thereof. BVD-723 is a selective PI3Kγ inhibitor. BVD-723 can be synthesized by methods described, for example, in US publication No. 2016/0214980, which is incorporated herein by reference in its entirety. Also included within the scope of the present invention are enantiomers and racemic mixtures of both enantiomers of BVD-723.

[0192] As used herein, the term “toxin” means an antigenic agent or poison of plant or animal origin. An example is diphtheria toxin or parts thereof.

[0193] As used herein, the term “radionuclide” means a radioactive substance administered to a patient, for example, intravenously or orally, after which it travels through the patient's normal metabolism to a target organ or tissue where it provides localized radiation over a short period time. Examples of radionuclides include, but are not limited to, I-125, At-211, Lu-177, Cu-67, I-131, Sm-153, Re-186, P-32, Re-188, In-114m and Y -90.

[0194] As used herein, the term “immunomodulator” means a substance that modifies the immune response by enhancing or decreasing the ability of the immune system to produce antibodies or sensitized cells that recognize and react with the antigen that triggered their production. Immunomodulators can be recombinant, synthetic or natural drugs and include cytokines, corticosteroids, cytotoxic agents, thymosin and immunoglobulins. Several immunomodulators are naturally present in the body and some of them are available in pharmaceutical preparations. Examples of immunomodulators include, but are not limited to, granulocyte colony stimulating factor (G-CSF), LAG-3, IMP-321, JCAR-014, ASLAN-002 (BMS-777607), interferons, imiquimod and cell membrane fractions from bacteria, IL -2, IL-7, IL-12, CCL3, CCL26, CXCL7, synthetic cytosine phosphate-guanosine (CpG), immune checkpoint inhibitors and combinations thereof.

[0195] As used herein, the term “photoactive drug” means compounds and compositions that become active upon exposure to light. Certain examples of photoactive drugs are described, for example, in US Patent Application Serial No. 2011/0152230 A1, "Photoactive Metal Nitrosyls For Blood Pressure Regulation And Cancer Therapy."

[0196] As used herein, the term “radiosensitizing agent” means a compound that makes tumor cells more sensitive to radiation therapy. Examples of radiosensitizers include misonidazole, metronidazole, tirapazamine and sodium trans-crocetinate, and combinations thereof.

[0197] As used herein, the term “hormone” means a substance released by cells in one part of the body that affects cells in another part of the body. Examples of hormones include, but are not limited to, prostaglandins, leukotrienes, prostacyclin, thromboxane, amylin, anti-Mullerian hormone, adiponectin, adrenocorticotropic hormone, angiotensinogen, angiotensin, vasopressin, atriopeptide, brain natriuretic peptide, calcitonin, cholistokinin, corticotropin-releasing hormone, encephalin , endothelin, erythropoietin, follicle-stimulating hormone, galanin, gastrin, ghrelin, glucagon, gonadotropin-releasing hormone, growth hormone-releasing factor, human chorionic gonadotropin, human placental lactogen, growth hormone, inhibin, insulin, somatomedin, leptin, liptropin, luteinizing hormone , melanocyte-stimulating hormone, motilin, orexin, oxytocin, pancreatic polypeptide, parathyroid hormone, prolactin, prolactin-releasing hormone, relaxin, renin, secretin, somatostatin, thrombopoietin, thyroid-stimulating hormone, testosterone, dehydroepiandrosterone, androstenedione, dihydrotestosterone, aldosterone, estradiol, estrone, estriol, cortisol, progesterone, calcitriol and calcidiol.

[0198] Some compounds interfere with the activity of certain hormones or stop the production of certain hormones. These hormone-interfering compounds include, but are not limited to, tamoxifen (Nolvadex®), anastrozole (Arimidex®), lectrozole (Femara®), and fulvestrant (Faslodex®). Such compounds are also included within the meaning of the term "hormone" within the meaning of the present invention.

[0199] As used herein, an “antiangiogenic” agent means a substance that reduces or inhibits the growth of new blood vessels, such as, for example, a vascular endothelial growth factor (VEGF) inhibitor and an endothelial cell migration inhibitor. Antiangiogenic agents include, but are not limited to, 2-methoxyestradiol, angiostatin, bevacizumab, cartilage angiogenesis inhibitory factor, endostatin, IFN-α, IL-12, itraconazole, linomide, platelet factor 4, prolactin, SU5416, suramin, tasquinimod, tecogalan, tetrathiomolybdate, thalidomide, thrombospondin, thrombospondin, TNP-470, ziv-aflibercept, pharmaceutically acceptable salts, prodrugs and combinations thereof.

[0200] In accordance with one aspect, the present invention provides a method of treating or mitigating the effects of a cancer in an individual, comprising (a) identifying an individual with a cancer having a BRAF mutation other than V600E/K; and (b) administering to the individual an effective amount of an ERK inhibitor or a pharmaceutically acceptable salt thereof.

[0201] In accordance with one embodiment, the ERK inhibitor is selected from the group consisting of BVD-523, SCH-722984 (Merck & Co.), SCH-772984 (Merck & Co.), SCH-900353 (MK-8353) ( Merck & Co.), LY3214996 (Lilly), AEZS-140 (Aeterna Zentaris), AEZS-131 (Aeterna Zentaris), AEZS-136 (Aeterna Zentaris), LTT-462 (Novartis), RG-7842 (Genentech), CC -90003 (Celgene), KIN-4050 (Kinentia) and combinations thereof. In accordance with one embodiment, the ERK inhibitor is BVD-523. In one aspect of this embodiment, BVD-523 or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition further comprising a pharmaceutically acceptable carrier or diluent.

[0202] In accordance with one aspect, the present invention relates to identifying an individual with a cancer having a BRAF mutation other than V600E/K, comprising (i) obtaining a biological sample from the individual; and (ii) screening the sample to determine whether the individual has a BRAF mutation other than V600E/K.

[0203] Suitable and preferred individuals are those described herein. In this embodiment, the methods can be used to treat the cancers described above, including cancers with the mutational basis identified above. Methods for identifying such mutations are also as described above.

[0204] Within the scope of the present invention, biological samples include, but are not limited to, blood, plasma, urine, skin, saliva, and biopsies. Biological samples are obtained from an individual using standard techniques and methods that are known in the art. Non-limiting examples of mutation identification methods include PCR, sequencing, hybrid trap, solution capture, invertible molecular probes, fluorescence in situ hybridization (FISH) assay methods, and combinations thereof.

[0205] In accordance with one embodiment, the method further includes administering to the individual at least one additional drug selected from the group consisting of a MEK inhibitor, a RAF inhibitor, an HDAC inhibitor, and combinations thereof. Suitable and preferred individuals are those as described herein. In this embodiment, the methods can be used to treat the cancers described above, including cancers with the mutational basis identified above, using one or more additional drugs described above. Methods for identifying such mutations are also as described above.

[0206] In accordance with one aspect, the present invention provides a method for identifying an individual having a cancer that would benefit from therapy with an ERK inhibitor or a pharmaceutically acceptable salt thereof, the method comprising (a) obtaining a biological sample from the individual; and (b) screening the sample to determine whether the individual has a non-V600E/K BRAF mutation, wherein the presence of a non-V600E/K BRAF mutation confirms that the individual would benefit from therapy with an ERK inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises administering to the individual an ERK inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the method further includes administering to the individual at least one additional drug. In this embodiment, the method can be used to identify the mutational basis identified above in the cancers described above. Methods for identifying such mutations are also as described above. In this embodiment, the ERK inhibitor that would be beneficial to the identified patient is as described above. Additional medications are as described above. Suitable and preferred individuals are as described above.

[0207] In accordance with one aspect, the present invention provides a method of treating or mitigating the effects of a cancer in an individual, comprising (a) identifying an individual with a cancer having a BRAF mutation other than V600E/K; and (b) administering to the individual an effective amount of BVD-523 or a pharmaceutically acceptable salt thereof. In accordance with one aspect, the present invention provides a method for identifying an individual having a cancer that would benefit from therapy with BVD-523 or a pharmaceutically acceptable salt thereof, the method comprising (a) obtaining a biological sample from the individual; and (b) screening the sample to determine whether the individual has a non-V600E/K BRAF mutation, wherein the presence of a non-V600E/K BRAF mutation confirms that the individual would benefit from therapy with BVD-523 or a pharmaceutically acceptable salt thereof. In these embodiments, the method can be used to identify the mutational basis identified above in the cancers described above. Methods for identifying such mutations are also indicated above. Suitable and preferred individuals are those described above.

[0208] Another aspect of the present invention relates to a kit for treating or mitigating the effects of a cancer in an individual having a non-V600E/K BRAF mutation. In some embodiments, the kit contains an effective amount of an ERK inhibitor, as described above, and optionally an additional drug, as described above.

[0209] The kits may also include suitable storage containers, for example, ampoules, vials, tubes, etc., for each anti-cancer agent of the present invention (which may, for example, be in the form of pharmaceutical compositions), and other reagents eg, buffers, balanced salt solutions, etc., for use in administering anticancer agents to individuals. The anticancer agents of the invention and other reagents may be present in the kits in any convenient form, such as, for example, solution or powder form. In addition, the kits may include a packaging container, optionally having one or more compartments for containing the pharmaceutical composition and other optional reagents.

[0210] As used herein, an "effective amount" or a "therapeutically effective amount" of an anticancer agent of the invention, including pharmaceutical compositions containing the same as described herein, is an amount of such agent or composition that is sufficient to provide beneficial or desirable results as described herein when administered to an individual. Effective dosage forms, routes of administration and dosages can be determined empirically and making such determinations is within the scope of skill in the art. Those skilled in the art will appreciate that dosage will vary depending on the route of administration, rate of excretion, duration of treatment, type of any other drugs administered, age, size and species of the mammalian patient, e.g., human patient, and similar factors, well known in the field of medicine and veterinary medicine. Generally, a suitable dosage of an agent or composition of the invention is an amount of the agent or composition that is the lowest dose effective to produce the desired effect. An effective dose of the agent or composition of the present invention can be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day.

[0211] A suitable non-limiting example dosage of BVD-523, a RAF inhibitor, an ERK inhibitor, or other anti-cancer agent described herein is from about 1 mg/kg to about 2400 mg/kg per day, such as from about 1 mg/kg to about 1200 mg/kg per day, 75 mg/kg per day to about 300 mg/kg per day, including about 1 mg/kg to about 100 mg/kg per day. Other representative dosages of such agents include approximately 1 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg. kg, 45 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/ kg, 175 mg/kg, 200 mg/kg, 250 mg/kg, 300 mg/kg, 400 mg/kg, 500 mg/kg, 600 mg/kg, 700 mg/kg, 800 mg/kg, 900 mg/ kg, 1000 mg/kg, 1100 mg/kg, 1200 mg/kg, 1300 mg/kg, 1400 mg/kg, 1500 mg/kg, 1600 mg/kg, 1700 mg/kg, 1800 mg/kg, 1900 mg/ kg, 2000 mg/kg, 2100 mg/kg, 2200 mg/kg and 2300 mg/kg per day. An effective dose of BVD-523, RAF inhibitors, ERK inhibitors or other anti-cancer agents described herein can be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day.

[0212] BVD-523, RAF inhibitors, ERK inhibitors, or other drugs or pharmaceutical compositions containing them of the present invention can be administered in any desired or effective manner: by oral administration or as an ointment or drops for topical administration to the eye, and by parenteral or other administration by any suitable route, such as intraperitoneal, intratumoral, subcutaneous, topical, intradermal, inhalation, intrapulmonary, rectal, vaginal, sublingual, intramuscular, intravenous, intraarterial, intrathecal, or intralymphatic. In addition, BVD-523, RAF inhibitors or other drugs or pharmaceutical compositions containing them of the present invention can be administered in conjunction with other treatments. If desired, BVD-523, RAF inhibitors or other drugs or pharmaceutical compositions containing them can be encapsulated or otherwise protected against gastric or other secretions.

[0213] The pharmaceutical compositions of the invention contain one or more active ingredients, for example, drugs, in admixture with one or more pharmaceutically acceptable diluents or carriers and, optionally, one or more other compounds, drugs, ingredients and/or materials. Regardless of the route of administration chosen, the agents/compounds of the present invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art. See, for example, Remington, The Science and Practice of Pharmacy (21st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa.).

[0214] Pharmaceutically acceptable diluents or carriers are well known in the art (see, for example, Remington, The Science and Practice of Pharmacy (21st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa.) and The National Formulary (American Pharmaceutical Association, Washington, D.C.) and include sugars (for example, lactose, sucrose, mannitol and sorbitol), starches, cellulose preparations, calcium phosphates (for example, dicalcium phosphate, tricalcium phosphate and calcium hydrogen phosphate), sodium citrate, water, aqueous solutions (for example, saline, sodium chloride injection, Ringer's solution for injection, dextrose solution for injection, dextrose and sodium chloride injection, lactated Ringer's solution for injection), alcohols (for example, ethyl alcohol, propyl alcohol and benzyl alcohol), polyols (for example, glycerin, propylene glycol and polyethylene glycol), organic esters (e.g. ethyl oleate and triglycerides), biodegradable polymers (e.g. polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides)), elastomeric matrices, liposomes, microspheres, oils (e.g. germ, olive, castor, sesame, cottonseed and peanut oil), cocoa butter, waxes (for example, suppository waxes), paraffins, silicones, talc, silicylate, etc. Each pharmaceutically acceptable diluent or carrier used in the pharmaceutical composition of the invention must be "acceptable" in terms of compatibility with the other ingredients of the composition and not harmful to the individual. Diluents or carriers suitable for the selected dosage form and intended route of administration are well known in the art, and suitable diluents or carriers for the selected dosage form and route of administration can be determined using normal skill in the art.

[0215] The pharmaceutical compositions of the invention may optionally contain additional ingredients and/or materials commonly used in pharmaceutical compositions. These ingredients and materials are well known in the art and include (1) fillers or diluents such as starches, lactose, sucrose, glucose, mannitol and silicic acid; (2) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, hydroxypropylmethylcellulose, sucrose and gum arabic; (3) humectants such as glycerin; (4) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium starch glycolate, cross-linked sodium carboxymethylcellulose and sodium carbonate; (5) dissolution retardants such as paraffin; (6) absorption accelerating agents such as quaternary ammonium compounds; (7) wetting agents such as cetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols and sodium lauryl sulfate; (10) suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth; (11) buffering agents; (12) excipients such as lactose, milk sugars, polyethylene glycols, animal and vegetable fats, oils, waxes, paraffins, cocoa butter, starches, tragacanth, cellulose derivatives, polyethylene glycol, silicones, bentonites, silicic acid, talc, salicylate, zinc oxide , aluminum hydroxide, calcium silicates and polyamide powder; (13) inert diluents such as water or other solvents; (14) preservatives; (15) surfactants; (16) dispersants; (17) controlled release or absorption retarding agents such as hydroxypropyl methylcellulose, other polymer matrices, biodegradable polymers, liposomes, microspheres, aluminum monostearate, gelatin and waxes; (18) opacifiers; (19) adjuvants; (20) wetting agents; (21) emulsifying and suspending agents; (22) solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed, peanut, corn, germ, olive, castor and sesame oil), glycerin, tetrahydrofuryl alcohol, polyethylene glycols and sorbitan fatty acid esters; (23) propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane; (24) antioxidants; (25) agents that ensure that the composition is isotonic with the blood of the intended recipient, such as sugars and sodium chloride; (26) thickeners; (27) coating materials such as lecithin; and (28) sweeteners, flavors, colors, flavors and preservatives. Each such ingredient or material must be "acceptable" in terms of compatibility with the other ingredients of the formulation and not harmful to the individual. Ingredients and materials suitable for the selected dosage form and intended route of administration are well known in the art, and suitable ingredients and materials for the selected dosage form and route of administration can be determined using standard skill in the art.

[0216] The pharmaceutical compositions of the present invention suitable for oral administration may be in the form of capsules, starch capsules, pills, tablets, powders, granules, solution or suspension in an aqueous or non-aqueous liquid, oil-in-water liquid emulsion or water in oil", elixir or syrup, lozenge, bolus, electuary or paste. These compositions can be prepared by methods known in the art, for example, through conventional methods of whole coating, mixing, granulating or lyophilization.

[0217] Solid oral dosage forms (capsules, tablets, pills, dragees, powders, granules, etc.) can be prepared, for example, by mixing the active ingredient(s) with one or more pharmaceutically acceptable diluents or carriers and optionally one or more fillers, diluents, binders, humectants, disintegrants, dissolution retardants, absorption enhancers, wetting agents, absorbents, lubricants and/or colorants. Solid compositions of a similar type can be used as fillers in soft and hard filled gelatin capsules using a suitable excipient. A tablet may be prepared by compression or molding, optionally with one or more additional ingredients. Compressed tablets can be prepared using a suitable binder, lubricant, inert diluent, preservative, disintegrant, surfactant or dispersant. Molded tablets can be obtained by molding in a suitable device. Tablets and other solid dosage forms, such as dragees, capsules, pills and granules, do not necessarily have a groove or can be formulated with coatings and coatings, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They can also be formulated to provide a slow or controlled release of the active ingredient. They can be sterilized, for example, by filtration through a bacteria-retaining filter. These compositions may also optionally contain opacifiers and may be formulated such that they release the active ingredient only or preferentially in a specific part of the gastrointestinal tract, optionally in a delayed manner. The active ingredient may also be in microencapsulated form.

[0218] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms may contain suitable inert diluents commonly used in the art. In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, colors, fragrances and preservatives. Suspensions may contain suspending agents.

[0219] The pharmaceutical compositions of the present invention for rectal or vaginal administration may be provided as a suppository, which may be prepared by mixing one or more active ingredient(s) with one or more suitable non-irritating diluents or carriers that are solid when room temperature, but liquid at body temperature and thus melt in the rectum or vaginal cavity and release the active compound. Pharmaceutical compositions of the present invention that are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such pharmaceutically acceptable diluents or carriers as are known in the art as useful.

[0220] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, drops, and inhalable forms. The active substance(s)/compound(s) may be mixed under sterile conditions with a suitable pharmaceutically acceptable diluent or carrier. Ointments, pastes, creams and gels may contain excipients. Powders and sprays may contain excipients and propellants.

[0221] The pharmaceutical compositions of the present invention suitable for parenteral administration may contain one or more agent(s)/compound(s) in combination with one or more pharmaceutically acceptable isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use, which may contain suitable antioxidants, buffers, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending agents or thickening agents. Proper fluidity can be maintained, for example, by the use of coating materials, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. These pharmaceutical compositions may also contain suitable adjuvants such as wetting agents, emulsifiers and dispersants. It may also be desirable to include isotonicity agents. In addition, prolonged absorption of the injectable pharmaceutical form can be achieved by including substances that delay absorption.

[0222] In some cases, to prolong the effect of a drug (eg, a pharmaceutical formulation), it is desirable to slow its absorption after subcutaneous or intramuscular injection. This can be accomplished using a liquid suspension of crystalline or amorphous material having low solubility in water.

[0223] As a result, the rate of absorption of the active substance/drug depends on the rate of its dissolution, which in turn may depend on the crystal size and crystalline form. Alternatively, delayed parenteral absorption of the substance/drug can be achieved by dissolving or suspending the active substance/drug in an oily vehicle. Injectable depot forms can be prepared by forming active ingredient matrices microencapsulated in biodegradable polymers. Depending on the ratio of active ingredient to polymer and the nature of the particular polymer used, the rate of release of the active ingredient can be controlled. Injectable depot formulations are also prepared by enclosing the drug in liposomes or microemulsions that are compatible with body tissue. Injection materials can be sterilized, for example, by filtration through bacteria-retaining filters.

[0224] The formulations may be provided in closed single-dose or multi-dose containers, such as ampoules and vials, and may be stored in a lyophilized state, requiring only the addition of a sterile liquid diluent or carrier, such as injectable water, immediately prior to use. Solutions and suspensions for preparation immediately before injection can be prepared from sterile powders, granules and tablets of the type described above.

[0225] The following examples are provided to further illustrate the methods of the present invention. These examples are illustrative only and are not intended to limit the scope of the invention in any way.

EXAMPLE 1

[0226] The example below presents results from the phase 1b trial of BVD-523 in a solid tumor. The waterfall chart presented in FIG. 2 provides an illustration of human clinical trial patient information demonstrating each individual's response to BVD-523 treatment as measured by % change in tumor burden. Patients were primarily administered 600 mg twice daily (BID), with some patients receiving a reduced dose of 300 mg-400 mg BID if side effects could not be controlled with other palliative medical intervention.

[0227] As shown in Figure 2, tumor response to BVD-523 was assessed in 28 evaluable patients using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). One patient did not have both lesion scans and was thus not evaluated. The horizontal axis through the graph serves as a baseline for each patient. The vertical axis measures the maximum percentage change from baseline; those. percentage increase or decrease in tumor burden as determined by radiological determination according to RECIST v1.1. Radiological determination included computed tomography (CT) scans and sometimes magnetic resonance imaging (MRI).

[0228] The tumor load data presented in FIG. 2 is plotted from the worst value (ie, greatest progression of tumor load) on the left of the graph to the best value (ie, greatest decrease in tumor load) on the right of the graph. The RECIST v1.1 response criteria for measured lesions have been described previously (see Eisenhauer, E.A., et al., New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1), European J. of Cancer 45, 228-247 ( 2009), incorporated herein by reference in its entirety). The response criteria are as follows:

[0229] Complete response (CR) - disappearance of all target lesions;

[0230] Partial response (PR) - at least a 30% reduction in the sum of the diameters of the target lesions when using the original sum of diameters as a reference; as shown in Figure 2, the 30% reduction threshold for partial response is indicated by the horizontal line;

[0231] Progressive disease (PD) - at least a 20% increase in the sum of target lesion diameters using the smallest sum in the study as the reference (this includes the original sum if it is the smallest in the study). In addition to a relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm (note: the appearance of one or more new lesions is also considered progression);

[0232] Stable disease (SD) is not a sufficient decrease to be defined as PR, nor a sufficient increase to be defined as PD when using the smallest sum of diameters in the trial as the reference.

[0233] FIG. 2 also shows the type of cancer or organ where tumor burden was determined for each patient and the type of atypical BRAF mutation identified in that patient's tumor sample. Of the 28 patients presented, 13 patient tumors harbored the BRAF D594 mutation (seven cases D594G and six cases D594N); the tumor of 1 patient contained the BRAF F247L mutation; 1 patient's tumor contained a fusion of the BRAF gene with the nuclear factor IC (NFIC) gene (ie, a BRAF-NFIC fusion mutation); the tumor of 1 patient contained the BRAF G466V mutation; tumors from 5 patients contained the BRAF G469 mutation (one was G469V and four were G469A); tumors from 3 patients contained the BRAF K601E mutation; the tumor of 1 patient contained the BRAF L485W mutation; tumors from 3 patients contained a BRAF L597 mutation (one was unidentified and two were L597Q), and tumors from 2 patients contained a T599 duplication. The type of BRAF mutation is indicated according to the color code and type of malignancy for each patient (see Fig. 2).

[0234] Five patients with PR had 35% to 100% reduction in the sum of target lesions from baseline. These patients had: a gallbladder tumor containing the L485W mutation; squamous cell tumor of the head/neck containing the G469A mutation; non-small cell lung carcinoma containing the BRAF L597Q mutation or BRAF T599 duplication; and a small intestinal tumor containing the BRAF G469A mutation. 19 patients demonstrated stable disease. Three patients had progressive disease at first evaluation (see Figure 2). In summary, treatment with BVD-523 unexpectedly resulted in partial response or stable disease in 24 of 28 patients with atypical BRAF mutations (i.e., non-V600E/K).

[0235] Figure 3 shows the duration of treatment on the pool lane graph, divided into groups. Group 1 members are any patients with any BRAF mutation in any tumor type other than colorectal cancer (CRC) and non-small cell lung carcinoma (NSCLC) and who have been previously treated with a MAPK cascade inhibitor. Members of group 2 represent patients with any BRAF mutation in CRC who have not previously been treated with a MAPK cascade inhibitor. Members of group 3 are patients with the BRAF V600E/K mutation who are refractory to a MAPK inhibitor. Group 6 members represent patients with any BRAF mutation present in NSCLC. As shown in Figure 3, all 28 patients are included, as shown by the horizontal bars, one for each individual. The duration of treatment for each individual in each group is illustrated from top (longest treatment duration) to bottom (shortest treatment duration) by group. The horizontal axis represents the duration in days of an individual's stay in the study. Figure 3 also shows the type of response achieved by each patient according to RECIST v1.1 (diamond=partial response; circle=stable disease; vertical bar=progressive disease; triangle=not assessed).

[0236] Figure 4 shows the duration of treatment on a waterfall chart according to BRAF mutation. All 28 patients meeting RECIST v1.1 response criteria were included, plus additional patients not assessed by RECIST v1.1 (diamond=partial response; circle=stable disease; vertical bar=progressive disease; triangle=not assessed) . The median duration of BVD-523 treatment before discontinuation of treatment for tumors harboring the indicated BRAF mutation was: D594, 73.6 days; G469, 208.14 days; K601E, 50.25 days; L597, 73.3 days; T599 Dup, 63.5 days. For cases of one patient with a specific BRAF mutation, the duration of treatment was: L485W, 304 days; F247L, 84 days; G466V, 77 days; BRAF fusion, 65 days; BRAF-AGAP3 rearrangement, 43 days; BRAF exon 15 splice variant. By genomically screening cancer patients for BRAF mutations and treating them before fully characterizing these mutations in vitro (as a trigger mutation), BVD-523 is shown to be suitable for studying and developing effective treatment options for patients harboring BRAF mutations. Clinical patient population and efficacy are determined primarily not by tumor type, but rather by the mutational status of enzymes such as BRAF upstream of ERK 1/2 kinase activation.

[0237] In general, the examples provide data from a Phase 1b trial of BVD-523, a novel ERK inhibitor, in solid tumors as a treatment for patients with cancers harboring atypical BRAF mutations. Continuous twice daily administration of BVD-523 provided antitumor effects in several patients and was not limited to any one specific cancer type or atypical BRAF mutation.

Documentation

ABSALAN, Farnaz, Mostafa Ronaghi (2008). Molecular Inversion Probe Assay. Methods in Molecular Biology 396. Humana Press. pp. 315-330.

AHRONIAN LG, Sennott EM, Van Allen EM, Wagle N, Kwak EL, Faris JE, et al. Clinical resistance acquired to RAF inhibitor combinations in BRAF-mutant colorectal cancer through MAPK pathway alterations. Cancer Discov 2015;5:358-67.

ARCILA ME, Drilon A, Sylvester BE, Lovly CM, Borsu L, Reva B, et al. MAP2K1 (MEK1) mutations define a distinct subset of lung adenocarcinoma associated with smoking. Clin Cancer Res 2015;21:1935-43.

ARONOV AM, Baker C, Bemis GW, Cao J, Chen G, Ford PJ, et al. Flipped out: structure-guided design of selective pyrazolylpyrrole ERK inhibitors. J Med Chem 2007;50:1280-7.

ARONOV AM, Tang Q, Martinez-Botella G, Bemis GW, Cao J, Chen G, et al. Structure-guided design of potent and selective pyrimidylpyrrole inhibitors of extracellular signal-regulated kinase (ERK) using conformational control. J Med Chem 2009;52:6362-8.

ARRINGTON AK, Heinrich EL, Lee W, Duldulao M, Patel S, Sanchez J, et al. Prognostic and predictive roles of KRAS mutation in colorectal cancer. Int J Mol Sci 2012;13:12153-68.

CARGNELLO M, Roux PP. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev 2011;75:50-83.

CARLINO MS, Fung C, Shahheydari H, Todd JR, Boyd SC, Irvine M, et al. Preexisting MEK1P124 mutations diminish response to BRAF inhibitors in metastatic melanoma patients. Clin Cancer Res 2015;21:98-105.

CHAPMAN PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-16.

CORCORAN, R. B., et al. BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. Sci Signal (2010);3(149): ra84.

DAI, B., et al. STAT3 mediates resistance to MEK inhibitor through microRNA miR-17. Cancer Res (2011);71:3658-3668.

DAVIES H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949-54.

DESCHENES-SIMARD X, Kottakis F, Meloche S, Ferbeyre G. ERKs in cancer: friends or foes? Cancer Res 2014;74:412-9.

DOBRZYCKA B, Terlikowski SJ, Kowalczuk O, Niklinska W, Chyczewski L, Kulikowski M. Mutations in the KRAS gene in ovarian tumors. Folia Histochem Cytobiol 2009;47:221-4.

EMERY, C. M., et al. MEK1 mutations confer resistance to MEK and B-RAF inhibition. PNAS (2009); 106(48):20411-6.

FEDOROV O, Niesen FH, Knapp S. Kinase inhibitor selectivity profiling using differential scanning fluorimetry. Methods Mol Biol 2012;795:109-18.

FERNÁNDEZ-MEDARDE A, Santos E. Ras in cancer and developmental diseases. Genes Cancer 2011;2:344-58.

FLAHERTY KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012;367:1694-703.

GOETZ EM, Ghandi M, Treacy DJ, Wagle N, Garraway LA. ERK mutations confer resistance to mitogen-activated protein kinase pathway inhibitors. Cancer Res 2014;74:7079-89.

GOLLOB JA, Wilhelm S, Carter C, Kelley SL. Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. Semin Oncol 2006;33:392-406.

GREGER, James G., et al. "Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations." Molecular cancer therapeutics 11.4 (2012): 909-920.

GROENENDIJK FH, Bernards R. Drug resistance to targeted therapies: deja vu all over again. Mol Oncol 2014;8:1067-83.

HALL RD, Kudchadkar RR. BRAF mutations: signaling, epidemiology, and clinical experience in multiple malignancies. Cancer Control 2014;21:221-30.

HARDENBOL, P., et al. Multiplexed genotyping with sequence-tagged molecular inversion probes. Nat. Biotechnol. 2003, no.21, p.673-678.

HATZIVASSILIOU, Georgia, et al. "RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth." Nature 464.7287 (2010): 431-435.

HATZIVASSILIOU G, Liu B, O'Brien C, Spoerke JM, Hoeflich KP, Haverty PM, et al. ERK inhibition overcomes acquired resistance to MEK inhibitors. Mol Cancer Ther 2012;11:1143-54.

HAUSCHILD A, Grob J-J, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomized controlled trial. Lancet 2012;380:358-65.

HAYES TK, Neel NF, Hu C, Gautam P, Chenard M, Long B, et al. Long-Term ERK Inhibition in KRAS-Mutant Pancreatic Cancer Is Associated with MYC Degradation and Senescence-like Growth Suppression. Cancer Cell 2016;29:75-89.

HEZEL AF, Noel MS, Allen JN, Abrams TA, Yurgelun M, Faris JE, et al. Phase II study of gemcitabine, oxaliplatin in combination with panitumumab in KRAS wild-type unresectable or metastatic biliary tract and gallbladder cancer. Br J Cancer 2014;111:430-6.

JHA S, Morris EJ, Hruza A, Mansueto MS, Schroeder G, Arbanas J, et al. Dissecting therapeutic resistance to ERK inhibition. Mol Cancer Ther 2016;15:548-59.

JOHANNESSEN, C. M., et al. COT/MAP3K8 drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature (2010);468(7326):968-972.

JOHNSON DB, Menzies AM, Zimmer L, Eroglu Z, Ye F, Zhao S, et al. Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behavior, and phenotypic associations of resistance mechanisms. Eur J Cancer 2015;51:2792-9.

KANDA M, Matthaei H, Wu J, Hong SM, Yu J, Borges M, et al. Presence of somatic Mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology 2012;142:730-733.

KHATTAK M, Fisher R, Turajlic S, Larkin J. Targeted therapy and immunotherapy in advanced melanoma: an evolving paradigm. Ther Adv Med Oncol 2013;5:105-18.

KING, Alastair J., et al. "Dabrafenib; preclinical characterization, increased efficacy when combined with trametinib, while BRAF/MEK tool combination reduced skin lesions." PloS one 8.7 (2013): e67583.

LARKIN J, Ascierto PA, Dréno B, Atkinson V, Liszkay G, Maio M, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 2014;371:1867-76.

LITTLE, A.S., et al., Amplification of the Driving Oncogene, KRAS or BRAF, Underpins Acquired Resistance to MEK1/2 Inhibitors in Colorectal Cancer Cells. Sci. Signal. 4, ra17 (2011).

LIU, Dingxie, et al. "BRAF V600E maintains proliferation, transformation, and tumorigenicity of BRAF-mutant papillary thyroid cancer cells." Journal of Clinical Endocrinology & Metabolism 92.6 (2007): 2264-2271.

LIU B, Fu L, Zhang C, Zhang L, Zhang Y, Ouyang L, et al. Computational design, chemical synthesis, and biological evaluation of a novel ERK inhibitor (BL-EI001) with apoptosis-inducing mechanisms in breast cancer. Oncotarget 2015;6:6762-75.

LONG GV, Fung C, Menzies AM, Pupo GM, Carlino MS, Hyman J, et al. Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma. Nat Commun 2014;5:5694.

LONG GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomized controlled trial. Lancet 2015;386:444-51.

MANANDHAR SP, Hildebrandt ER, Schmidt WK. Small-molecule inhibitors of the Rce1p CaaX protease. J Biomol Screen. 2007;12(7):983-993.

MASSEY PR, Prasad V, Figg WD, Fojo T. Multiplying therapies and reducing toxicity in metastatic melanoma. Cancer Biol Ther 2015;16:1014-8.

MAURER, T, Garrenton, LS, Oh, A, Pitts, K, Anderson, DJ, Skelton, NJ, Fauber, BP, Pan, B, Malek, S, Stokoe, D, Ludlam, MJC, Bowman, KK, Wu, J, Giannetti, AM, Starovasnik, MA, Mellman, I, Jackson, PK, Rudolph, J, Wang, W, Fang, G. Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity. PNAS. 2012;109(14):5299-304.

MCARTHUR GA, Chapman PB, Robert C, Larkin J, Haanen JB, Dummer R, et al. Safety and efficacy of vemurafenib in BRAFv600E and BRAFv600K mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomized, open-label study. Lancet Oncol 2014;15:323-32.

MEKINIST [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014.

METZKER, Emerging technologies in DNA sequencing Genome Res. 2005. 15: 1767-1776.

MITTAL, Rohit et al. "The acetyltransferase activity of the bacterial toxin YopJ of Yersinia is activated by eukaryotic host cell inositol hexakisphosphate." Journal of Biological Chemistry 285.26 (2010): 19927-19934.

MORRIS EJ, Jha S, Restaino CR, Dayananth P, Zhu H, Cooper A, et al. Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors. Cancer Discov 2013;3:742-50.

NAZARIAN, R., et al. Melanomas acquire resistance to B-RAF (V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010; 468(7326):973-977.

NIKOLAEV SI, Rimoldi D, Iseli C, Valsesia A, Robyr D, Gehrig C, et al. Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma. Nat Genet 2012;44:133-9.

NILSSON, M., et al. Padlock probes: circularizing oligonucleotides for localized DNA detection. Science. 1994, no.265, p.2085-2088.

O'HARA AJ, Bell DW. The genomics and genetics of endometrial cancer. Adv Genomics Genet 2012;2012:33-47.

OJESINA AI, Lichtenstein L, Freeman SS, Pedamallu CS, Imaz-Rosshandler I, Pugh TJ, et al. Landscape of genomic alterations in cervical carcinomas. Nature 2014;506:371-5.

OTA et al., Single nucleotide polymorphism detection by polymerase chain reaction-restriction fragment length polymorphism. Nat Protoc. 2007;2(11):2857-64.

PARAISO KHT, Fedorenko IV, Cantini LP, Munko AC, Hall M, Sondak VK, et al. Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy. Br J Cancer 2010;102:1724-30.

PATGIRI A, Yadav, KK, Arora, PS, Bar-Sagi, D. An orthosteric inhibitor of the Ras-Sos interaction. Nat Chem Biol. 2011;7:585-587.

PENNYCUICK A, Simpson T, Crawley D, Lal R, Santis G, Cane P, et al. Routine EGFR and KRAS mutation analysis using COLD-PCR in non-small cell lung cancer. Int J Clin Pract 2012;66:748-52.

PORTER SB, Hildebrandt ER, Breevoort SR, Mokry DZ, Dore TM, Schmidt WK. Inhibition of the CaaX proteases Rce1p and Ste24p by peptidyl (acyloxy)methyl ketones. Biochim Biophys Acta.2007;1773(6):853-862.

POULIKAKOS PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 2011;480:387-90.

QUEIROLO P, Picasso V, Spagnolo F. Combined BRAF and MEK inhibition for the treatment of BRAF-mutated metastatic melanoma. Cancer Treat Rev 2015;41:519-26.

RASOLA A, Sciacovelli M, Chiara F, Pantic B, Brusilow WS, Bernardi P. Activation of mitochondrial ERK protects cancer cells from death through inhibition of the permeability transition. Proc Natl Acad Sci U S A 2010;107:726-31.

RIZOS H, Menzies AM, Pupo GM, Carlino MS, Fung C, Hyman J, et al. BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact. Clin Cancer Res 2014;20:1965-77.

ROBERT C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 2015;372:30-9.

ROMEO Y, Zhang X, Roux PP. Regulation and function of the RSK family of protein kinases. Biochem J 2012;441:553-69.

RUDOLPH J, Xiao Y, Pardi A, Ahn NG. Slow inhibition and conformation selective properties of extracellular signal-regulated kinase 1 and 2 inhibitors. Biochemistry 2015;54:22-31.

SHAUL YD, Seger R. The MEK/ERK cascade: from signaling specificity to diverse functions. Biochim Biophys Acta 2007;1773:1213-26.

SHI H, Hugo W, Kong X, Hong A, Koya RC, Moriceau G, et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov 2014;4:80-93.

SHIMA, F, Yoshikawa, Y, Ye, M, Araki, M, Matsumoto, S, Liao, J, Hu, L, Sugimoto, T, Ijiri, Y, Takeda, A, Nishiyama, Y, Sato, C, Muraoka, S, Tamura, A, Osoda, T, Tsuda, K-I, Miyakawa, T, Fukunishi, H, Shimada, J, Kumasaka, Yamamoto, M, Kataoka, T. In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras-effect interaction. PNAS. 2013;110(20):8182-7.

SCHUBBERT S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 2007;7:295-308.

SUN C, Hobor S, Bertotti A, Zecchin D, Huang S, Galimi F, et al. Intrinsic resistance to MEK inhibition in KRAS mutant lung and colon cancer through transcriptional induction of ERBB3. Cell Rep 2014;7:86-93.

TAFLINAR [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2015.

TRUNZER K, Pavlick AC, Schuchter L, Gonzalez R, McArthur GA, Hutson TE, et al. Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma. J Clin Oncol 2013;31:1767-74.

VILLANUEVA, J., et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell. 2010;18:683-695.

WAGLE, N., et al. Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. Journal of Clinical Oncology 2011;29(22):3085-3096.

WAGLE N, Van Allen EM, Treacy DJ, Frederick DT, Cooper ZA, Taylor-Weiner A, et al. MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition. Cancer Discov 2014;4:61-8.

Wainstein E, Seger R. The dynamic subcellular localization of ERK: mechanisms of translocation and role in various organelles. Curr Opin Cell Biol 2016;39:15-20.

WANG, H., et al. Identification of the MEK1(F129L) activating mutation as a potential mechanism of acquired resistance to MEK inhibition in human cancers carrying the B-RAF V600E mutation. Cancer Res (2011);71(16):5535-45.

YANG W, Soares J, Greninger P, Edelman EJ, Lightfoot H, Forbes S, et al. Genomics of Drug Sensitivity in Cancer (GDSC): a resource for therapeutic biomarker discovery in cancer cells. Nucleic Acids Res 2013;41:D955-D961.

YAO Z, Torres NM, Tao A, Gao Y, Luo L, Li Q, et al. BRAF Mutants Evade ERK-Dependent Feedback by Different Mechanisms that Determine Their Sensitivity to Pharmacologic Inhibition. Cancer Cell 2015;28:370-83.

YOHE S. Molecular genetic markers in acute myeloid leukemia. J Clin Med 2015;4:460-78.

ZELBORAF [package insert]. South San Francisco, CA: Genentech USA, Inc.; 2015.

All documents cited in this application are incorporated by reference in their entirety.

Although the present description has described illustrative embodiments of the present invention, it should be understood that the invention is not limited to the embodiments described and that various other changes or modifications may be made by one skilled in the art without departing from the scope and spirit of the invention.

--->

LIST OF SEQUENCES:

<110> Biomed Valley Discoveries, Inc.

<120> COMPOSITIONS AND METHODS FOR TREATING MALIGNANT TUMOR WITH

ATYPICAL BRAF MUTATIONS

<130> C065272/2391211

<140> US 62/506,995

<141> 2017-05-16

<160> 44

<210> 1

<211> 2949

<212> DNA

<213> Homo sapiens

<400> 1

cgcctccctt ccccctcccc gcccgacagc ggccgctcgg gccccggctc tcggttataa

60

gatggcggcg ctgagcggtg gcggtggtgg cggcgcggag ccgggccagg ctctgttcaa

120

cggggacatg gagcccgagg ccggcgccgg cgccggcgcc gcggcctctt cggctgcgga

180

ccctgccatt ccggaggagg tgtggaatat caaacaaatg attaagttga cacaggaaca

240

tatagaggcc ctattggaca aatttggtgg ggagcataat cccacatcaa tatatctgga

300

ggcctatgaa gaatacacca gcaagctaga tgcactccaa caaagagaac aacagttatt

360

ggaatctctg gggaacggaa ctgatttttc tgtttctagc tctgcatcaa tggataccgt

420

tacatcttct tcctcttcta gcctttcagt gctaccttca tctctttcag tttttcaaaa

480

tccccacagat gtggcacgga gcaaccccaa gtcaccacaa aaacctatcg ttagagtctt

540

cctgcccaac aaacagagga cagtggtacc tgcaaggtgt ggagttacag tccgagacag

600

tctaaagaaa gcactgatga tgagaggtct aatcccagag tgctgtgctg tttacagaat

660

tcaggatgga gagaagaaac caattggttg ggacactgat atttcctggc ttactggaga

720

agaattgcat gtggaagtgt tggagaatgt tccacttaca acacacaact ttgtacgaaa

780

aacgtttttc accttagcat tttgtgactt ttgtcgaaag ctgcttttcc agggtttccg

840

ctgtcaaaca tgtggttata aatttcacca gcgttgtagt acagaagttc cactgatgtg

900

tgttaattat gaccaacttg atttgctgtt tgtctccaag ttctttgaac accacccaat

960

accaccaggaa gaggcgtcct tagcagagac tgccctaaca tctggatcat ccccttccgc

1020

acccgcctcg gactctattg ggccccaaat tctcaccagt ccgtctcctt caaaatccat

1080

tccaattcca cagcccttcc gaccagcaga tgaagatcat cgaaatcaat ttgggcaacg

1140

agaccgatcc tcatcagctc ccaatgtgca tataaacaca atagaacctg tcaatattga

1200

tgacttgatt agagaccaag gatttcgtgg tgatggagga tcaaccacag gtttgtctgc

1260

taccccccct gcctcattac ctggctcact aactaacgtg aaagccttac agaaatctcc

1320

aggacctcag cgagaaagga agtcatcttc atcctcagaa gacaggaatc gaatgaaaac

1380

acttggtaga cgggactcga gtgatgattg ggagattcct gatgggcaga ttacagtggg

1440

acaaagaatt ggatctggat catttggaac agtctacaag ggaaagtggc atggtgatgt

1500

ggcagtgaaa atgttgaatg tgacagcacc tacacctcag cagttacaag ccttcaaaaa

1560

tgaagtagga gtactcagga aaacacgaca tgtgaatatc ctactcttca tgggctattc

1620

cacaaagcca caactggcta ttgttaccca gtggtgtgag ggctccagct tgtatcacca

1680

tctccatatc attgagacca aatttgagat gatcaaactt atagatattg cacgacagac

1740

tgcacaggc atggattact tacacgccaa gtcaatcatc cacagagacc tcaagagtaa

1800

taatatattt cttcatgaag acctcacagt aaaaataggt gattttggtc tagctacagt

1860

gaaatctcga tggagtgggt cccatcagtt tgaacagttg tctggatcca ttttgtggat

1920

ggcaccagaa gtcatcagaa tgcaagataa aaatccatac agctttcagt cagatgtata

1980

tgcatttgga attgttctgt atgaattgat gactggacag ttaccttatt caaacatcaa

2040

caacagggac cagataattt ttatggtggg acgaggatac ctgtctccag atctcagtaa

2100

ggtacggagt aactgtccaa aagccatgaa gagattaatg gcagagtgcc tcaaaaagaa

2160

aagagatgag agaccactct ttccccaaat tctcgcctct attgagctgc tggcccgctc

2220

attgccaaaa attcaccgca gtgcatcaga accctccttg aatcgggctg gtttccaaac

2280

agaggatttt agtctatatg cttgtgcttc tccaaaaaca cccatccagg cagggggata

2340

tggtgcgttt cctgtccact gaaacaaatg agtgagagag ttcaggagag tagcaacaaa

2400

aggaaaataa atgaacatat gtttgcttat atgttaaatt gaataaaata ctctcttttt

2460

ttttaaggtg aaccaaagaa cacttgtgtg gttaaagact agatataatt tttccccaaa

2520

ctaaaattta tacttaacat tggattttta acatccaagg gttaaaatac atagacattg

2580

ctaaaaattg gcagagcctc ttctagaggc tttactttct gttccgggtt tgtatcattc

2640

acttggttat tttaagtagt aaacttcagt ttctcatgca acttttgttg ccagctatca

2700

catgtccact agggactcca gaagaagacc ctacctatgc ctgtgtttgc aggtgagaag

2760

ttggcagtcg gttagcctgg gttagataag gcaaactgaa cagatctaat ttaggaagtc

2820

agtagaattt aataattcta ttattattct taataatttt tctataacta tttcttttta

2880

taacaatttg gaaaatgtgg atgtctttta tttccttgaa gcaataaact aagtttcttt

2940

ttataaaaa

2949

<210> 2

<211> 766

<212> PROTEIN

<213> Homo sapiens

<400> 2

Met Ala Ala Leu Ser Gly Gly Gly Gly Gly Gly Ala Glu Pro Gly Gln

1 5 10 15

Ala Leu Phe Asn Gly Asp Met Glu Pro Glu Ala Gly Ala Gly Ala Gly

20 25 30

Ala Ala Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp

35 40 45

Asn Ile Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu

50 55 60

Leu Asp Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu

65 70 75 80

Ala Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu

85 90 95

Gln Gln Leu Leu Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser

100 105 110

Ser Ser Ala Ser Met Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu

115 120 125

Ser Val Leu Pro Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val

130 135 140

Ala Arg Ser Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe

145 150 155 160

Leu Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr

165 170 175

Val Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro

180 185 190

Glu Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile

195 200 205

Gly Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val

210 215 220

Glu Val Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys

225 230 235 240

Thr Phe Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe

245 250 255

Gln Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys

260 265 270

Ser Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu

275 280 285

Leu Phe Val Ser Lys Phe Phe Glu His His Pro Ile Pro Gln Glu Glu

290 295 300

Ala Ser Leu Ala Glu Thr Ala Leu Thr Ser Gly Ser Ser Pro Ser Ala

305 310 315 320

Pro Ala Ser Asp Ser Ile Gly Pro Gln Ile Leu Thr Ser Pro Ser Pro

325 330 335

Ser Lys Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp

340 345 350

His Arg Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn

355 360 365

Val His Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg

370 375 380

Asp Gln Gly Phe Arg Gly Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala

385 390 395 400

Thr Pro Pro Ala Ser Leu Pro Gly Ser Leu Thr Asn Val Lys Ala Leu

405 410 415

Gln Lys Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser

420 425 430

Glu Asp Arg Asn Arg Met Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp

435 440 445

Asp Trp Glu Ile Pro Asp Gly Gln Ile Thr Val Gly Gln Arg Ile Gly

450 455 460

Ser Gly Ser Phe Gly Thr Val Tyr Lys Gly Lys Trp His Gly Asp Val

465 470 475 480

Ala Val Lys Met Leu Asn Val Thr Ala Pro Thr Pro Gln Gln Leu Gln

485 490 495

Ala Phe Lys Asn Glu Val Gly Val Leu Arg Lys Thr Arg His Val Asn

500 505 510

Ile Leu Leu Phe Met Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val

515 520 525

Thr Gln Trp Cys Glu Gly Ser Ser Leu Tyr His His Leu His Ile Ile

530 535 540

Glu Thr Lys Phe Glu Met Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr

545 550 555 560

Ala Gln Gly Met Asp Tyr Leu His Ala Lys Ser Ile Ile His Arg Asp

565 570 575

Leu Lys Ser Asn Asn Ile Phe Leu His Glu Asp Leu Thr Val Lys Ile

580 585 590

Gly Asp Phe Gly Leu Ala Thr Val Lys Ser Arg Trp Ser Gly Ser His

595 600 605

Gln Phe Glu Gln Leu Ser Gly Ser Ile Leu Trp Met Ala Pro Glu Val

610 615 620

Ile Arg Met Gln Asp Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr

625 630 635 640

Ala Phe Gly Ile Val Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr

645 650 655

Ser Asn Ile Asn Asn Arg Asp Gln Ile Ile Phe Met Val Gly Arg Gly

660 665 670

Tyr Leu Ser Pro Asp Leu Ser Lys Val Arg Ser Asn Cys Pro Lys Ala

675 680 685

Met Lys Arg Leu Met Ala Glu Cys Leu Lys Lys Lys Arg Asp Glu Arg

690 695 700

Pro Leu Phe Pro Gln Ile Leu Ala Ser Ile Glu Leu Leu Ala Arg Ser

705 710 715 720

Leu Pro Lys Ile His Arg Ser Ala Ser Glu Pro Ser Leu Asn Arg Ala

725 730 735

Gly Phe Gln Thr Glu Asp Phe Ser Leu Tyr Ala Cys Ala Ser Pro Lys

740 745 750

Thr Pro Ile Gln Ala Gly Gly Tyr Gly Ala Phe Pro Val His

755 760 765

<210> 3

<211> 3906

<212> DNA

<213> Rattus norvegicus

<400> 3

atggcggcgc tgagtggcgg cggtggcagc agcagcggtg gcggtggcgg cggcggcggc

60

ggcggtggtg gcggcggcgg cggcggcgcc gaacagggac aggctctgtt caatggcgac

120

atggagccgg aggccggcgc tggcgccgcg gcctcttcgg ccgcggaccc ggccattcct

180

gaagaggtgt ggaatatcaa gcaaatgatt aagttgacac aggaacatat agaggcccta

240

ttggacaagt ttggtgggga gcataaccca ccgtcaatat acctggaggc ctatgaagag

300

tacaccagca agctagatgc ccttcagcag agagagcagc agctgttgga atccctggtt

360

tttcaaactc ccacagatgt atcacggaac aaccccaagt caccacagaa acctatcgtt

420

cgtgtcttcc tgcccaacaa acagaggaca gtggtgcccg caagatgtgg tgtaacggtc

480

cgagacagtc taaagaaagc actaatgatg aggggtctca tcccagagtg ctgtgctgtt

540

tacagaattc aggacggaga gaagaaacca attggctggg acactgacat ttcctggctt

600

actggagagg agctacatgt tgaagtacta gagaatgttc ctctgacaac ccacaacttc

660

gtacggaaaa cttttttcac cttagcattt tgtgactttt gccgaaagct gcttttccag

720

ggtttccgct gtcaaacatg tggttataag tttcaccagc gttgtagtac agaggttcca

780

ctgatgtgtg ttaattatga ccaacttgat ttgctgtttg tctccaagtt ctttgagcat

840

caccagtac cacaggagga ggccttctca gcagagacta cccttccatc tggatgctct

900

tccgcacccc cctcagactc tattgggccc caaatcctca ccagtccatc tccttcaaaa

960

tccattccaa ttccacagcc cttccggcca gcagatgaag atcatcgcaa tcagtttggg

1020

caacgagacc gctcctcctc cgctcccaat gttcatataa acacaatcga acctgtcaat

1080

attgatgaaa aattcccaga agtggaatta caggatcaaa gggatttgat tagagaccag

1140

gggtttcgtg gggatggagc ccctttgaac cagctgatgc gctgtcttcg gaaataccaa

1200

tcccggactc ccagccccct cctccattct gtccccagtg aaatagtgtt tgattttgag

1260

cctggcccag tgttcagagg gtcaaccaca ggcttgtcgg ccaccccacc tgcctcatta

1320

cctggctcac tcactaacgt gaaagcctta cagaaatctc caggacctca gcgggaaagg

1380

aagtcctcct cctcctcctc ctccacggaa gacagaagtc ggatgaaaac acttggtaga

1440

agagattcaa gtgatgattg ggagattcct gatggacaga ttacagtggg acagagaatt

1500

ggatctgggt cctttggaac tgtctacaag ggaaagtggc atggcgacgt ggcagtgaaa

1560

atgctgaatg tgacagcacc cacacctcag cagttacagg ccttcaaaaa cgaagtcgga

1620

gtactcagga aaactcgaca tgtgaacatc ctccttttca tgggctattc tacaaagcca

1680

cagctggcta ttgttacaca gtggtgtgaa ggctccagct tatatcacca tctccacatc

1740

attgagacca aatttgagat gatcaaactt atagatattg cacggcagac tgcacagggc

1800

atggattact tacacgccaa gtcaatcatc cacagagacc tcaagagtaa taatatattt

1860

cttcatgaag acctcacggt aaaaataggt gactttggtt tagccacagt gaagtcccga

1920

tggagtgggt cccatcagtt tgaacagttg tctggatcta ttttgtggat ggcacccgaa

1980

gtaatcagaa tgcaagataa aaacccatat agctttcagt cagacgtgta tgcatttggg

2040

attgttctgt atgaactgat gactggtcag ctaccttatt caaacatcaa caacagggat

2100

cagataattt ttatggtggg acgaggatac ctatctccag atctcagtaa ggtacggagt

2160

aactgtccaa aagccatgaa gagattaatg gcagagtgcc tcaaaaagaa aagagacgag

2220

agaccactct ttccccaaat tctcgcctct attgagctgc tggcccgctc attgccaaaa

2280

attcaccgca gtgcatcaga accctccttg aatcgggctg gtttccaaac agaagatttt

2340

agtctgtatg cttgtgcttc tccaaaaaca cccatccaag cagggggata tggagaattt

2400

gcagccttca agtagccact ccatcatggc agcatctact ctttatttct taagtcttgt

2460

gttcatacaa tttgttaaca tcaaaacaca gttctgttcc tcaaattttt tttaaagata

2520

caaaattttc aatgcataag ctcgtgtgga acagaatgga atttcctatt caacaaaaga

2580

gggaagaatg ttttaggaac cagaattctc tgctgcccgt gtttcttctt caacacaaat

2640

atcatgtgca tacaactctg cccattccca agaagaaaga gggagagaccc cgaattctgc

2700

ccttttggtg gtcaggcatg atggaaagaa tttgctgctg cagcttggga aaaattgcta

2760

tggaaagtct gccagtcaac tttgcccttc taaccaccag atccatttgt ggctggtcat

2820

ctgatggggc gatttcaatc accaagcatc gttcttgcct gttgtgggat tatgtcgtgg

2880

agcactttcc ctatccacca ccgttaattt ccgagggatg gagtaaatgc agcataccct

2940

ttgtgtagca cctgtccagt cctcaaccaa tgctatcaca gtgaagctct ttaaatttaa

3000

gtggtgggtg agtgttgagg agagactgcc ttggggggcag agaaaagggg atgctgcatc

3060

ttcttcctca cctccagctc tctcacctcg ggttgccttg cacactgggc tccgcctaac

3120

cactcgggct gggcagtgct ggcacacatt gccgcctttt ctcattgggt ccagcaattg

3180

agcagaggt tgggggattg tttcctccac aatgtagcaa attctcagga aaatacagtc

3240

catatcttcc tctcagctct tccagtcacc aaatacttac gtggctcctt tgtccaggac

3300

ataaaacacc gtggacaaca cctaattaaa agcctacaaa actgcttact gacagttttg

3360

aatgtgagac atttgtgtaa tttaaatgta aggtacaggt cttaatttct tctattaagt

3420

ttcttctatt tttatttaaa cgaagaaaat aattttcagg tttaattgga ataaacgaat

3480

acttcccaaa agactatata ccctgaaaat tatatttttg ttaattgtaa acaactttta

3540

aaaaatggtt attatccttt tctctaccta aaattatggg aaatcttagc ataatgacaa

3600

ttatttatac tttttaaata aatggtactt gctggatcca cactaacatc tttgctaaca

3660

ttcccattgt ttcttccaac ttcactccta cactacatcc tccatcctct ttctagtctt

3720

ttatctataa tatgcaacct aaaataaaag tggtggtgtc tccattcatt cttcttcttc

3780

cttttttccc caagcctggt cttcaaaagg ttgggtaatt tagtagctga gttccctagg

3840

tagaaataga actattaggg acattggggt tgtaggaaag cgtgaggcct gtcaccagtt

3900

gttctt

3906

<210> 4

<211> 804

<212> PROTEIN

<213> Rattus norvegicus

<400> 4

Met Ala Ala Leu Ser Gly Gly Gly Gly Ser Ser Ser Gly Gly Gly Gly

1 5 10 15

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Ala Glu Gln

20 25 30

Gly Gln Ala Leu Phe Asn Gly Asp Met Glu Pro Glu Ala Gly Ala Gly

35 40 45

Ala Ala Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp

50 55 60

Asn Ile Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu

65 70 75 80

Leu Asp Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu

85 90 95

Ala Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu

100 105 110

Gln Gln Leu Leu Glu Ser Leu Val Phe Gln Thr Pro Thr Asp Val Ser

115 120 125

Arg Asn Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu

130 135 140

Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val

145 150 155 160

Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu

165 170 175

Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly

180 185 190

Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu

195 200 205

Val Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr

210 215 220

Phe Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln

225 230 235 240

Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser

245 250 255

Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu Leu

260 265 270

Phe Val Ser Lys Phe Phe Glu His His Pro Val Pro Gln Glu Glu Ala

275 280 285

Phe Ser Ala Glu Thr Thr Leu Pro Ser Gly Cys Ser Ser Ala Pro Pro

290 295 300

Ser Asp Ser Ile Gly Pro Gln Ile Leu Thr Ser Pro Ser Pro Ser Lys

305 310 315 320

Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His Arg

325 330 335

Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val His

340 345 350

Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Glu Lys Phe Pro Glu Val

355 360 365

Glu Leu Gln Asp Gln Arg Asp Leu Ile Arg Asp Gln Gly Phe Arg Gly

370 375 380

Asp Gly Ala Pro Leu Asn Gln Leu Met Arg Cys Leu Arg Lys Tyr Gln

385 390 395 400

Ser Arg Thr Pro Ser Pro Leu Leu His Ser Val Pro Ser Glu Ile Val

405 410 415

Phe Asp Phe Glu Pro Gly Pro Val Phe Arg Gly Ser Thr Thr Gly Leu

420 425 430

Ser Ala Thr Pro Pro Ala Ser Leu Pro Gly Ser Leu Thr Asn Val Lys

435 440 445

Ala Leu Gln Lys Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser

450 455 460

Ser Ser Ser Ser Thr Glu Asp Arg Ser Arg Met Lys Thr Leu Gly Arg

465 470 475 480

Arg Asp Ser Ser Asp Asp Trp Glu Ile Pro Asp Gly Gln Ile Thr Val

485 490 495

Gly Gln Arg Ile Gly Ser Gly Ser Phe Gly Thr Val Tyr Lys Gly Lys

500 505 510

Trp His Gly Asp Val Ala Val Lys Met Leu Asn Val Thr Ala Pro Thr

515 520 525

Pro Gln Gln Leu Gln Ala Phe Lys Asn Glu Val Gly Val Leu Arg Lys

530 535 540

Thr Arg His Val Asn Ile Leu Leu Phe Met Gly Tyr Ser Thr Lys Pro

545 550 555 560

Gln Leu Ala Ile Val Thr Gln Trp Cys Glu Gly Ser Ser Leu Tyr His

565 570 575

His Leu His Ile Ile Glu Thr Lys Phe Glu Met Ile Lys Leu Ile Asp

580 585 590

Ile Ala Arg Gln Thr Ala Gln Gly Met Asp Tyr Leu His Ala Lys Ser

595 600 605

Ile Ile His Arg Asp Leu Lys Ser Asn Asn Ile Phe Leu His Glu Asp

610 615 620

Leu Thr Val Lys Ile Gly Asp Phe Gly Leu Ala Thr Val Lys Ser Arg

625 630 635 640

Trp Ser Gly Ser His Gln Phe Glu Gln Leu Ser Gly Ser Ile Leu Trp

645 650 655

Met Ala Pro Glu Val Ile Arg Met Gln Asp Lys Asn Pro Tyr Ser Phe

660 665 670

Gln Ser Asp Val Tyr Ala Phe Gly Ile Val Leu Tyr Glu Leu Met Thr

675 680 685

Gly Gln Leu Pro Tyr Ser Asn Ile Asn Asn Arg Asp Gln Ile Ile Phe

690 695 700

Met Val Gly Arg Gly Tyr Leu Ser Pro Asp Leu Ser Lys Val Arg Ser

705 710 715 720

Asn Cys Pro Lys Ala Met Lys Arg Leu Met Ala Glu Cys Leu Lys Lys

725 730 735

Lys Arg Asp Glu Arg Pro Leu Phe Pro Gln Ile Leu Ala Ser Ile Glu

740 745 750

Leu Leu Ala Arg Ser Leu Pro Lys Ile His Arg Ser Ala Ser Glu Pro

755 760 765

Ser Leu Asn Arg Ala Gly Phe Gln Thr Glu Asp Phe Ser Leu Tyr Ala

770 775 780

Cys Ala Ser Pro Lys Thr Pro Ile Gln Ala Gly Gly Tyr Gly Glu Phe

785 790 795 800

Ala Ala Phe Lys

<210> 5

<211> 9728

<212> DNA

<213> Mus musculus

<400> 5

ccctcaggct cggctgcgcc ggggccgccg gcgggttcca gaggtggcct ccgccccggc

60

cgctccgccc acgccccccg cgcctccgcg cccgcctccg cccgccctgc gcctcccttc

120

cccctccccg ccccgcggcg gccgctcggc ccggctcgcg cttcgaagat ggcggcgctg

180

agtggcggcg gtggcagcag cagcggtggc ggcggcggcg gtggcggcgg cggtggcggt

240

ggcgacggcg gcggcggcgc cgagcagggc caggctctgt tcaatggcga catggagccg

300

gaggccggcg ctggcgccgc ggcctcttcg gctgcggacc cggccattcc tgaagaggta

360

tggaatatca agcaaatgat taagttgaca caggaacata tagaggccct attggacaaa

420

tttggtggag agcataaccc accatcaata tacctggagg cctatgaaga gtacaccagc

480

aagctagatg cccttcagca aagagaacag cagcttttgg aatccctggt ttttcaaact

540

cccacagatg catcacggaa caaccccaag tcaccacaga aacctatcgt tagagtcttc

600

ctgcccaaca aacagaggac agtggtaccc gcaagatgtg gtgttacagt tcgagacagt

660

ctaaagaaag cactgatgat gagaggtctc atcccagaat gctgtgctgt ttacagaatt

720

caggatggag agaagaaacc aattggctgg gacacggaca tttcctggct tactggagag

780

gagttacatg ttgaagtact ggagaatgtc ccacttacaa cacacaactt tgtacggaaa

840

acttttttca ccttagcatt ttgtgacttt tgccgaaagc tgcttttcca gggtttccgt

900

tgtcaaacat gtggttataa atttcaccag cgttgtagta cagaggttcc actgatgtgt

960

gtaaattatg accaacttga tttgctgttt gtctccaagt tctttgagca tcacccagta

1020

ccacaggagg aggcctcctt cccagagact gcccttccat ctggatcctc ttccgcaccc

1080

ccctcagact ctactgggcc ccaaatcctc accagtccat ctccttcaaa atccattcca

1140

attccacagc ccttccgacc agcagatgaa gatcatcgca atcagtttgg gcaacgagac

1200

cggtcctcct cagctcccaa tgttcatata aacacaattg agcctgtgaa tatcgatgaa

1260

aaattcccag aagtggaatt acaggatcaa agggatttga ttagagacca ggggtttcgt

1320

ggtgatggag cccccttgaa ccaactgatg cgctgtcttc ggaaatacca atcccggact

1380

cccagccccc tcctccattc tgtccccagt gaaatagtgt ttgattttga gcctggccca

1440

gtgttcagag ggtcaaccac aggcttgtcc gccaccccgc ctgcctcatt acctggctca

1500

ctcactaacg tgaaagcctt acagaaatct ccaggtcctc agcgggaaag gaagtcatct

1560

tcttcctcat cctcggagga cagaagtcgg atgaaaacac ttggtagaag agattcaagt

1620

gatgactggg agattcctga tggacagatt acagtgggac agagaattgg atctgggtca

1680

tttggaactg tctacaaggg aaagtggcat ggtgatgtgg cagtgaaaat gttgaatgtg

1740

acagcaccca cacctcaaca gctacaggcc ttcaaaaatg aagtaggagt gctcaggaaa

1800

actcgacatg tgaatatcct ccttttcatg ggctattcta caaagccaca actggcaatt

1860

gttacacagt ggtgtgaggg ctccagctta tatcaccatc tccacatcat tgagaccaaa

1920

tttgagatga tcaaacttat agatattgct cggcagactg cacagggcat ggattactta

1980

cacgccaagt caatcatcca cagagacctc aagagtaata atatatttct tcatgaagac

2040

ctcacggtaa aaataggtga ctttggtcta gccacagtga aatctcggtg gagtgggtcc

2100

catcagtttg aacagttgtc tggatctatt ttgtggatgg caccagaagt aatcagaatg

2160

caagataaaa acccgtatag ctttcagtca gacgtgtatg cgtttgggat tgttctgtac

2220

gaactgatga ccggccagct accttattca aacatcaaca acagggatca gataattttt

2280

atggtgggac gaggatacct atctccagat ctcagtaagg tacggagtaa ctgtccaaaa

2340

gccatgaaga gattaatggc agagtgcctc aaaaagaaaa gagacgagag accactcttt

2400

ccccaaattc tcgcctccat tgagctgctg gcccgctcat tgccaaaaat tcaccgcagt

2460

gcatcagaac cttccttgaa tcgggctggt ttccaaacag aagattttag tctgtatgct

2520

tgtgcttctc cgaaaacacc catccaagca gggggatatg gagaatttgc agccttcaag

2580

tagccagtcc atcatggcag catctactct ttatttctta agtcttgtgt tcatacagtt

2640

tgttaacatc aaaacacagt tctgttcctc aaaaaatttt ttaaagatac aaaattttca

2700

atgcataagt tcatgtggaa cagaatggaa tttcctattc aacaaaagag ggaagaatgt

2760

tttaggaacc agaattctct gctgcccgtg tttcttcttc aacataacta tcacgtgcat

2820

acaagtctgc ccattcccaa gaagaaagag gagagaccct gaattctgcc cttttggtgg

2880

tcaggcatga tggaaagaat ttgctgctgc agcttgggaa aattgctatg gaaagtctgc

2940

cagtcgactt tgcccttcta accaccagat cagcctgtgg ctggtcatct gatggggcga

3000

tttccatcac caagcatcgt tcttgcctat tctgggatta tgttgtggag cactttccct

3060

gtccagcacc gttcatttct gagggatgga gtaaatgcag cattcccttg tgtagcgcct

3120

gttcagtcct cagcagctgc tgtcacagcg aagcttttta cagttaagtg gtggggggaga

3180

gttgaggaga gcctgcctcg gggcagagaa aagggggtgc tgcatcttct tcctcacctc

3240

cagctctctc acctcgggtt gccttgctca ctgggctccg cctaaccact caggctgctc

3300

agtgctggca cacattgcct tcttttctca ttgggtccag caattgagga gagggttggg

3360

ggattgtttc ctcctcaatg tagcaaattc tcaggaaaat acagtccata tcttcctctc

3420

agctcttcca gtcaccaaat acttacgtgg ctcctttgtc caggacataa aacaccgtgg

3480

acaacaccta attaaaagcc tacaaaactg cttactgaca gttttgaatg tgagacactt

3540

gtgtaattta aatgtaaggt acaggtttta atttctgagt ttcttctatt tttatttaaa

3600

agaagaaaat aattttcagt tttaattgga ataaatgagt acttcccaca agactatata

3660

ccctgaaaat tatatttttg ttaattgtaa acaactttta aagaataatt attatccttt

3720

tctctaccta aaaattatgg ggaatcttag cataatgaca attatttata ctttttaaat

3780

aaatggtact tgctggatcc acactaacat ctttgctaac aatcccattg tttcttccaa

3840

cttaactcct acactacatc ctacatcctc tttctagtct tttatctata atatgcaacc

3900

taaaataaac gtggtggcgt ctccattcat tctccctctt cctgttttcc ccaagcctgg

3960

tcttcaaaag gttgggtaat cggtccctga gctccctagc tggcaatgca actattaggg

4020

acattggagt tgcaggagag caggaagcct gtccccagct gttcttctag aaccctaaat

4080

cttatctttg cacagatcaa aagtatcacc tcgtcacagt tctccttagc ctttacttac

4140

aggtaatata aataaaaatc accatagtag taaagaaaac aactggatgg attgatgacc

4200

agtacctctc agagccagga atcttgaatc tccaggattt atacgtgcaa atttaaggag

4260

atgtacttag caacttcaag ccaagaactt ccaaaatact agcgaatcta aaataaaatg

4320

gaattttgag ttatttttaa agttcaaatt ataattgata ccactatgta tttaagccta

4380

ctcacagcaa gttagatgga ttttgctaaa ctcattgcca gactgtggtg gtggtggtgg

4440

tagtgtgcac ctttaatcca agcaactcag caatcagaat gaggtaaatc tctgtgaata

4500

caaggcctgc ctagtctgca gcgctagttc caggatagcc agggctacac acacaaaaac

4560

cctctctcaa aaaaaacaaa attaattagt tgataataaa aaataactaa agtatcatca

4620

aaggaaggcc tactggaagt tttatatatt cccagtaaat tgaaaaatat tctgaagtta

4680

ttaaccagtt agcaacaatg tgtttttaag tcttacataa acagagcaaa gtcttcaaat

4740

gtttcagagc tgagaagata attgtgcttg atatgaaaaa tagcctctcc atatgatgtg

4800

ccacattgaa aggcgtcatt acccttttaa atacttctta atgtggcttt gttcccttta

4860

cccaggatta gctagaaaga gctaggtagg cttcggccac agttgcacat ttcgggcctg

4920

ctgaagaatg ggagctttga aggctggcct tggtggagga gcccctcagt gctggagggt

4980

ggggcgtgta cgcagcatgg aagtggtcta gacagagtgc aaagggacag acttctttct

5040

cattttagta tagggtgatg tctcacttga aatgagaaag tagagttgat attaaacgaa

5100

gctgtgccca gaaaccaggc tcagggtatt gtgagatttt ctttttaaat agagaatata

5160

aaagatagaa ataaatattt aaaccttcct tcttattttc tatcaaatag atttttttta

5220

tcatttgcaa acaacataaa aaaaggtttc ttttgtgggg ttttctttcc ttcttttttt

5280

tttttttttt tttttaagac tgcagataat cttgttgagc tcctcggaaa atacaaggaa

5340

gtccgtgttt gtgcagagcg ctttatgagt aactgtatag acagtgtggc tgcttcactc

5400

atcccagagg gctgcagctg tcggcccatg aagtggctgc agtgcctcgt gagatctgct

5460

ttgttttgtt tggagtgaag tctttgaaag gtttgagtgc aactatatag gactgttttt

5520

aaataagtag tattcctcat gaactttctc attgttaagc tacaggaccc aaactctacc

5580

actaagatat tattaacctc aaaatgtagt ttatagaagg aatttgcaaa tagaatatcc

5640

agttcgtact tatatgcatc ttcaacaaag attctctgtg acttgttgga tttggttcct

5700

gaacagccca tttctgtatt tgaggttagg agggcataat gaggcatcct aaaagacaat

5760

ctgatataaa ctgtatgcta gatgtatgct ggtaggggag aaagcattct gtaaagacat

5820

gatttaagac ttcagctctg tcaaccagaa accttgtaaa tacttcctgt cttggtgcag

5880

ccccgcccct ttgatcacac gatgttgtct tgtgcttgtc agacactgtc agagctgctg

5940

ttcgtccctc tgcagatctc acctgtcccc actgcacacc cacctcctgc ctcttgcaga

6000

cctcagcatc tagctttagt tggaaacagt tcagggttca ggtgacttct taaaaaaaaa

6060

aaaaaaccct acctcctcag aatgaggtaa tgaatagtta tttatttaaa gtatgaagag

6120

tcaggagcgc tcgaacatga aggtgattta agatggttcc tttcgtgtgt attgtagctg

6180

agcacttgtt tttgtcctaa agggcattat acatttaagc agtgattctg tttaaagatg

6240

tttttcttta aaggtgtagc tcagagtatc tgttgttgga attggtgcca gagtctgctt

6300

aatagatttc agaatcctaa gcttaagtca gtcgcatgaa gttaagtagt tatggtaaca

6360

ctttgctagc catgatataa ttctactttt taggagtagg tttggcaaaa ctgtatgcct

6420

tcaaagtgag ttggccacag ctttgtcaca tgcacagata ctcatctgaa gagactgccc

6480

agctaagagg gcggaaggat accctttttt cctacgattc gcttctttgt ccacgttggc

6540

attgttagta ctagtttatc agcaccttga ccagcagatg tcaaccaata agctattttt

6600

aaaaccatag ccagagatgg agaggtcact gtgagtagaa acagcaggac gcttacagga

6660

gtgaaatggt gtagggaggc tctagaaaaa tatcttgaca atttgccaaa tgatcttact

6720

gtgccttcat gatgcaataa aaaagctaac attttagcag aaatcagtga tttacgaaga

6780

gagtggccag tctggtttaa ctcagctggg ataatatttt tagagtgcaa tttagactgc

6840

gaagataaat gcactaaaga gtttatagcc aattcacatt tgaaaaataa gaaaatggta

6900

aattttcagt gaaatatttt tttaaagcac ataatcccta gtgtagccag aaatatttac

6960

cacatagagc agctaggctg agatacagtc cagtgacatt tctagagaaa ccttttctac

7020

tcccacgggc tcctcaaagc atggaaattt tatacaaaat gtttgacatt ttaagatact

7080

gctgtagttt agttttgaaa tagtatgtgc tgagcagcaa tcatgtacta actcagagag

7140

agaaaacaac aacaaattgt gcatctgatt tgttttcaga gaaatgctgc caacttagat

7200

actgagttct cagagcttca agtgtaaact tgcctcccaa gtcctgtttg caaatgaagt

7260

tggctagtgc tactgactgc tccagcacat gatggaaggc aggggctgt ctctgaagtg

7320

tcttctataa agggacaata gaatagtgag agacctggtc agtgtgtgtc agctggacac

7380

tccatgctat gggacttgca tcttctgtcc tcaccatccc caagacattg tgctttcctc

7440

agttgtcctc tagctgtttc actcagacac caagatgaat tactgatgcc agaaggggcc

7500

aaaatggcca gtgtgttttg ggggttgtat cagttgactg gacaataact ttaatagttt

7560

cagatcattt atttttactt ccattttgac agacatttaa atggaaattt agtcctaact

7620

tttgtcattt gaaaggaaaa attaacagtt cctataagat acttttgagg tggaatctga

7680

catcctaatt ttttttcttt tcagtgggtt tgcagcgagg gtcttgtatg cactaggcaa

7740

gggttctacc actaagccac atttcccagg aaataaaatg ttaacagtta aaacatacac

7800

acaaatacac aaacacctta ttaccacttt agtaaagtga gagatgtgcg tcctttgtct

7860

cagtctccac gatttcagct gccccttgta tgaataactc agtctcgcta aactgtttac

7920

ttttatttac ctggtttgac tagttgcagc tatataacca gttgtgcatg aggacaacag

7980

ccagtgtgtt tgttttgttt ttggtttttt gtggtacatt ttttgtaaag aattctgtag

8040

attgaagtgc tctttgaaaa cagaactgag atatatttat tcttgttagc atcaaaaaac

8100

attttgtgca aatgatttgc ttttcctggc aggctgagta ccatatccag cgcccacaat

8160

tgcgggttcc catctaccat gtccacaggg gagacagacg ggaagcacat gaggggtgtg

8220

tttacagagt tgtaggagtt atgtagttct cttgttgcct tggaaatcac tgttgtttta

8280

agactgttga acccgtgtgt ttggctgggc tgtgagttac atgaagaaac tgcaaactag

8340

catatgcaga caaagctcac agactaggcg taaatggagg aaaatggacc aaaataaggc

8400

agggtgacac ataaaccttg ggcttcggag aaaactaagg gtggagatga actataatca

8460

cctgaataca atgtaagagt gcaataagtg tgcttattct aagctgtgaa cttcttttaa

8520

atcattcctt tctaatacat ttatgtatgt tccattgctg actaaaacca gctatgagaa

8580

catatgcctt tttattcatg ttaactacca gtttaagtgg ctaaccttaa tgtcttattt

8640

atcttcattt tgtattagtt tacataccag gtatgtgtgt gtgctgtact cttcttccct

8700

ttatttgaaa acacttttca ctgggtcatc tccttggcca ttccacaaca caactttggt

8760

ttggctttca atgtcacctt atttgatggc ctgtgtccca gtagcagaat ttatggtatt

8820

cccattgctg gctgctcttc cgaccctttg cttctacagc acttgtctct cctaagatag

8880

tcagaaacta actgatcagg ggatggactt caccattcat cgtgtctctt caattctatt

8940

aaatagacca ctcttgggct ttagaccagg aaaaaggaga cagctctagc catctaccaa

9000

gcctcaccct aaaaggtcac ccgtacttct tggtctgagg acaagtctcc actccagtaa

9060

gggagagggg aggaaatgct tcctgtttga aatgcagtga attcctatgg ctcctgtttc

9120

accacccgca cctatggcaa cccatataca ttcctcttgt ctgtaactgc caaaggttgg

9180

gtttatgtca cttcagttcc actcaagcat tgaaaaggtt ctcatggagt ctggggtgtg

9240

cccagtgaaa agatggggac tttttcatta tccacagacc tctctatacc tgctttgcaa

9300

aaattataat ggagtaacta tttttaaagc ttatttttca attcataaga aaaagacatt

9360

tattttcaat caaatggatg atgtctctta tcccttatcc ctcaatgttt gcttgaattt

9420

tgtttgttcc ctatacctac tccctaattc tttagttcct tcctgctcag gtcccttcat

9480

ttgtactttg gagtttttct catgtaaatt tgtataatgg aaaatattgt tcagtttgga

9540

tagaaagcat ggagaaataa ataaaaaaag atagctgaaa atcaaattga agaaatttat

9600

ttctgtgtaa agttatttaa aaactctgta ttatatttaa agaaaaaagc ccaacccccc

9660

aaaaagtgct atgtaattga tgtgaatatg cgaatactgc tataataaag attgactgca

9720

tggagaaa

9728

<210> 6

<211> 804

<212> PROTEIN

<213> Mus musculus

<400> 6

Met Ala Ala Leu Ser Gly Gly Gly Gly Ser Ser Ser Gly Gly Gly Gly

1 5 10 15

Gly Gly Gly Gly Gly Gly Gly Gly Gly Asp Gly Gly Gly Gly Ala Glu

20 25 30

Gln Gly Gln Ala Leu Phe Asn Gly Asp Met Glu Pro Glu Ala Gly Ala

35 40 45

Gly Ala Ala Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val

50 55 60

Trp Asn Ile Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala

65 70 75 80

Leu Leu Asp Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu

85 90 95

Glu Ala Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg

100 105 110

Glu Gln Gln Leu Leu Glu Ser Leu Val Phe Gln Thr Pro Thr Asp Ala

115 120 125

Ser Arg Asn Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe

130 135 140

Leu Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr

145 150 155 160

Val Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro

165 170 175

Glu Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile

180 185 190

Gly Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val

195 200 205

Glu Val Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys

210 215 220

Thr Phe Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe

225 230 235 240

Gln Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys

245 250 255

Ser Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu

260 265 270

Leu Phe Val Ser Lys Phe Phe Glu His His Pro Val Pro Gln Glu Glu

275 280 285

Ala Ser Phe Pro Glu Thr Ala Leu Pro Ser Gly Ser Ser Ser Ala Pro

290 295 300

Pro Ser Asp Ser Thr Gly Pro Gln Ile Leu Thr Ser Pro Ser Pro Ser

305 310 315 320

Lys Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His

325 330 335

Arg Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val

340 345 350

His Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Glu Lys Phe Pro Glu

355 360 365

Val Glu Leu Gln Asp Gln Arg Asp Leu Ile Arg Asp Gln Gly Phe Arg

370 375 380

Gly Asp Gly Ala Pro Leu Asn Gln Leu Met Arg Cys Leu Arg Lys Tyr

385 390 395 400

Gln Ser Arg Thr Pro Ser Pro Leu Leu His Ser Val Pro Ser Glu Ile

405 410 415

Val Phe Asp Phe Glu Pro Gly Pro Val Phe Arg Gly Ser Thr Thr Gly

420 425 430

Leu Ser Ala Thr Pro Pro Ala Ser Leu Pro Gly Ser Leu Thr Asn Val

435 440 445

Lys Ala Leu Gln Lys Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser

450 455 460

Ser Ser Ser Ser Ser Glu Asp Arg Ser Arg Met Lys Thr Leu Gly Arg

465 470 475 480

Arg Asp Ser Ser Asp Asp Trp Glu Ile Pro Asp Gly Gln Ile Thr Val

485 490 495

Gly Gln Arg Ile Gly Ser Gly Ser Phe Gly Thr Val Tyr Lys Gly Lys

500 505 510

Trp His Gly Asp Val Ala Val Lys Met Leu Asn Val Thr Ala Pro Thr

515 520 525

Pro Gln Gln Leu Gln Ala Phe Lys Asn Glu Val Gly Val Leu Arg Lys

530 535 540

Thr Arg His Val Asn Ile Leu Leu Phe Met Gly Tyr Ser Thr Lys Pro

545 550 555 560

Gln Leu Ala Ile Val Thr Gln Trp Cys Glu Gly Ser Ser Leu Tyr His

565 570 575

His Leu His Ile Ile Glu Thr Lys Phe Glu Met Ile Lys Leu Ile Asp

580 585 590

Ile Ala Arg Gln Thr Ala Gln Gly Met Asp Tyr Leu His Ala Lys Ser

595 600 605

Ile Ile His Arg Asp Leu Lys Ser Asn Asn Ile Phe Leu His Glu Asp

610 615 620

Leu Thr Val Lys Ile Gly Asp Phe Gly Leu Ala Thr Val Lys Ser Arg

625 630 635 640

Trp Ser Gly Ser His Gln Phe Glu Gln Leu Ser Gly Ser Ile Leu Trp

645 650 655

Met Ala Pro Glu Val Ile Arg Met Gln Asp Lys Asn Pro Tyr Ser Phe

660 665 670

Gln Ser Asp Val Tyr Ala Phe Gly Ile Val Leu Tyr Glu Leu Met Thr

675 680 685

Gly Gln Leu Pro Tyr Ser Asn Ile Asn Asn Arg Asp Gln Ile Ile Phe

690 695 700

Met Val Gly Arg Gly Tyr Leu Ser Pro Asp Leu Ser Lys Val Arg Ser

705 710 715 720

Asn Cys Pro Lys Ala Met Lys Arg Leu Met Ala Glu Cys Leu Lys Lys

725 730 735

Lys Arg Asp Glu Arg Pro Leu Phe Pro Gln Ile Leu Ala Ser Ile Glu

740 745 750

Leu Leu Ala Arg Ser Leu Pro Lys Ile His Arg Ser Ala Ser Glu Pro

755 760 765

Ser Leu Asn Arg Ala Gly Phe Gln Thr Glu Asp Phe Ser Leu Tyr Ala

770 775 780

Cys Ala Ser Pro Lys Thr Pro Ile Gln Ala Gly Gly Tyr Gly Glu Phe

785 790 795 800

Ala Ala Phe Lys

<210> 7

<211> 2232

<212> DNA

<213> Oryctolagus cuniculus

<400> 7

atggggaatg tgtggaatat caaacaaatg attaagttga cacaggagca tatagaggcc

60

ctattggaca aatttggtgg ggagcataat cccacatcaa tatatctgga ggcctacgaa

120

gaatacacca gcaagctaga tgccctccaa caaagagaac agcagttatt ggaatcccta

180

gtttttcaaa atcccacaga tgtgtcacgg agcaacccca agtcaccaca aaaacctatt

240

gttagagtct tcctgcccaa caaacagagg acagtggtac ctgcaagatg tggagttacg

300

gttcgagaca gtctaaagaa agcgctgatg atgagaggtc tgatcccaga atgctgtgct

360

gtttacagaa ttcaggatgg agagaagaag ccaattggct gggacactga tatttcctgg

420

ctcactggag aagagctgca tgtggaagtg ttagagaatg tcccactcac cacacataac

480

tttgtacgga aaactttttt caccttagca ttttgtgact tctgtagaaa gctgcttttc

540

cagggtttcc gctgtcaaac atgtggctac aaatttcacc agcgttgtag tacggaagtt

600

ccactgatgt gtgttaatta tgaccaactt gatttgctgt ttgtctccaa gttctttgaa

660

caccacccag taccacagga ggaggcctcc ttagcagaga ctgccctcac atctgggtca

720

tcgccttccg cacctccctc agactctatt gggcaccaaa ttctcaccag tccgtcccct

780

tcaaaatcca ttccgattcc acagtccttc cgaccagcag atgaagatca tcgaaatcag

840

tttgggcaac gagaccggtc ttcatcagcg cctaatgttc acattaacac aatagaacct

900

gtcaatattg atgaaaaatt cccagaagtg gaattacagg atcaaaggga cttgattaga

960

gaccaagggt ttcgtggtga tggagcccct ttgaaccagc tgatgcgctg tcttcggaaa

1020

taccaatccc ggactcccag tcccctccta ccttctgtcc ccagtgacat agtgtttgat

1080

tttgagcctg gcccagtgtt cagaggatcg accacgggtt tgtctgccac tccccctgcc

1140

tcattacctg gctcactcac tagtgtgaaa gctgtacaga gatccccagg acctcagcga

1200

gagaggaagt cgtcttcctc ctcagaagac aggaatcgaa tgaaaactct tggtagacgg

1260

gattcaagtg atgattggga gattcctgat gggcagatca ccgtgggaca gagaattgga

1320

tctggatcat ttggaaccgt ctacaaggga aaatggcacg gtgatgtggc agtaaaaatg

1380

ttgaatgtga cagcacctac acctcagcag ttacaggcct tcaaaaatga agtaggagta

1440

ctcaggaaaa cacgacatgt gaatatccta cttttcatgg gctattccac aaagccacag

1500

ctggctattg ttacccagtg gtgtgagggc tccagtttat atcaccatct ccacatcatt

1560

gagaccaaat tcgagatgat caaacttata gatattgcac ggcagactgc acagggcatg

1620

gattacttac acgccaagtc aatcatccac agagacctca agagtaataa tatatttctt

1680

catgaagacc tcacagtaaa aataggtgat tttggtctag ccacagtgaa atctcgatgg

1740

agtgggtccc atcagtttga acaattgtct ggatccattt tgtggatggc accagaagta

1800

atcagaatgc aagacaaaaa cccatatagc tttcagtcag atgtatatgc atttgggatt

1860

gttctgtatg aattgatgac tgggcagtta ccttactcaa acatcaacaa cagggaccag

1920

atcattttta tggtgggacg tggctacctg tctccagacc tcagtaaggt acggagtaac

1980

tgtccgaaag ccatgaagag attaatggca gagtgcctca aaaagaaaag agatgagaga

2040

ccactctttc cccaaattct cgcctccat gagctgctgg cccgctcatt gccaaaaatc

2100

caccgcagtg catcagaacc ctccttgaat cgggctggtt tccagacaga ggattttagt

2160

ctatatgctt gtgcttctcc aaaaacaccc atccaggcag ggggatatgg agaatttgca

2220

gccttcaagt ag

2232

<210> 8

<211> 743

<212> PROTEIN

<213> Oryctolagus cuniculus

<400> 8

Met Gly Asn Val Trp Asn Ile Lys Gln Met Ile Lys Leu Thr Gln Glu

1 5 10 15

His Ile Glu Ala Leu Leu Asp Lys Phe Gly Gly Glu His Asn Pro Pro

20 25 30

Ser Ile Tyr Leu Glu Ala Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala

35 40 45

Leu Gln Gln Arg Glu Gln Gln Leu Leu Glu Ser Leu Val Phe Gln Asn

50 55 60

Pro Thr Asp Val Ser Arg Ser Asn Pro Lys Ser Pro Gln Lys Pro Ile

65 70 75 80

Val Arg Val Phe Leu Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg

85 90 95

Cys Gly Val Thr Val Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg

100 105 110

Gly Leu Ile Pro Glu Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu

115 120 125

Lys Lys Pro Ile Gly Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu

130 135 140

Glu Leu His Val Glu Val Leu Glu Asn Val Pro Leu Thr Thr His Asn

145 150 155 160

Phe Val Arg Lys Thr Phe Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg

165 170 175

Lys Leu Leu Phe Gln Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe

180 185 190

His Gln Arg Cys Ser Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp

195 200 205

Gln Leu Asp Leu Leu Phe Val Ser Lys Phe Phe Glu His His Pro Val

210 215 220

Pro Gln Glu Glu Ala Ser Leu Ala Glu Thr Ala Leu Thr Ser Gly Ser

225 230 235 240

Ser Pro Ser Ala Pro Pro Ser Asp Ser Ile Gly His Gln Ile Leu Thr

245 250 255

Ser Pro Ser Pro Ser Lys Ser Ile Pro Ile Pro Gln Ser Phe Arg Pro

260 265 270

Ala Asp Glu Asp His Arg Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser

275 280 285

Ser Ala Pro Asn Val His Ile Asn Thr Ile Glu Pro Val Asn Ile Asp

290 295 300

Glu Lys Phe Pro Glu Val Glu Leu Gln Asp Gln Arg Asp Leu Ile Arg

305 310 315 320

Asp Gln Gly Phe Arg Gly Asp Gly Ala Pro Leu Asn Gln Leu Met Arg

325 330 335

Cys Leu Arg Lys Tyr Gln Ser Arg Thr Pro Ser Pro Leu Leu Pro Ser

340 345 350

Val Pro Ser Asp Ile Val Phe Asp Phe Glu Pro Gly Pro Val Phe Arg

355 360 365

Gly Ser Thr Thr Gly Leu Ser Ala Thr Pro Pro Ala Ser Leu Pro Gly

370 375 380

Ser Leu Thr Ser Val Lys Ala Val Gln Arg Ser Pro Gly Pro Gln Arg

385 390 395 400

Glu Arg Lys Ser Ser Ser Ser Ser Glu Asp Arg Asn Arg Met Lys Thr

405 410 415

Leu Gly Arg Arg Asp Ser Ser Asp Asp Trp Glu Ile Pro Asp Gly Gln

420 425 430

Ile Thr Val Gly Gln Arg Ile Gly Ser Gly Ser Phe Gly Thr Val Tyr

435 440 445

Lys Gly Lys Trp His Gly Asp Val Ala Val Lys Met Leu Asn Val Thr

450 455 460

Ala Pro Thr Pro Gln Gln Leu Gln Ala Phe Lys Asn Glu Val Gly Val

465 470 475 480

Leu Arg Lys Thr Arg His Val Asn Ile Leu Leu Phe Met Gly Tyr Ser

485 490 495

Thr Lys Pro Gln Leu Ala Ile Val Thr Gln Trp Cys Glu Gly Ser Ser

500 505 510

Leu Tyr His His Leu His Ile Ile Glu Thr Lys Phe Glu Met Ile Lys

515 520 525

Leu Ile Asp Ile Ala Arg Gln Thr Ala Gln Gly Met Asp Tyr Leu His

530 535 540

Ala Lys Ser Ile Ile His Arg Asp Leu Lys Ser Asn Asn Ile Phe Leu

545 550 555 560

His Glu Asp Leu Thr Val Lys Ile Gly Asp Phe Gly Leu Ala Thr Val

565 570 575

Lys Ser Arg Trp Ser Gly Ser His Gln Phe Glu Gln Leu Ser Gly Ser

580 585 590

Ile Leu Trp Met Ala Pro Glu Val Ile Arg Met Gln Asp Lys Asn Pro

595 600 605

Tyr Ser Phe Gln Ser Asp Val Tyr Ala Phe Gly Ile Val Leu Tyr Glu

610 615 620

Leu Met Thr Gly Gln Leu Pro Tyr Ser Asn Ile Asn Asn Arg Asp Gln

625 630 635 640

Ile Ile Phe Met Val Gly Arg Gly Tyr Leu Ser Pro Asp Leu Ser Lys

645 650 655

Val Arg Ser Asn Cys Pro Lys Ala Met Lys Arg Leu Met Ala Glu Cys

660 665 670

Leu Lys Lys Lys Arg Asp Glu Arg Pro Leu Phe Pro Gln Ile Leu Ala

675 680 685

Ser Ile Glu Leu Leu Ala Arg Ser Leu Pro Lys Ile His Arg Ser Ala

690 695 700

Ser Glu Pro Ser Leu Asn Arg Ala Gly Phe Gln Thr Glu Asp Phe Ser

705 710 715 720

Leu Tyr Ala Cys Ala Ser Pro Lys Thr Pro Ile Gln Ala Gly Gly Tyr

725 730 735

Gly Glu Phe Ala Ala Phe Lys

740

<210> 9

<211> 2186

<212> DNA

<213> Cavia porcellus

<400> 9

atggcggcgc tcagcggcgg cggtggcgcg gagcagggcc aggctctgtt caacggggac

60

atggagctcg aggccggcgc cggcgccgca gcctcttcgg ctgcagaccc tgccattccc

120

gaggaggtat ggaatatcaa acaaatgatt aagttgacgc aggaacacat agaggcccta

180

ttggacaaat ttggtggaga gcataatcca ccatcaatat acctggaggc ctatgaagaa

240

tacaccagca aactagatgc cctccaacaa agagaacagc agttactgga atccctcggg

300

aatggaactg atttttctgt ttctagctct gcatcactgg acaccgttac atcttcttct

360

tcttctagcc tttcagtact accttcatct ctttcagttt ttcaaaatcc tacagatgtg

420

tcacggagca accccaaatc accacaaaaa cctattgtta gagtcttcct gcccaacaaa

480

cagaggacag tggtacctgc aaggtgtgga gttacagtcc gagacagtct gaagaaagca

540

ctcatgatga gaggtcttat cccagagtgc tgtgctgtgt acagaattca ggatggagaa

600

aagaaaccaa ttggctggga cactgacatt tcctggctta ctggggaaga attacatgta

660

gaagtattgg agaatgttcc acttacaaca cacaattttg tatgtatctt tatatttttt

720

ttgctgtttg tctccaagtt ctttgaacac cacccaatac cacaggagga ggcttcctta

780

gcagagacca cccttacatc tggatcatcc ccttctgcac ccccctcaga gtccattggg

840

cccccaattc tcaccagccc atctccttca aaatccattc caattccaca gcctttccgg

900

ccaggagagg aagatcatcg aaatcaattt gggcagcgag accggtcctc atctgctccc

960

aatgtgcata taaacacaat agaacctgtc aatattgatg atttgattag agaccaaggg

1020

tttcgtagtg atggaggatc aactacaggt ttgtctgcca ccccacctgc ctcattacct

1080

ggctcactca ctaatgtgaa agccttacag aaatctccag gacctcagcg agaaaggaag

1140

tcatcttcat cctcagaaga cagaaatcga atgaaaacgc ttggtagacg ggactcaagt

1200

gatgattggg agattcctga tgggcagatt acagtgggac aaagaattgg atctgggtca

1260

tttggaacag tctacaaggg gaagtggcat ggtgacgtgg cagtgaaaat gttgaatgtg

1320

acagcaccca cacctcaaca gttacaggcc ttcaaaaatg aagtaggagt actcaggaaa

1380

acacgacatg tgaatatcct actcttcatg ggctattcca caaagccaca gctagctatt

1440

gttacccagt ggtgtgaggg ctccagctta taccaccatc tccacatcat cgagaccaaa

1500

tttgagatga tcaaacttat agatattgca cgacagactg cccagggcat ggattactta

1560

cacgccaagt caatcatcca cagagacctc aagagtaata atatatttct tcacgaagac

1620

ctcacggtta aaataggtga ttttggtcta gccacagtga aatctcgatg gagtgggtcc

1680

catcagtttg aacagttgtc tggatccatt ttgtggatgg caccagaagt aatcagaatg

1740

cgagataaaa acccatacag ttttcagtcc gatgtatatg catttgggat tgttctatat

1800

gaattgatga ctgggcagtt accctattca aatatcaaca acagggacca gataattttt

1860

atggtgggac gaggatatct atctccagat ctcagcaagg tacggagtaa ctgtccaaaa

1920

gccatgaaga ggttaatggc ggagtgcctc aaaaagaaaa gagatgagag accactcttt

1980

ccccaaattc tcgcctctat tgagctgctg gcccgctcat tgccaaaaat tcaccgcagt

2040

gcatcagaac cctccttgaa tcgggctggt ttccaaacag aggattttag tctctatgct

2100

tgtgcttctc caaaaacacc catccaggca gggggatatg gtgcgtttcc tgtccactga

2160

tgcaaattaa atgagtgaga aataaa

2186

<210> 10

<211> 719

<212> PROTEIN

<213> Cavia porcellus

<400> 10

Met Ala Ala Leu Ser Gly Gly Gly Gly Ala Glu Gln Gly Gln Ala Leu

1 5 10 15

Phe Asn Gly Asp Met Glu Leu Glu Ala Gly Ala Gly Ala Ala Ala Ser

20 25 30

Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp Asn Ile Lys Gln

35 40 45

Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu Asp Lys Phe

50 55 60

Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala Tyr Glu Glu

65 70 75 80

Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln Gln Leu Leu

85 90 95

Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser Ser Ala Ser

100 105 110

Leu Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser Val Leu Pro

115 120 125

Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val Ser Arg Ser Asn

130 135 140

Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu Pro Asn Lys

145 150 155 160

Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val Arg Asp Ser

165 170 175

Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu Cys Cys Ala

180 185 190

Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly Trp Asp Thr

195 200 205

Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu Val Leu Glu

210 215 220

Asn Val Pro Leu Thr Thr His Asn Phe Val Cys Ile Phe Ile Phe Phe

225 230 235 240

Leu Leu Phe Val Ser Lys Phe Phe Glu His His Pro Ile Pro Gln Glu

245 250 255

Glu Ala Ser Leu Ala Glu Thr Thr Leu Thr Ser Gly Ser Ser Pro Ser

260 265 270

Ala Pro Pro Ser Glu Ser Ile Gly Pro Pro Ile Leu Thr Ser Pro Ser

275 280 285

Pro Ser Lys Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Gly Glu Glu

290 295 300

Asp His Arg Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro

305 310 315 320

Asn Val His Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile

325 330 335

Arg Asp Gln Gly Phe Arg Ser Asp Gly Gly Ser Thr Thr Gly Leu Ser

340 345 350

Ala Thr Pro Pro Ala Ser Leu Pro Gly Ser Leu Thr Asn Val Lys Ala

355 360 365

Leu Gln Lys Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser

370 375 380

Ser Glu Asp Arg Asn Arg Met Lys Thr Leu Gly Arg Arg Asp Ser Ser

385 390 395 400

Asp Asp Trp Glu Ile Pro Asp Gly Gln Ile Thr Val Gly Gln Arg Ile

405 410 415

Gly Ser Gly Ser Phe Gly Thr Val Tyr Lys Gly Lys Trp His Gly Asp

420 425 430

Val Ala Val Lys Met Leu Asn Val Thr Ala Pro Thr Pro Gln Gln Leu

435 440 445

Gln Ala Phe Lys Asn Glu Val Gly Val Leu Arg Lys Thr Arg His Val

450 455 460

Asn Ile Leu Leu Phe Met Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile

465 470 475 480

Val Thr Gln Trp Cys Glu Gly Ser Ser Leu Tyr His His Leu His Ile

485 490 495

Ile Glu Thr Lys Phe Glu Met Ile Lys Leu Ile Asp Ile Ala Arg Gln

500 505 510

Thr Ala Gln Gly Met Asp Tyr Leu His Ala Lys Ser Ile Ile His Arg

515 520 525

Asp Leu Lys Ser Asn Asn Ile Phe Leu His Glu Asp Leu Thr Val Lys

530 535 540

Ile Gly Asp Phe Gly Leu Ala Thr Val Lys Ser Arg Trp Ser Gly Ser

545 550 555 560

His Gln Phe Glu Gln Leu Ser Gly Ser Ile Leu Trp Met Ala Pro Glu

565 570 575

Val Ile Arg Met Arg Asp Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val

580 585 590

Tyr Ala Phe Gly Ile Val Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro

595 600 605

Tyr Ser Asn Ile Asn Asn Arg Asp Gln Ile Ile Phe Met Val Gly Arg

610 615 620

Gly Tyr Leu Ser Pro Asp Leu Ser Lys Val Arg Ser Asn Cys Pro Lys

625 630 635 640

Ala Met Lys Arg Leu Met Ala Glu Cys Leu Lys Lys Lys Arg Asp Glu

645 650 655

Arg Pro Leu Phe Pro Gln Ile Leu Ala Ser Ile Glu Leu Leu Ala Arg

660 665 670

Ser Leu Pro Lys Ile His Arg Ser Ala Ser Glu Pro Ser Leu Asn Arg

675 680 685

Ala Gly Phe Gln Thr Glu Asp Phe Ser Leu Tyr Ala Cys Ala Ser Pro

690 695 700

Lys Thr Pro Ile Gln Ala Gly Gly Tyr Gly Ala Phe Pro Val His

705 710 715

<210> 11

<211> 3229

<212> DNA

<213> Canis familiaris

<400> 11

gtaatgctgg attttcatgg aataagtttg acctgtgctg cagtggcctc cagcaaggta

60

cccgcaagat gtggagttac agtccgggac agtctaaaga aagctctgat gatgagaggt

120

ctaatcccag agtgctgtgc tgtttacaga attcaggatg gagagaagaa accgattggc

180

tgggacactg atatttcctg gctcactgga gaggaattgc atgtagaagt gttggaaaat

240

gttccgctta ccacacacaa ctttgtacgg aaaacttttt tcaccttagc attttgtgac

300

ttttgtcgaa agctgctttt ccagggtttt cgctgtcaaa catgtggtta taaatttcac

360

cagcgttgta gtacagaggt tccactgatg tgtgttaatt atgaccaact tgatttgctg

420

tttgtctcca agttctttga acaccaccca ataccacagg aggaggcctc catagcagag

480

actgccctta cgtctggatc atccccttct gctcccccct ccgattctcc tgggccccca

540

attctgacca gtccgtctcc ttcaaaatcc attccaattc cacagccttt ccgaccagca

600

gatgaagatc atcgaaatca gtttggacaa cgagaccggt cctcatcagc tccaaatgtg

660

catataaaca caatagaacc cgtcaacatt gatgacttga ttagagacca agggtttcgt

720

agtgatggag gatcaaccac aggtttgtct gccacccccc ctgcctcatt gcctggctca

780

ctcactaatg taaaagcatt acagaaatct ccaggacctc agcgggaaag aaaatcatct

840

tcatcctcag aagataggaa tcgaatgaaa acacttggta gacgggattc aagtgatgat

900

tggggagatac ctgatgggca gatcacagtg ggacagagaa ttggatccgg gtcatttggg

960

acagtctaca agggaaagtg gcatggtgac gtggcagtga aaatgttgaa tgtgacagca

1020

cccacacctc agcagttaca ggccttcaaa aatgaagtag gagtactcag gaaaactcga

1080

catgtgaata tcctactctt tatgggctat tcaacaaagc cccaactggc tattgttacc

1140

cagtggtgtg agggctccag cttatatcac catctccaca tcattgagac caaatttgag

1200

atgataaagc ttatagatat tgcacggcag actgcacagg gcatggatta cttacacgcc

1260

aagtcaatca tccacagaga cctcaagagt aataatattt ttcttcatga agacctcaca

1320

gtaaaaatag gtgattttgg tctagccaca gtgaaatctc gatggagtgg gtcccatcag

1380

tttgaacagt tgtctggatc cattttgtgg atggcaccag aagtgatccg aatgcaagac

1440

aaaaacccat atagcttcca gtcagatgta tacgcatttg ggattgttct atatgaattg

1500

atgacagggc agttacctta ttcaaacatc aacaacaggg accagataat ttttatggtg

1560

ggacgaggat atctttctcc agatctcagt aaggtacgga gtaactgtcc aaaagccatg

1620

aagagattga tggcagagtg cctaaaaaag aaaagagatg agaggccact ctttccccaa

1680

attctcgcct ctattgagct gctggcccgc tcattgccaa aaattcaccg cagtgcatca

1740

gaaccctcct tgaatcgggc tggcttccaa acagaggatt ttagtctcta tgcttgcgct

1800

tctccaaaaa cacccatcca ggcaggggga tacggagaat ttgcagcctt caagtagcca

1860

caccatcatg gcaacaacta ctcttatttc ttaagtcttg tgttcgtaca atttgttaac

1920

atcaaaacac agttctgttc ctcaaatctt tttttaaaga tacagaattt tcaatgcata

1980

agctggtgtg gaacagaatg gaatttccca tccaacaaaa gagggaagaa tgttttagga

2040

accagaattc tctgctgcca gtgtttcttc ttcaacacaa ataccacgtg catacaagtc

2100

tgcccactcc caggaaggaa gagggagagcc tgagttctga ccttttgatg gtcaggcatg

2160

atggaaagaa actgctgcta cagcttggga gattggctgt gggagagcctg cccgtcagct

2220

ctgcccttct aaccgccaga tgagtgtgtg gctggtcacc tgacagggca gctgcaatcg

2280

ccaagcatcg ttctctttcc tgtcctggga ttttgtcgtg gagctctttc cccctagtca

2340

ccaccggttc atttctgagg gatggaacaa aaatgcagca tggcctttct gtgtggtgca

2400

tgtccggtct ttgacaaatt tttatcaagt gaagctcttg tatttaaatg gagaatgaga

2460

ggcgagggggg ggggatcacg ttttggtgta ggggcaaagg gaatgctgca tctttttcct

2520

gacccactgg gtttctggcc tttgtttcct tgctcactga gggtgtctgc ctataaccac

2580

gcaggctgga aagtgctggc acacatgcc ttctcttctc actgggtcca gcaatgaaga

2640

caagtgttgg ggattttttt ttttgccctc cacaatgtag caagttctca ggaaaataca

2700

gttaatatct tcctcctaag ctcttccagt catcaagtac ttatgtggct actttgtcca

2760

gggcacaaaa tgccatggcg gtatccaatt aaaagcctac aaaactgctt gataacagtt

2820

ttgaatgtgt gagacattta tgtaatttaa atgtaaggta caagttttaa tttctgagtt

2880

tctctattat atttttatta aaaagaaaat aattttcaga tttaattgaa ttggaataaa

2940

ataatacttc ccaccagaat tatatatcct ggaaaattgt atttttgtta tataaacaac

3000

ttttaaagaa agatcattat ccttttctct acctaaatat ggggagtctt agcataatga

3060

cagatattta taatttttaa attaatggta cttgctggat cccacactaac atctttgcta

3120

atatctcatg ttttcctcca acttactcct acactacatc ctccatcctc tttccagtct

3180

tttatctaga atatgcaacc taaaataaaa atggtggtgt ctccattca

3229

<210> 12

<211> 617

<212> PROTEIN

<213> Canis familiaris

<400> 12

Met Leu Asp Phe His Gly Ile Ser Leu Thr Cys Ala Ala Val Ala Ser

1 5 10 15

Ser Lys Val Pro Ala Arg Cys Gly Val Thr Val Arg Asp Ser Leu Lys

20 25 30

Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu Cys Cys Ala Val Tyr

35 40 45

Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly Trp Asp Thr Asp Ile

50 55 60

Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu Val Leu Glu Asn Val

65 70 75 80

Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr Phe Phe Thr Leu Ala

85 90 95

Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln Gly Phe Arg Cys Gln

100 105 110

Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser Thr Glu Val Pro Leu

115 120 125

Met Cys Val Asn Tyr Asp Gln Leu Asp Leu Leu Phe Val Ser Lys Phe

130 135 140

Phe Glu His His Pro Ile Pro Gln Glu Glu Ala Ser Ile Ala Glu Thr

145 150 155 160

Ala Leu Thr Ser Gly Ser Ser Pro Ser Ala Pro Pro Ser Asp Ser Pro

165 170 175

Gly Pro Pro Ile Leu Thr Ser Pro Ser Pro Ser Lys Ser Ile Pro Ile

180 185 190

Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His Arg Asn Gln Phe Gly

195 200 205

Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val His Ile Asn Thr Ile

210 215 220

Glu Pro Val Asn Ile Asp Asp Leu Ile Arg Asp Gln Gly Phe Arg Ser

225 230 235 240

Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala Thr Pro Pro Ala Ser Leu

245 250 255

Pro Gly Ser Leu Thr Asn Val Lys Ala Leu Gln Lys Ser Pro Gly Pro

260 265 270

Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser Glu Asp Arg Asn Arg Met

275 280 285

Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp Asp Trp Glu Ile Pro Asp

290 295 300

Gly Gln Ile Thr Val Gly Gln Arg Ile Gly Ser Gly Ser Phe Gly Thr

305 310 315 320

Val Tyr Lys Gly Lys Trp His Gly Asp Val Ala Val Lys Met Leu Asn

325 330 335

Val Thr Ala Pro Thr Pro Gln Gln Leu Gln Ala Phe Lys Asn Glu Val

340 345 350

Gly Val Leu Arg Lys Thr Arg His Val Asn Ile Leu Leu Phe Met Gly

355 360 365

Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val Thr Gln Trp Cys Glu Gly

370 375 380

Ser Ser Leu Tyr His His Leu His Ile Ile Glu Thr Lys Phe Glu Met

385 390 395 400

Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr Ala Gln Gly Met Asp Tyr

405 410 415

Leu His Ala Lys Ser Ile Ile His Arg Asp Leu Lys Ser Asn Asn Ile

420 425 430

Phe Leu His Glu Asp Leu Thr Val Lys Ile Gly Asp Phe Gly Leu Ala

435 440 445

Thr Val Lys Ser Arg Trp Ser Gly Ser His Gln Phe Glu Gln Leu Ser

450 455 460

Gly Ser Ile Leu Trp Met Ala Pro Glu Val Ile Arg Met Gln Asp Lys

465 470 475 480

Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr Ala Phe Gly Ile Val Leu

485 490 495

Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr Ser Asn Ile Asn Asn Arg

500 505 510

Asp Gln Ile Ile Phe Met Val Gly Arg Gly Tyr Leu Ser Pro Asp Leu

515 520 525

Ser Lys Val Arg Ser Asn Cys Pro Lys Ala Met Lys Arg Leu Met Ala

530 535 540

Glu Cys Leu Lys Lys Lys Arg Asp Glu Arg Pro Leu Phe Pro Gln Ile

545 550 555 560

Leu Ala Ser Ile Glu Leu Leu Ala Arg Ser Leu Pro Lys Ile His Arg

565 570 575

Ser Ala Ser Glu Pro Ser Leu Asn Arg Ala Gly Phe Gln Thr Glu Asp

580 585 590

Phe Ser Leu Tyr Ala Cys Ala Ser Pro Lys Thr Pro Ile Gln Ala Gly

595 600 605

Gly Tyr Gly Glu Phe Ala Ala Phe Lys

610 615

<210> 13

<211> 1889

<212> DNA

<213> Canis familiaris

<400> 13

ggaatatcaa acaaatgatt aagttgacac aggaacatat agaagcccta ttggacaagt

60

ttggtgggga gcataatcca ccatcaatat atctggaggc ctatgaagaa tacaccagca

120

aactagatgc cctccaacag cgagaacaac agttattgga atccctgggg aatggaactg

180

atttttctgt ttctagctct gcatcaacgg acaccgttac atcttcttcc tcttctagcc

240

tttcagtgct accttcatct ctttcagttt ttcaaaatcc cacagatata tcacggagca

300

atcccaagtc accacaaaaa cctatcgtta gagtcttcct gcccaataaa cagaggacgg

360

tggtacccgc aagatgtgga gttacagtcc gggacagtct aaagaaagct ctgatgatga

420

gaggtctaat cccagagtgc tgtgctgttt acagaattca ggatggagag aagaaaccga

480

ttggctggga cactgatatt tcctggctca ctggagagga attgcatgta gaagtgttgg

540

aaaatgttcc gcttaccaca cacaactttg tacggaaaac ttttttcacc ttagcatttt

600

gtgacttttg tcgaaagctg cttttccagg gttttcgctg tcaaacatgt ggttataaat

660

ttcaccagcg ttgtagtaca gaggttccac tgatgtgtgt taattatgac caacttgatt

720

tgctgtttgt ctccaagttc tttgaacacc acccaatacc acaggaggag gcctccatag

780

cagagactgc ccttacgtct ggatcatccc cttctgctcc cccctccgat tctcctgggc

840

ccccaattct gaccagtccg tctccttcaa aatccattcc aattccacag cctttccgac

900

cagcagatga agatcatcga aatcagtttg gacaacgaga ccggtcctca tcagctccaa

960

atgtgcatat aaacacaata gaacccgtca acattgatga cttgattaga gaccaagggt

1020

ttcgtagtga tggaggatca accacaggtt tgtctgccac cccccctgcc tcattgcctg

1080

gctcactcac taatgtaaaa gcattacaga aatctccagg acctcagcgg gaaagaaaat

1140

catcttcatc ctcagaagat aggaatcgaa tgaaaacact tggtagacgg gattcaagtg

1200

atgattggga gatacctgat gggcagatca cagtgggaca gagaattgga tccgggtcat

1260

ttgggacagt ctacaaggga aagtggcatg gtgacgtggc agtgaaaatg ttgaatgtga

1320

cagcacccac acctcagcag ttacaggcct tcaaaaatga agtaggagta ctcaggaaaa

1380

ctcgacatgt gaatatccta ctctttatgg gctattcaac aaagccccaa ctggctattg

1440

ttacccagtg gtgtgagggc tccagcttat atcaccatct ccacatcatt gagaccaaat

1500

ttgagatgat aaagcttata gatattgcac ggcagactgc acagggcatg gattacttac

1560

acgccaagtc aatcatccac agagacctca agagtaataa tatttttctt catgaagacc

1620

tcacagtaaa aataggtgat tttggtctag ccacagtgaa atctcgatgg agtgggtccc

1680

atcagtttga acagttgtct ggatccatt tgtggatggc accagaagtg atccgaatgc

1740

aagacaaaaa cccatatagc ttccagtcag atgtatacgc atttgggatt gttctatatg

1800

aattgatgac agggcagtta ccttattcaa acatcaacaa cagggaccag ctcagatcat

1860

gatcacggtg tcatgagatc aagccccac

1889

<210> 14

<211> 615

<212> PROTEIN

<213> Canis familiaris

<400> 14

Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu Asp Lys Phe

1 5 10 15

Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala Tyr Glu Glu

20 25 30

Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln Gln Leu Leu

35 40 45

Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser Ser Ala Ser

50 55 60

Thr Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser Val Leu Pro

65 70 75 80

Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Ile Ser Arg Ser Asn

85 90 95

Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu Pro Asn Lys

100 105 110

Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val Arg Asp Ser

115 120 125

Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu Cys Cys Ala

130 135 140

Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly Trp Asp Thr

145 150 155 160

Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu Val Leu Glu

165 170 175

Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr Phe Phe Thr

180 185 190

Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln Gly Phe Arg

195 200 205

Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser Thr Glu Val

210 215 220

Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu Leu Phe Val Ser

225 230 235 240

Lys Phe Phe Glu His His Pro Ile Pro Gln Glu Glu Ala Ser Ile Ala

245 250 255

Glu Thr Ala Leu Thr Ser Gly Ser Ser Pro Ser Ala Pro Pro Ser Asp

260 265 270

Ser Pro Gly Pro Pro Ile Leu Thr Ser Pro Ser Pro Ser Lys Ser Ile

275 280 285

Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His Arg Asn Gln

290 295 300

Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val His Ile Asn

305 310 315 320

Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg Asp Gln Gly Phe

325 330 335

Arg Ser Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala Thr Pro Pro Ala

340 345 350

Ser Leu Pro Gly Ser Leu Thr Asn Val Lys Ala Leu Gln Lys Ser Pro

355 360 365

Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser Glu Asp Arg Asn

370 375 380

Arg Met Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp Asp Trp Glu Ile

385 390 395 400

Pro Asp Gly Gln Ile Thr Val Gly Gln Arg Ile Gly Ser Gly Ser Phe

405 410 415

Gly Thr Val Tyr Lys Gly Lys Trp His Gly Asp Val Ala Val Lys Met

420 425 430

Leu Asn Val Thr Ala Pro Thr Pro Gln Gln Leu Gln Ala Phe Lys Asn

435 440 445

Glu Val Gly Val Leu Arg Lys Thr Arg His Val Asn Ile Leu Leu Phe

450 455 460

Met Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val Thr Gln Trp Cys

465 470 475 480

Glu Gly Ser Ser Leu Tyr His His Leu His Ile Ile Glu Thr Lys Phe

485 490 495

Glu Met Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr Ala Gln Gly Met

500 505 510

Asp Tyr Leu His Ala Lys Ser Ile Ile His Arg Asp Leu Lys Ser Asn

515 520 525

Asn Ile Phe Leu His Glu Asp Leu Thr Val Lys Ile Gly Asp Phe Gly

530 535 540

Leu Ala Thr Val Lys Ser Arg Trp Ser Gly Ser His Gln Phe Glu Gln

545 550 555 560

Leu Ser Gly Ser Ile Leu Trp Met Ala Pro Glu Val Ile Arg Met Gln

565 570 575

Asp Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr Ala Phe Gly Ile

580 585 590

Val Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr Ser Asn Ile Asn

595 600 605

Asn Arg Asp Gln Leu Arg Ser

610 615

<210> 15

<211> 3521

<212> DNA

<213> Felis catus

<220>

<221> additional feature

<222> (630)..(649)

<223> n is a, c, g, or t

<400> 15

atgcctaacc tcagtctctg ccaccacggc caatttgctc atgtgcccac tgtgtcggca

60

ctgggatatt ttgtgatttg ccttggccat tgtccactgt ccttgacatt gcctgaagga

120

gaaccactga tgctaatgtt gaaggtgacc tttgcaggct ctccactact cataccaaag

180

atgcggcccc ctgataatcc cagagccact gtctgcacat gggcaaaaca ggctacattc

240

tgtgcagact ggggagaaag gttccaagaa cacagtgcca tagttttggg cagagagttt

300

caacacagca tagtgtctat ggcagtatct ggatttggcc gggggaagtg cccaagagga

360

gacagtcagg ctgtgtccta cggccaagga cctgcactta tttttgcatg cagtggttta

420

gcacagggaa gagaacgaag taggaaatcg gagccatgga aacggcagag cggaggaaac

480

gtgcacgcgc gagggtgggc acgaaaggaa agaaccctcc ccagaagact gcgcgagggc

540

gctcctagga ttacgtcacg caccccgcga aaactgaaat gtactgtgtg tggtctttta

600

attgaactat cttccttatg tgcacttaan nnnnnnnnnn nnnnnnnnng cggcggcggc

660

ggtggcgcgg agcagggcca ggctctgttc aacggggaca tggagcccga agccggcgcc

720

gcggcctctt cggctgcgga ccctgccatt cccgaggagg tgtggaatat caaacaaatg

780

attaagttga cacaggaaca tatagaggcc ctattggaca aatttggtgg ggagcataat

840

cccacatcaa tatatctaga ggcctatgaa gaatacacca gcaagctaga tgccctccaa

900

cagagagaac aacagttatt ggaatccctg gggaatggaa ctgatttttc tgtttctagc

960

tctgcatcaa cagacaccgt tacatcttcc tcctcttcta gcctttcagt gctaccttca

1020

tctctttcag tttttcaaaa ccccacagat gtgtcacgga gcaatcccaa gtcaccacag

1080

aaacctatcg ttagagtctt cctgcctaat aaacagagga cagtggtacc tgcaagatgt

1140

ggagttacag tccgggacag tctaaagaaa gctctgatga tgagaggtct aatccctgag

1200

tgctgtgctg tttacagaat tcaggatgga gagaagaaac caattggctg ggacactgat

1260

atctcctggc tcaccggaga ggaattgcat gtagaagtgt tggaaaatgt tccacttaca

1320

actcacaact ttgtatgtac ggaaaacgtt ttcaccttag cattttgtga cttttgtcga

1380

aagctgcttt tccaaggttt tcgctgtcaa acgtgtggtt ataaatttca ccagcgttgt

1440

agtacagagg ttccactgat gtgtgttaat tatgaccaac ttgatttgct gtttgtctcc

1500

aagttctttg aacaccaccc aataccacag gaggaggcct ccatagcaga gactgcccta

1560

acgtctggat cgtccccttc tgcccccccc tccgattcta ctgggcccca aattctcacc

1620

agtccgtctc cttcaaaatc cattccaatt ccacagcctt tccgaccagc agatgaagat

1680

catcgaaatc aatttggaca gcgagaccgg tcctcatcag ctccaaatgt gcatataaat

1740

acaatagaac ctgtcaatat tgatgacttg attagagacc aggggtttcg tagtgatgga

1800

ggatcaacca caggcttgtc tgccaccccc cctgcctcat tgccgggctc tctcactaat

1860

gtaaaagcat tacagaaatc tccagggcct cagcgggaaa ggaaatcttc ttcatcctca

1920

gaagatagga atcgaatgaa aacacttggt agaagggatt caagtgatga ttgggagatt

1980

cctgatgggc agatcacagt gggacagaga attggatccg ggtcatttgg gacagtctac

2040

aagggaaagt ggcatggtga tgtggcagtg aaaatgttga atgtgacagc acccacacct

2100

cagcagttac aggccttcaa aaatgaagta ggagtactca ggaaaactcg gcatgtgaac

2160

atcctgctct tcatgggcta ttcaacaaag ccccagctgg ctattgtcac ccagtggtgt

2220

gagggctcca gcttatacca ccatctccac atcatcgaga ccaaattcga gatgatcaag

2280

ctgatagata ttgctcggca gactgcgcag ggcatggatt acttacacgc caagtcaatc

2340

atccacagag acctcaagag taataatatt tttcttcacg aagacctcac agtaaaaata

2400

ggtgattttg gtctagccac agtgaaatct cgatggagtg ggtcccatca gtttgaacag

2460

ttgtctggat ccattttgtg gatggcacca gaagtaattc gaatgcaaga taaaaaccca

2520

tatagctttc agtcagatgt atatgcattt gggattgttc tatatgaatt gatgactgga

2580

cagttacctt attcaaacat caacaacagg gaccagataa tttttatggt gggacgagga

2640

tatctttctc cagatctcag taaggtacga agtaactgtc caaaagccat gaagagattg

2700

atggcagagt gcctaaaaaa gaaaagagat gagaggccac tgtttcccca aattcttgcc

2760

tctattgagc tgctggcccg ctcattgcca aaaattcacc gcagtgcatc agaaccctcc

2820

ttgaatcggg ctggcttcca gacagaggat tttagtctct atgcttgtgc ttctccaaaa

2880

acacccatcc aggcaggggg atatggtgcg tttcccgtcc actgagataa gttagatgag

2940

tgcgcgagtg caggggggccg gggccaagga ggtggaaatg tgcgtgcttc tgtactaagt

3000

tggatagcat cttctttttt aaaaaaagat gaaccaaaga atgtgtatgt ttttaaagac

3060

tagatataat tatttcctga tctaaaatgt atacttagct ttggattttc aatatccaag

3120

ggttttcaaa atgcacagac attgctgaac atttgcagta cctcttctgg aggctttact

3180

tcctgttaca aattggtttt gtttactggc ttatcctaat tattaaactt caattaaact

3240

tttctcctgc accttttgtt atgagctatc acatgtccct tagggactcg caagagcagt

3300

actgcccccg tgtacgggct tgcaggtaga aaggggatga cgggttttaa cacctgtgtg

3360

aggcaaggca gtccgaacag atctcattta ggaagccacg agagttgaat aagttatttt

3420

tattcttagt attttttctg taactacttt ttattataac ttggaaaata tggatgtcct

3480

ttatacacct tagcaataga ctgaatttct ttttataaat t

3521

<210> 16

<211> 974

<212> PROTEIN

<213> Felis catus

<220>

<221> additional feature

<222> (210)..(217)

<223> Xaa can be any naturally occurring

amino acid

<400> 16

Met Pro Asn Leu Ser Leu Cys His His Gly Gln Phe Ala His Val Pro

1 5 10 15

Thr Val Ser Ala Leu Gly Tyr Phe Val Ile Cys Leu Gly His Cys Pro

20 25 30

Leu Ser Leu Thr Leu Pro Glu Gly Glu Pro Leu Met Leu Met Leu Lys

35 40 45

Val Thr Phe Ala Gly Ser Pro Leu Leu Ile Pro Lys Met Arg Pro Pro

50 55 60

Asp Asn Pro Arg Ala Thr Val Cys Thr Trp Ala Lys Gln Ala Thr Phe

65 70 75 80

Cys Ala Asp Trp Gly Glu Arg Phe Gln Glu His Ser Ala Ile Val Leu

85 90 95

Gly Arg Glu Phe Gln His Ser Ile Val Ser Met Ala Val Ser Gly Phe

100 105 110

Gly Arg Gly Lys Cys Pro Arg Gly Asp Ser Gln Ala Val Ser Tyr Gly

115 120 125

Gln Gly Pro Ala Leu Ile Phe Ala Cys Ser Gly Leu Ala Gln Gly Arg

130 135 140

Glu Arg Ser Arg Lys Ser Glu Pro Trp Lys Arg Gln Ser Gly Gly Asn

145 150 155 160

Val His Ala Arg Gly Trp Ala Arg Lys Glu Arg Thr Leu Pro Arg Arg

165 170 175

Leu Arg Glu Gly Ala Pro Arg Ile Thr Ser Arg Thr Pro Arg Lys Leu

180 185 190

Lys Cys Thr Val Cys Gly Leu Leu Ile Glu Leu Ser Ser Leu Cys Ala

195 200 205

Leu Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Gly Gly Gly Gly Gly Ala Glu

210 215 220

Gln Gly Gln Ala Leu Phe Asn Gly Asp Met Glu Pro Glu Ala Gly Ala

225 230 235 240

Ala Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp Asn

245 250 255

Ile Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu

260 265 270

Asp Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala

275 280 285

Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln

290 295 300

Gln Leu Leu Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser

305 310 315 320

Ser Ala Ser Thr Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser

325 330 335

Val Leu Pro Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val Ser

340 345 350

Arg Ser Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu

355 360 365

Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val

370 375 380

Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu

385 390 395 400

Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly

405 410 415

Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu

420 425 430

Val Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Cys Thr Glu

435 440 445

Asn Val Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe

450 455 460

Gln Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys

465 470 475 480

Ser Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu

485 490 495

Leu Phe Val Ser Lys Phe Phe Glu His His Pro Ile Pro Gln Glu Glu

500 505 510

Ala Ser Ile Ala Glu Thr Ala Leu Thr Ser Gly Ser Ser Pro Ser Ala

515 520 525

Pro Pro Ser Asp Ser Thr Gly Pro Gln Ile Leu Thr Ser Pro Ser Pro

530 535 540

Ser Lys Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp

545 550 555 560

His Arg Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn

565 570 575

Val His Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg

580 585 590

Asp Gln Gly Phe Arg Ser Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala

595 600 605

Thr Pro Pro Ala Ser Leu Pro Gly Ser Leu Thr Asn Val Lys Ala Leu

610 615 620

Gln Lys Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser

625 630 635 640

Glu Asp Arg Asn Arg Met Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp

645 650 655

Asp Trp Glu Ile Pro Asp Gly Gln Ile Thr Val Gly Gln Arg Ile Gly

660 665 670

Ser Gly Ser Phe Gly Thr Val Tyr Lys Gly Lys Trp His Gly Asp Val

675 680 685

Ala Val Lys Met Leu Asn Val Thr Ala Pro Thr Pro Gln Gln Leu Gln

690 695 700

Ala Phe Lys Asn Glu Val Gly Val Leu Arg Lys Thr Arg His Val Asn

705 710 715 720

Ile Leu Leu Phe Met Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val

725 730 735

Thr Gln Trp Cys Glu Gly Ser Ser Leu Tyr His His Leu His Ile Ile

740 745 750

Glu Thr Lys Phe Glu Met Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr

755 760 765

Ala Gln Gly Met Asp Tyr Leu His Ala Lys Ser Ile Ile His Arg Asp

770 775 780

Leu Lys Ser Asn Asn Ile Phe Leu His Glu Asp Leu Thr Val Lys Ile

785 790 795 800

Gly Asp Phe Gly Leu Ala Thr Val Lys Ser Arg Trp Ser Gly Ser His

805 810 815

Gln Phe Glu Gln Leu Ser Gly Ser Ile Leu Trp Met Ala Pro Glu Val

820 825 830

Ile Arg Met Gln Asp Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr

835 840 845

Ala Phe Gly Ile Val Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr

850 855 860

Ser Asn Ile Asn Asn Arg Asp Gln Ile Ile Phe Met Val Gly Arg Gly

865 870 875 880

Tyr Leu Ser Pro Asp Leu Ser Lys Val Arg Ser Asn Cys Pro Lys Ala

885 890 895

Met Lys Arg Leu Met Ala Glu Cys Leu Lys Lys Lys Arg Asp Glu Arg

900 905 910

Pro Leu Phe Pro Gln Ile Leu Ala Ser Ile Glu Leu Leu Ala Arg Ser

915 920 925

Leu Pro Lys Ile His Arg Ser Ala Ser Glu Pro Ser Leu Asn Arg Ala

930 935 940

Gly Phe Gln Thr Glu Asp Phe Ser Leu Tyr Ala Cys Ala Ser Pro Lys

945 950 955 960

Thr Pro Ile Gln Ala Gly Gly Tyr Gly Ala Phe Pro Val His

965 970

<210> 17

<211> 3853

<212> DNA

<213> Bos taurus

<400> 17

ctcagctgcg ccgggtctca caagacggtt cccgaggtgg cccaggcgcc gtcccaccgc

60

cgacgccgcc cgggccgccc gggccgtccc tccccgctgc cccccgtcct ccgcctccgc

120

ctccccccgc cctcagcctc ccttccccct ccccgcccag cagcggtcgc tcgggcccgg

180

ctctcggtta taagatggcg gcgctgagtg gcggcggcgg cggcggcggc ggtggcgcgg

240

agcaggcca ggctctgttc aacggggaca tggagcccga ggccggcgcc gcggcctctt

300

cggctgcgga ccccgccatt cccgaggagg tgtggaatat caaacaaatg attaagttga

360

cacaggagca tatagaggcc ctattggaca aatttggtgg ggagcataat caccatcaa

420

tatatctgga ggcctatgaa gaatacacca gcaagctaga tgccctccaa caaagagaac

480

aacagttatt ggaatccctg gggaatggaa ctgatttttc tgtttctagc tctgcatcaa

540

cggacaccgt tacatcttct tcctcttcta gcctttcagt gctgccttca tctctttcag

600

tttttcaaaa tccccacagat gtgtcacgga gcaaccccaa gtcaccacaa aaacctatcg

660

ttagagtctt cctgcccaat aaacagagga cagtggtacc tgcacggtgt ggagtcacag

720

tccgggacag cctgaagaag gcactgatga tgagaggtct aatcccagag tgctgtgctg

780

tttacagaat tcaggatggg gagaagaaac caattggctg ggacactgat atttcctggc

840

ttactggaga ggagttgcat gtagaagtgt tggagaatgt tccacttaca acacacaact

900

ttgtacggaa aacttttttc accttagcat tttgtgactt ctgtagaaag ctgcttttcc

960

agggattccg ctgtcaaaca tgtggttata aatttcacca gcgttgtagt acagaggttc

1020

cactgatgtg tgttaattat gaccaactag atttgctgtt tgtctccaag ttctttgaac

1080

accacccaat accacaggag gaggcctcct tagcagagac tacccttcca tgtggctcat

1140

ccccttctgc acccccctcc gattctattg ggcccccaat tctcaccagt ccatctcctt

1200

caaaatccat tccaattcca cagcctttcc gaccagcaga tgaagatcat cgaaatcagt

1260

ttggacaacg agaccggtcc tcatcagctc caaatgtgca tataaacaca atagaacccg

1320

tcaatattga tgacttgatt agagaccaag ggtttcgtag tgatggagga tcaaccacag

1380

gtttatccgc cacaccccct gcctcattac ctggctcact ctctaatgtg aaagcattgc

1440

agaaatctcc aggacctcag cgagaaagaa agtcctcttc atcctcagaa gacaggaatc

1500

gaatgaaaac gcttggtaga cgggattcaa gtgacgattg ggagattcct gatggacaga

1560

tcacagtggg acaaagaatt ggatcagggt catttgggac agtctacaag ggaaagtggc

1620

atggtgatgt ggcagtgaaa atgttgaatg tgacagcacc cacacctcag cagttacagg

1680

ccttcaaaaa tgaagtagga gtactcagga aaacgcgaca tgtgaatatc ctcctcttca

1740

tgggttattc aacaaagcca caactggcta ttgttaccca gtggtgtgag ggctccagtt

1800

tatatcatca tctccacatc attgagacca aattcgagat gatcaaactt atagatattg

1860

cacggcagac tgcacagggc atggattact tacacgccaa gtcaatcatc cacagagacc

1920

tcaagagtaa taatattttt cttcatgaag acctcacagt aaaaataggt gattttggtc

1980

tagccacagt gaaatctcga tggagtgggt cccatcagtt tgaacagttg tctggatcca

2040

ttttgtggat ggcaccagaa gtaatcagaa tgcaagataa aaacccatat agctttcagt

2100

cagatgtata tgcatttggg attgttctgt atgaattgat gaccggacag ttaccttatt

2160

caaatatcaa caacagggac cagataattt ttatggtggg acgaggatat ctgtctccag

2220

atctcagtaa ggtacggagt aactgtccaa aagccatgaa gagattaatg gcagagtgcc

2280

taaaaaagaa aagagatgaa agaccactct ttccccaaat tctcgcctct attgagctgc

2340

tggcccgctc attgccaaaa attcaccgca gtgcatcaga accctccttg aatcgggctg

2400

gcttccaaac agaggatttt agtctatatg cttgtgcttc tccaaaaaca cccattcagg

2460

cagggggata tggtacgttt cctgttcact gaaacaaacc gagtgagtga cagcatgtag

2520

gagggtaggg acaaaagaaa gtgaacaaat gtttgcttat atatttgtta aattgaatag

2580

gattttcttt ttctttaaag gtgaacaaga gaacatgtgt gtttttaaag tttggatata

2640

gttttcttcc cagtctaaaa cccatagtta gcattacatt ttcaacatcg aatttttttt

2700

taattcatag acattgctga aaatttataa taccttttcc agaggcttta cttcccattc

2760

caagtttgtt ttgtttactt ggttagtcta atcattaaac tttaaacttt ccccacctac

2820

cttttgctgt tagctatccc gcatccatta ggggctccaa gaacagcact gtctgcgtgt

2880

gtgtgttggc aggtgggaag ctgatggtaa gttaggctgt gttagtgaag gtaaactgac

2940

caggtctaat taggagtcac tagaattgaa taagcttatt tttattaata ttttttctta

3000

taactatttc tttttgtaat aatttagaaa atataattgt tctttattcc cttacagcag

3060

tataaattat tggtgcaggt aaccaaagat attactgagg agtggcatgt ttgacatgag

3120

tgacatggtt taactttgga tttttagtta atatttcttt atatattaag gatgtcttac

3180

acattataga agtcaaattt actgacaaag gtattgcctc ctcttcctcc ccaaaaacac

3240

agcaaaattc tctgggaact cgtagcattg ttggttttct tttggatgac tatggttgcc

3300

aaacaaccaa gtaattgatt ttttttaaat tattattgct ttagattata ctcacctctc

3360

atgatgcctg ttagcaatca cctttatcca tgtgtcttgt aaaatatctt tcctccttat

3420

attctttgcc caacaagagt ctacttgtta tgaatgagta ctattttctt tttttgattc

3480

cccagtataa ttagtatgtt tagtgctttc taggacttcc actttcttat gttaaaaaaa

3540

aaaacaaact aatgtggcag tcagtatatt cttactgtga atcagagtct ttactgggaa

3600

tcaaagtgaa agaagcagct gttctgactt cagagtcagc ctaggacca aaaccagcct

3660

cttaaataca ccttcattta ttcagtttgg atttgtgatg attttcatta tagctgacag

3720

ttcaaggtta ttcagtggca cacagatagc atctgcataa atgcctttct tcttgaaaat

3780

aaaggagaaa attgggaaga ctttacacca atagtttagt ctttaagtac cacagataac

3840

acacaccata aat

3853

<210> 18

<211> 764

<212> PROTEIN

<213> Bos taurus

<400> 18

Ala Ala Leu Ser Gly Gly Gly Gly Gly Gly Gly Gly Gly Ala Glu Gln

1 5 10 15

Gly Gln Ala Leu Phe Asn Gly Asp Met Glu Pro Glu Ala Gly Ala Ala

20 25 30

Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp Asn Ile

35 40 45

Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu Asp

50 55 60

Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala Tyr

65 70 75 80

Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln Gln

85 90 95

Leu Leu Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser Ser

100 105 110

Ala Ser Thr Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser Val

115 120 125

Leu Pro Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val Ser Arg

130 135 140

Ser Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu Pro

145 150 155 160

Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val Arg

165 170 175

Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu Cys

180 185 190

Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly Trp

195 200 205

Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu Val

210 215 220

Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr Phe

225 230 235 240

Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln Gly

245 250 255

Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser Thr

260 265 270

Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu Leu Phe

275 280 285

Val Ser Lys Phe Phe Glu His His Pro Ile Pro Gln Glu Glu Ala Ser

290 295 300

Leu Ala Glu Thr Thr Leu Pro Cys Gly Ser Ser Pro Ser Ala Pro Pro

305 310 315 320

Ser Asp Ser Ile Gly Pro Pro Ile Leu Thr Ser Pro Ser Pro Ser Lys

325 330 335

Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His Arg

340 345 350

Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val His

355 360 365

Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg Asp Gln

370 375 380

Gly Phe Arg Ser Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala Thr Pro

385 390 395 400

Pro Ala Ser Leu Pro Gly Ser Leu Ser Asn Val Lys Ala Leu Gln Lys

405 410 415

Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser Glu Asp

420 425 430

Arg Asn Arg Met Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp Asp Trp

435 440 445

Glu Ile Pro Asp Gly Gln Ile Thr Val Gly Gln Arg Ile Gly Ser Gly

450 455 460

Ser Phe Gly Thr Val Tyr Lys Gly Lys Trp His Gly Asp Val Ala Val

465 470 475 480

Lys Met Leu Asn Val Thr Ala Pro Thr Pro Gln Gln Leu Gln Ala Phe

485 490 495

Lys Asn Glu Val Gly Val Leu Arg Lys Thr Arg His Val Asn Ile Leu

500 505 510

Leu Phe Met Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val Thr Gln

515 520 525

Trp Cys Glu Gly Ser Ser Leu Tyr His His Leu His Ile Ile Glu Thr

530 535 540

Lys Phe Glu Met Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr Ala Gln

545 550 555 560

Gly Met Asp Tyr Leu His Ala Lys Ser Ile Ile His Arg Asp Leu Lys

565 570 575

Ser Asn Asn Ile Phe Leu His Glu Asp Leu Thr Val Lys Ile Gly Asp

580 585 590

Phe Gly Leu Ala Thr Val Lys Ser Arg Trp Ser Gly Ser His Gln Phe

595 600 605

Glu Gln Leu Ser Gly Ser Ile Leu Trp Met Ala Pro Glu Val Ile Arg

610 615 620

Met Gln Asp Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr Ala Phe

625 630 635 640

Gly Ile Val Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr Ser Asn

645 650 655

Ile Asn Asn Arg Asp Gln Ile Ile Phe Met Val Gly Arg Gly Tyr Leu

660 665 670

Ser Pro Asp Leu Ser Lys Val Arg Ser Asn Cys Pro Lys Ala Met Lys

675 680 685

Arg Leu Met Ala Glu Cys Leu Lys Lys Lys Arg Asp Glu Arg Pro Leu

690 695 700

Phe Pro Gln Ile Leu Ala Ser Ile Glu Leu Leu Ala Arg Ser Leu Pro

705 710 715 720

Lys Ile His Arg Ser Ala Ser Glu Pro Ser Leu Asn Arg Ala Gly Phe

725 730 735

Gln Thr Glu Asp Phe Ser Leu Tyr Ala Cys Ala Ser Pro Lys Thr Pro

740 745 750

Ile Gln Ala Gly Gly Tyr Gly Thr Phe Pro Val His

755 760

<210> 19

<211> 4936

<212> DNA

<213> Bos taurus

<400> 19

ctcagctgcg ccgggtctca caagacggtt cccgaggtgg cccaggcgcc gtcccaccgc

60

cgacgccgcc cgggccgccc gggccgtccc tccccgctgc cccccgtcct ccgcctccgc

120

ctccccccgc cctcagcctc ccttccccct ccccgcccag cagcggtcgc tcgggcccgg

180

ctctcggtta taagatggcg gcgctgagtg gcggcggcgg cggcggcggc ggtggcgcgg

240

agcaggggcca ggctctgttc aacggggaca tggagcccga ggccggcgcc gcggcctctt

300

cggctgcgga ccccgccatt cccgaggagg tgtggaatat caaacaaatg attaagttga

360

cacaggagca tatagaggcc ctattggaca aatttggtgg ggagcataat caccatcaa

420

tatatctgga ggcctatgaa gaatacacca gcaagctaga tgccctccaa caaagagaac

480

aacagttatt ggaatccctg gggaatggaa ctgatttttc tgtttctagc tctgcatcaa

540

cggacaccgt tacatcttct tcctcttcta gcctttcagt gctgccttca tctctttcag

600

tttttcaaaa tccccacagat gtgtcacgga gcaaccccaa gtcaccacaa aaacctatcg

660

ttagagtctt cctgcccaat aaacagagga cagtggtacc tgcacggtgt ggagtcacag

720

tccgggacag cctgaagaag gcactgatga tgagaggtct aatcccagag tgctgtgctg

780

tttacagaat tcaggatggg gagaagaaac caattggctg ggacactgat atttcctggc

840

ttactggaga ggagttgcat gtagaagtgt tggagaatgt tccacttaca acacacaact

900

ttgtacggaa aacttttttc accttagcat tttgtgactt ctgtagaaag ctgcttttcc

960

agggattccg ctgtcaaaca tgtggttata aatttcacca gcgttgtagt acagaggttc

1020

cactgatgtg tgttaattat gaccaactag atttgctgtt tgtctccaag ttctttgaac

1080

accacccaat accacaggag gaggcctcct tagcagagac tacccttcca tgtggctcat

1140

ccccttctgc acccccctcc gattctattg ggcccccaat tctcaccagt ccatctcctt

1200

caaaatccat tccaattcca cagcctttcc gaccagcaga tgaagatcat cgaaatcagt

1260

ttggacaacg agaccggtcc tcatcagctc caaatgtgca tataaacaca atagaacccg

1320

tcaatattga tgacttgatt agagaccaag ggtttcgtag tgatggagga tcaaccacag

1380

gtttatccgc cacaccccct gcctcattac ctggctcact ctctaatgtg aaagcattgc

1440

agaaatctcc aggacctcag cgagaaagaa agtcctcttc atcctcagaa gacaggaatc

1500

gaatgaaaac gcttggtaga cgggattcaa gtgacgattg ggagattcct gatggacaga

1560

tcacagtggg acaaagaatt ggatcagggt catttgggac agtctacaag ggaaagtggc

1620

atggtgatgt ggcagtgaaa atgttgaatg tgacagcacc cacacctcag cagttacagg

1680

ccttcaaaaa tgaagtagga gtactcagga aaacgcgaca tgtgaatatc ctcctcttca

1740

tgggttattc aacaaagcca caactggcta ttgttaccca gtggtgtgag ggctccagtt

1800

tatatcatca tctccacatc attgagacca aattcgagat gatcaaactt atagatattg

1860

cacggcagac tgcacagggc atggattact tacacgccaa gtcaatcatc cacagagacc

1920

tcaagagtaa taatattttt cttcatgaag acctcacagt aaaaataggt gattttggtc

1980

tagccacagt gaaatctcga tggagtgggt cccatcagtt tgaacagttg tctggatcca

2040

ttttgtggat ggcaccagaa gtaatcagaa tgcaagataa aaacccatat agctttcagt

2100

cagatgtata tgcatttggg attgttctgt atgaattgat gaccggacag ttaccttatt

2160

caaatatcaa caacagggac cagataattt ttatggtggg acgaggatat ctgtctccag

2220

atctcagtaa ggtacggagt aactgtccaa aagccatgaa gagattaatg gcagagtgcc

2280

taaaaaagaa aagagatgaa agaccactct ttccccaagt aggaaagact ctcctaagca

2340

agagacaaaa ttcagaagtt atcagggaaa aagataagca gattctcgcc tctattgagc

2400

tgctggcccg ctcattgcca aaaattcacc gcagtgcatc agaaccctcc ttgaatcggg

2460

ctggcttcca aacagaggat tttagtctat atgcttgtgc ttctccaaaa acacccattc

2520

aggcaggggg atatgaagca gatttggctc ttacatcaaa taaaaataga gtagaagttg

2580

ggatttagag atttcctgac atgcaagaag gaataagcaa gaaaaaaagg tttgttttcc

2640

ccaaatcata tctattgtct tttacttcta ttttttctta aattttttgt gatttcagag

2700

acatgtagag ttttattgat acctaaacta tgagttcttt tttttttttt tttttcatta

2760

ttttgatttt tttggccaag aggcatatgg gatcttagct tgagaaagca acaattttct

2820

tgatgtcatt ttgggtgagg gcacatattg ctgtgaacag tgtggtgata gccaccaggg

2880

accaaactca cacccgctgc attgaaaggt gaagtcttaa acactggacc agcagagaaa

2940

ttcctactct atgagttctt tttgtcatcc cctccccgca ccctccaccc ccaacctaaa

3000

gtctgatgat gaaatcaaca actattccat tagaagcagt agattctggt agcatgatct

3060

ttagtttgtt agtaagattt tgtgctttgt ggggttgtgt cgttttaagg ctaatattta

3120

agtttgtcaa atagaatgct gttcagattg taaaaatgag taataaacat ctgaagtttt

3180

ttttaagtta tttttaacat ggtatataca gttgagctta gagtttatca ttttctgata

3240

ttctcttact tagtagatga attctagcca ttttttataa agatttctgt taagcaaatc

3300

ctgttttcac atgggcttcc tttaagggat tttagattct gctggatatg gtgactgctc

3360

ataagactgt tgaaaattac ttttaagatg tattagaata cttctgaaaa aaaatagcaa

3420

ccttaaaacc ataagcaaaa gtagtaaggg tgtttataca tttctagagt ccctgtttag

3480

gtaatagcct cctatgattg tactttaaat gttttgctct ccaaggtttt agtaacttgg

3540

ctttttttct aatcagtgcc aaactccccc agttttttta actttaaata tgaggtaata

3600

aatcttttac ccttccttga tcttttgact tataatacct tggtcagttg tttcttaaaa

3660

ggaatcctta aatggaaaga gacaatatca ctgtctgcag ttctgattag tagttttatt

3720

cagaatggaa aaacagatta ttcatttttg aaaattgttc aggggtatgt tcattgttag

3780

gaccttggac tttggagtca gtgcctagct atgcattcca ggtctgccat tttctggctg

3840

tgaaattttg gacaagttac ttaaccactt taaaccccag ctttaagaag taaattaacc

3900

ccagtaaatt aagaagtaat agcagccact tcgtagagtt gttatgaggc tcagatgcag

3960

tgcaaatgtg tataaagtat tcagggagtc acctggtata ctataataga cactagaata

4020

gttgccaata ttatcagcat acaatctgag gattctgtca gccaatcatt agcaatctgt

4080

tgtttgttgg gacatgccag tgttctccag ttgaaatcag tagcaatcta aaaatggata

4140

gattattcct catttaaata gtgtgttcat ataagtgatt gcttggatcc ttatcagaag

4200

ttgctgttac tgaaaaatga taaggctgac taaattgtga tagttgtcag ttactaacca

4260

actcccagaa atgaataaga ggaacctatc tctagttcct agtagaaggt atggacaaaa

4320

tagtaggtga aaaataatgt cttgaacccc caaattaagt aagctttaaa gagtacaata

4380

cctcaaaggg tctttgcggt ttaaaatttg tatgctgaga atgatgttca ttgacatgtg

4440

cctatatgta attttttgat agtttaaaag gtgaaatgaa ctacagatgg gagaggtctg

4500

aattttcttg ccttcagtca aatgtgtaat gtggacatat tatttgacct gtgaatttta

4560

tcttttaaaa aagattaatt cctgcttctt ccttcctaat agttgcatta taataatgaa

4620

aatgagttga taatttgggg ggaaagtatt ctacaaatca accttattat tttaccattg

4680

gtttctgaga aattttgttc atttgaaccg tttatagctt gattagaatc atagcatgta

4740

aaacccaact gagggattat ctgcagactt aatgtagtat tatgtaagtt gtcttctttc

4800

atttcgacct tttttgcttt tgttgttgct agatctgtag tatgtagcta gtcacctttc

4860

agcgaggttt cagcgaggct tttctgtgtc tctaggttat ttgagataac ttttttaaaa

4920

ttagctcttg tcctcc

4936

<210> 20

<211> 797

<212> PROTEIN

<213> Bos taurus

<400> 20

Met Ala Ala Leu Ser Gly Gly Gly Gly Gly Gly Gly Gly Gly Ala Glu

1 5 10 15

Gln Gly Gln Ala Leu Phe Asn Gly Asp Met Glu Pro Glu Ala Gly Ala

20 25 30

Ala Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp Asn

35 40 45

Ile Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu

50 55 60

Asp Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala

65 70 75 80

Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln

85 90 95

Gln Leu Leu Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser

100 105 110

Ser Ala Ser Thr Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser

115 120 125

Val Leu Pro Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val Ser

130 135 140

Arg Ser Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu

145 150 155 160

Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val

165 170 175

Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu

180 185 190

Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly

195 200 205

Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu

210 215 220

Val Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr

225 230 235 240

Phe Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln

245 250 255

Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser

260 265 270

Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu Leu

275 280 285

Phe Val Ser Lys Phe Phe Glu His His Pro Ile Pro Gln Glu Glu Ala

290 295 300

Ser Leu Ala Glu Thr Thr Leu Pro Cys Gly Ser Ser Pro Ser Ala Pro

305 310 315 320

Pro Ser Asp Ser Ile Gly Pro Pro Ile Leu Thr Ser Pro Ser Pro Ser

325 330 335

Lys Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His

340 345 350

Arg Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val

355 360 365

His Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg Asp

370 375 380

Gln Gly Phe Arg Ser Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala Thr

385 390 395 400

Pro Pro Ala Ser Leu Pro Gly Ser Leu Ser Asn Val Lys Ala Leu Gln

405 410 415

Lys Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser Glu

420 425 430

Asp Arg Asn Arg Met Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp Asp

435 440 445

Trp Glu Ile Pro Asp Gly Gln Ile Thr Val Gly Gln Arg Ile Gly Ser

450 455 460

Gly Ser Phe Gly Thr Val Tyr Lys Gly Lys Trp His Gly Asp Val Ala

465 470 475 480

Val Lys Met Leu Asn Val Thr Ala Pro Thr Pro Gln Gln Leu Gln Ala

485 490 495

Phe Lys Asn Glu Val Gly Val Leu Arg Lys Thr Arg His Val Asn Ile

500 505 510

Leu Leu Phe Met Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val Thr

515 520 525

Gln Trp Cys Glu Gly Ser Ser Leu Tyr His His Leu His Ile Ile Glu

530 535 540

Thr Lys Phe Glu Met Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr Ala

545 550 555 560

Gln Gly Met Asp Tyr Leu His Ala Lys Ser Ile Ile His Arg Asp Leu

565 570 575

Lys Ser Asn Asn Ile Phe Leu His Glu Asp Leu Thr Val Lys Ile Gly

580 585 590

Asp Phe Gly Leu Ala Thr Val Lys Ser Arg Trp Ser Gly Ser His Gln

595 600 605

Phe Glu Gln Leu Ser Gly Ser Ile Leu Trp Met Ala Pro Glu Val Ile

610 615 620

Arg Met Gln Asp Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr Ala

625 630 635 640

Phe Gly Ile Val Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr Ser

645 650 655

Asn Ile Asn Asn Arg Asp Gln Ile Ile Phe Met Val Gly Arg Gly Tyr

660 665 670

Leu Ser Pro Asp Leu Ser Lys Val Arg Ser Asn Cys Pro Lys Ala Met

675 680 685

Lys Arg Leu Met Ala Glu Cys Leu Lys Lys Lys Arg Asp Glu Arg Pro

690 695 700

Leu Phe Pro Gln Val Gly Lys Thr Leu Leu Ser Lys Arg Gln Asn Ser

705 710 715 720

Glu Val Ile Arg Glu Lys Asp Lys Gln Ile Leu Ala Ser Ile Glu Leu

725 730 735

Leu Ala Arg Ser Leu Pro Lys Ile His Arg Ser Ala Ser Glu Pro Ser

740 745 750

Leu Asn Arg Ala Gly Phe Gln Thr Glu Asp Phe Ser Leu Tyr Ala Cys

755 760 765

Ala Ser Pro Lys Thr Pro Ile Gln Ala Gly Gly Tyr Glu Ala Asp Leu

770 775 780

Ala Leu Thr Ser Asn Lys Asn Arg Val Glu Val Gly Ile

785 790 795

<210> 21

<211> 4154

<212> DNA

<213> Bos taurus

<400> 21

ctcagctgcg ccgggtctca caagacggtt cccgaggtgg cccaggcgcc gtcccaccgc

60

cgacgccgcc cgggccgccc gggccgtccc tccccgctgc cccccgtcct ccgcctccgc

120

ctccccccgc cctcagcctc ccttccccct ccccgcccag cagcggtcgc tcgggcccgg

180

ctctcggtta taagatggcg gcgctgagtg gcggcggcgg cggcggcggc ggtggcgcgg

240

agcaggcca ggctctgttc aacggggaca tggagcccga ggccggcgcc gcggcctctt

300

cggctgcgga ccccgccatt cccgaggagg tgtggaatat caaacaaatg attaagttga

360

cacaggagca tatagaggcc ctattggaca aatttggtgg ggagcataat caccatcaa

420

tatatctgga ggcctatgaa gaatacacca gcaagctaga tgccctccaa caaagagaac

480

aacagttatt ggaatccctg gggaatggaa ctgatttttc tgtttctagc tctgcatcaa

540

cggacaccgt tacatcttct tcctcttcta gcctttcagt gctgccttca tctctttcag

600

tttttcaaaa tccccacagat gtgtcacgga gcaaccccaa gtcaccacaa aaacctatcg

660

ttagagtctt cctgcccaat aaacagagga cagtggtacc tgcacggtgt ggagtcacag

720

tccgggacag cctgaagaag gcactgatga tgagaggtct aatcccagag tgctgtgctg

780

tttacagaat tcaggatggg gagaagaaac caattggctg ggacactgat atttcctggc

840

ttactggaga ggagttgcat gtagaagtgt tggagaatgt tccacttaca acacacaact

900

ttgtacggaa aacttttttc accttagcat tttgtgactt ctgtagaaag ctgcttttcc

960

agggattccg ctgtcaaaca tgtggttata aatttcacca gcgttgtagt acagaggttc

1020

cactgatgtg tgttaattat gaccaactag atttgctgtt tgtctccaag ttctttgaac

1080

accacccaat accacaggag gaggcctcct tagcagagac tacccttcca tgtggctcat

1140

ccccttctgc acccccctcc gattctattg ggcccccaat tctcaccagt ccatctcctt

1200

caaaatccat tccaattcca cagcctttcc gaccagcaga tgaagatcat cgaaatcagt

1260

ttggacaacg agaccggtcc tcatcagctc caaatgtgca tataaacaca atagaacccg

1320

tcaatattga tgacttgatt agagaccaag ggtttcgtag tgatggagga tcaaccacag

1380

gtttatccgc cacaccccct gcctcattac ctggctcact ctctaatgtg aaagcattgc

1440

agaaatctcc aggacctcag cgagaaagaa agtcctcttc atcctcagaa gacaggaatc

1500

gaatgaaaac gcttggtaga cgggattcaa gtgacgattg ggagattcct gatggacaga

1560

tcacagtggg acaaagaatt ggatcagggt catttgggac agtctacaag ggaaagtggc

1620

atggtgatgt ggcagtgaaa atgttgaatg tgacagcacc cacacctcag cagttacagg

1680

ccttcaaaaa tgaagtagga gtactcagga aaacgcgaca tgtgaatatc ctcctcttca

1740

tgggttattc aacaaagcca caactggcta ttgttaccca gtggtgtgag ggctccagtt

1800

tatatcatca tctccacatc attgagacca aattcgagat gatcaaactt atagatattg

1860

cacggcagac tgcacagggc atggattact tacacgccaa gtcaatcatc cacagagacc

1920

tcaagagtaa taatattttt cttcatgaag acctcacagt aaaaataggt gattttggtc

1980

tagccacagt gaaatctcga tggagtgggt cccatcagtt tgaacagttg tctggatcca

2040

ttttgtggat ggcaccagaa gtaatcagaa tgcaagataa aaacccatat agctttcagt

2100

cagatgtata tgcatttggg attgttctgt atgaattgat gaccggacag ttaccttatt

2160

caaatatcaa caacagggac cagataattt ttatggtggg acgaggatat ctgtctccag

2220

atctcagtaa ggtacggagt aactgtccaa aagccatgaa gagattaatg gcagagtgcc

2280

taaaaaagaa aagagatgaa agaccactct ttccccaagt aggaaagact ctcctaagca

2340

agagacaaaa ttcagaagtt atcagggaaa aagataagca gattctcgcc tctattgagc

2400

tgctggcccg ctcattgcca aaaattcacc gcagtgcatc agaaccctcc ttgaatcggg

2460

ctggcttcca aacagaggat tttagtctat atgcttgtgc ttctccaaaa acacccattc

2520

aggcagggggg atatggctga gcacattgtc catcaccac aagtggctgg ttctcatcgc

2580

agaatctacg tagggaatcg ggcgtgaaat tcacttaaga gataggcag aggaagtgtt

2640

ctgtttacag gaatggagat gagagttatg agtaagttgc ttagtcagtt ggctttgttt

2700

tgaaaattat tgtgttatat ttgtgttaac ctacttgtgt tttgacagta tatgtcacat

2760

aggaagaaac ctcagactag cataataaca aagctcagac taggcacaga tgtacacaga

2820

atggaccaaa atgggatggg ggaaggtatg ggaataagtc taggggtagg gaaaaattga

2880

tgtgaggtg ggaaataaac tgtaattacc tgaaataaaa tgtaagagtg caataagtgt

2940

gctttttatt ctaagctgtg aatgggtttt ttaaaaaaag cattccttcc caatgcattt

3000

gcctatgttc catagctgat taaaaccagc tatataaaca tatgcctttt tattcatgtt

3060

aattaccaat ataaatggct aacctttacg tcttatttat cttcatgtta tgttagttta

3120

catacaggga tgtgtgtgtg tgtgtatgct ataaattttc cctccttcgt ttaaaaacgc

3180

gtttgttgga tcctctctgt ttccttaggc catgccacag ctcatagtct cagcttggcc

3240

ttcctgtcac ctgatctgaa ggactatcac agtgacgtag ctcgttcatt ggttgtacac

3300

actctaaccc ttttccttgc tcagcaatta ctgtgtcttc taaaacagga gtgtacaacc

3360

atgagattgc aattaattgt ttgacatatg tccctttgaa ttctatttat tagttatgat

3420

tgattgctct ttggtttgga ccaagaaaaa cgaaatccca cctccccacc ttttcactta

3480

tttcttactt tgaggacaat tctgtaagag agaggaaagg gaactccttc atgttttaac

3540

tgcagcaagt taatggccct ggtttacacc aaacattatg gtgattcaca ttcacattcc

3600

tctcctctct tgctgccaga ggtttggggtt ttgttcagtt ctgctcaagc actgaaaaag

3660

ttttcatgga gtctggagag tgcccagtga aaagatggtt tttaattgtc cacagacctt

3720

tctgttcctg ctttgcaaaa attacaaagg agtaactatt tttaaagctt atttttcaat

3780

tcataaaaaa gacatttatt ttcagtcaga tgatgtctcc ttgtccctta atcctcaatg

3840

tttgcttgaa tctttttttt ttttctgatt ttctcccatc cccacttctt gatacttctt

3900

gagttctctt tcctgctcag gtcctttcat ttgtactttg gagttttttc tcatgtaaat

3960

ttgtacaatg gaaaatattg ttcagtttgg atagaacgca tggagaatta aataaaaaag

4020

atagctgaaa ttcagattga aatttatttg tgtaaagtta tttaaaaact ctgtactata

4080

taaaaggcaa aaaaagttct atgtacttga tgtgaatatg cgaatactgc tataataaag

4140

attgactgca tgga

4154

<210> 22

<211> 781

<212> PROTEIN

<213> Bos taurus

<400> 22

Met Ala Ala Leu Ser Gly Gly Gly Gly Gly Gly Gly Gly Gly Ala Glu

1 5 10 15

Gln Gly Gln Ala Leu Phe Asn Gly Asp Met Glu Pro Glu Ala Gly Ala

20 25 30

Ala Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp Asn

35 40 45

Ile Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu

50 55 60

Asp Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala

65 70 75 80

Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln

85 90 95

Gln Leu Leu Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser

100 105 110

Ser Ala Ser Thr Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser

115 120 125

Val Leu Pro Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val Ser

130 135 140

Arg Ser Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu

145 150 155 160

Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val

165 170 175

Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu

180 185 190

Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly

195 200 205

Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu

210 215 220

Val Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr

225 230 235 240

Phe Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln

245 250 255

Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser

260 265 270

Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu Leu

275 280 285

Phe Val Ser Lys Phe Phe Glu His His Pro Ile Pro Gln Glu Glu Ala

290 295 300

Ser Leu Ala Glu Thr Thr Leu Pro Cys Gly Ser Ser Pro Ser Ala Pro

305 310 315 320

Pro Ser Asp Ser Ile Gly Pro Pro Ile Leu Thr Ser Pro Ser Pro Ser

325 330 335

Lys Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His

340 345 350

Arg Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val

355 360 365

His Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg Asp

370 375 380

Gln Gly Phe Arg Ser Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala Thr

385 390 395 400

Pro Pro Ala Ser Leu Pro Gly Ser Leu Ser Asn Val Lys Ala Leu Gln

405 410 415

Lys Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser Glu

420 425 430

Asp Arg Asn Arg Met Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp Asp

435 440 445

Trp Glu Ile Pro Asp Gly Gln Ile Thr Val Gly Gln Arg Ile Gly Ser

450 455 460

Gly Ser Phe Gly Thr Val Tyr Lys Gly Lys Trp His Gly Asp Val Ala

465 470 475 480

Val Lys Met Leu Asn Val Thr Ala Pro Thr Pro Gln Gln Leu Gln Ala

485 490 495

Phe Lys Asn Glu Val Gly Val Leu Arg Lys Thr Arg His Val Asn Ile

500 505 510

Leu Leu Phe Met Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val Thr

515 520 525

Gln Trp Cys Glu Gly Ser Ser Leu Tyr His His Leu His Ile Ile Glu

530 535 540

Thr Lys Phe Glu Met Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr Ala

545 550 555 560

Gln Gly Met Asp Tyr Leu His Ala Lys Ser Ile Ile His Arg Asp Leu

565 570 575

Lys Ser Asn Asn Ile Phe Leu His Glu Asp Leu Thr Val Lys Ile Gly

580 585 590

Asp Phe Gly Leu Ala Thr Val Lys Ser Arg Trp Ser Gly Ser His Gln

595 600 605

Phe Glu Gln Leu Ser Gly Ser Ile Leu Trp Met Ala Pro Glu Val Ile

610 615 620

Arg Met Gln Asp Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr Ala

625 630 635 640

Phe Gly Ile Val Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr Ser

645 650 655

Asn Ile Asn Asn Arg Asp Gln Ile Ile Phe Met Val Gly Arg Gly Tyr

660 665 670

Leu Ser Pro Asp Leu Ser Lys Val Arg Ser Asn Cys Pro Lys Ala Met

675 680 685

Lys Arg Leu Met Ala Glu Cys Leu Lys Lys Lys Arg Asp Glu Arg Pro

690 695 700

Leu Phe Pro Gln Val Gly Lys Thr Leu Leu Ser Lys Arg Gln Asn Ser

705 710 715 720

Glu Val Ile Arg Glu Lys Asp Lys Gln Ile Leu Ala Ser Ile Glu Leu

725 730 735

Leu Ala Arg Ser Leu Pro Lys Ile His Arg Ser Ala Ser Glu Pro Ser

740 745 750

Leu Asn Arg Ala Gly Phe Gln Thr Glu Asp Phe Ser Leu Tyr Ala Cys

755 760 765

Ala Ser Pro Lys Thr Pro Ile Gln Ala Gly Gly Tyr Gly

770 775 780

<210> 23

<211> 7914

<212> DNA

<213> Bos taurus

<400> 23

ctcagctgcg ccgggtctca caagacggtt cccgaggtgg cccaggcgcc gtcccaccgc

60

cgacgccgcc cgggccgccc gggccgtccc tccccgctgc cccccgtcct ccgcctccgc

120

ctccccccgc cctcagcctc ccttccccct ccccgcccag cagcggtcgc tcgggcccgg

180

ctctcggtta taagatggcg gcgctgagtg gcggcggcgg cggcggcggc ggtggcgcgg

240

agcaggcca ggctctgttc aacggggaca tggagcccga ggccggcgcc gcggcctctt

300

cggctgcgga ccccgccatt cccgaggagg tgtggaatat caaacaaatg attaagttga

360

cacaggagca tatagaggcc ctattggaca aatttggtgg ggagcataat caccatcaa

420

tatatctgga ggcctatgaa gaatacacca gcaagctaga tgccctccaa caaagagaac

480

aacagttatt ggaatccctg gggaatggaa ctgatttttc tgtttctagc tctgcatcaa

540

cggacaccgt tacatcttct tcctcttcta gcctttcagt gctgccttca tctctttcag

600

tttttcaaaa tccccacagat gtgtcacgga gcaaccccaa gtcaccacaa aaacctatcg

660

ttagagtctt cctgcccaat aaacagagga cagtggtacc tgcacggtgt ggagtcacag

720

tccgggacag cctgaagaag gcactgatga tgagaggtct aatcccagag tgctgtgctg

780

tttacagaat tcaggatggg gagaagaaac caattggctg ggacactgat atttcctggc

840

ttactggaga ggagttgcat gtagaagtgt tggagaatgt tccacttaca acacacaact

900

ttgtacggaa aacttttttc accttagcat tttgtgactt ctgtagaaag ctgcttttcc

960

agggattccg ctgtcaaaca tgtggttata aatttcacca gcgttgtagt acagaggttc

1020

cactgatgtg tgttaattat gaccaactag atttgctgtt tgtctccaag ttctttgaac

1080

accacccaat accacaggag gaggcctcct tagcagagac tacccttcca tgtggctcat

1140

ccccttctgc acccccctcc gattctattg ggcccccaat tctcaccagt ccatctcctt

1200

caaaatccat tccaattcca cagcctttcc gaccagcaga tgaagatcat cgaaatcagt

1260

ttggacaacg agaccggtcc tcatcagctc caaatgtgca tataaacaca atagaacccg

1320

tcaatattga tgacttgatt agagaccaag ggtttcgtag tgatggagga tcaaccacag

1380

gtttatccgc cacaccccct gcctcattac ctggctcact ctctaatgtg aaagcattgc

1440

agaaatctcc aggacctcag cgagaaagaa agtcctcttc atcctcagaa gacaggaatc

1500

gaatgaaaac gcttggtaga cgggattcaa gtgacgattg ggagattcct gatggacaga

1560

tcacagtggg acaaagaatt ggatcagggt catttgggac agtctacaag ggaaagtggc

1620

atggtgatgt ggcagtgaaa atgttgaatg tgacagcacc cacacctcag cagttacagg

1680

ccttcaaaaa tgaagtagga gtactcagga aaacgcgaca tgtgaatatc ctcctcttca

1740

tgggttattc aacaaagcca caactggcta ttgttaccca gtggtgtgag ggctccagtt

1800

tatatcatca tctccacatc attgagacca aattcgagat gatcaaactt atagatattg

1860

cacggcagac tgcacagggc atggattact tacacgccaa gtcaatcatc cacagagacc

1920

tcaagagtaa taatattttt cttcatgaag acctcacagt aaaaataggt gattttggtc

1980

tagccacagt gaaatctcga tggagtgggt cccatcagtt tgaacagttg tctggatcca

2040

ttttgtggat ggcaccagaa gtaatcagaa tgcaagataa aaacccatat agctttcagt

2100

cagatgtata tgcatttggg attgttctgt atgaattgat gaccggacag ttaccttatt

2160

caaatatcaa caacagggac cagataattt ttatggtggg acgaggatat ctgtctccag

2220

atctcagtaa ggtacggagt aactgtccaa aagccatgaa gagattaatg gcagagtgcc

2280

taaaaaagaa aagagatgaa agaccactct ttccccaaat tctcgcctct attgagctgc

2340

tggcccgctc attgccaaaa attcaccgca gtgcatcaga accctccttg aatcgggctg

2400

gcttccaaac agaggatttt agtctatatg cttgtgcttc tccaaaaaca cccattcagg

2460

cagggggata tggagaattt gcagccttca agtagccaca ccatcatgac agcatctact

2520

cttatttctt aagtcttgtg ttcgtacaat ttgttaacat caaaacacag ttctgttcct

2580

caactctttt taaagttaaa atttttcagt gcataagctg gtgtggaaca gaaggaaatt

2640

tcccatccaa caaaagaggg aagaatgttt taggaaccag aattctctgc tgccagtgtt

2700

tcttcttcaa cacaaatatc acaagtctgc ccactcccag gaagaaagag gagagaccct

2760

gagttctgac cttttgatgg tcaggcatga tggaaagaaa ctgctgctac agcttgggag

2820

atttgctctg ggaagtctgc cagtcaactt tgcccttcta accaccagat caatatgtgg

2880

ctgatcatct gatggggcag ttgcaatcac caagccttgt tctctttcct gttctgggat

2940

tgtgttgtgg aacccttttc cctagccacc accagttcat ttctgaggga tggaacaaaa

3000

atgcagcatg cccttcctgt gtggtgcatg ttcagtcctt gacaaatttt taccaaaatg

3060

aagctacttt atttaaaagg agggtgagag gtgaggaggt cactttgggt gtggcggaaa

3120

gggaatgctg catctttttc ctgggctgct ggggctctgg ccttggcttg ccagccggaa

3180

gcgctggcac gcatcgcctt cttttcccat tgggtccagc aatgaagacg agtgtttggg

3240

gttttttttt tctccaccat gtagcaagtt ctcaggaaaa tacaattgat atcttcctcc

3300

taagctcttc caatcagtca ccaagtactt atgtggttac tttgtccagg gcacaaaatg

3360

cctgtatcta attaaaagcc tacaaaactg cttgataaca gttttgaatg tgagacattt

3420

atgtaattta aatgtaaggt acaagtttta atttctgagt ttcttctatt atatttttat

3480

taaaaaaaga aaataatttt cagattgaat tggagtaaaa taatattact tcccactaga

3540

attatatatc ctggaaaatt gtatttttgt tacataagca gcttttaaag aaagatcatt

3600

acccttttct ctacataaat atatggggag tcttagccta atgacaaata tttataattt

3660

ttaaattaat ggtacttgct ggatccatac taacatcttt actaatacct cattgtttct

3720

tccaacttac tcctacacta catcctacat cttcttccta gtcttttatc tagaatatgc

3780

aacctcaaat aaaaatggtg gtgtcctcat tcattctcct ccttcctttt ttcccaagcc

3840

tgatcttcaa aaggttggtt aatttggcag ctgagttcct ccccaggcag agaatagacc

3900

aattttaggt gtattgggac tgagggagga tgtgtaaaga ttaacatcag taaagaaccg

3960

ctgtggagta attaagaact ttgttcttta taactggaga atataaccta accctaacat

4020

ccctcagcct ttactaaagt gtggcgtaaa tcacagtagt agcaaagaaa gtgactctgg

4080

atgtgttcct ggccagtacc tcccttatca tgaatgtaga ctctctcatc aagatttagg

4140

aatataaatc aaatcaaatg tgcccagcca agctatgtag taagggactt gaacaatatt

4200

aggcagaacc tataaaataa atcagggaat tagaaattat ttaaagtttt caaattgtaa

4260

attgccccgg tgtctttcag cctactgcca ttatttttgc tacaatacct acatttcaga

4320

ggagggccta ctgaaaattc catgcaagtg gaaaataatc ctcaagttat taatgagttt

4380

gaaaagcaat gagttcttaa gtctttgtga gtagagcaag atcctacaaa attcagaaat

4440

agtaaaaatg gattcatgct gatttgaaga gcatctgtgt gcataatata atgctgcatc

4500

tcttttaaaa gcagtctatt tttcttttta aatttgtccc catagatgct tttgaacatg

4560

aacatgctta tgttaccttt tccgaggttg ggaagagcca ggagctctca ggcagggccc

4620

cctccctcag ctgggcagga gctgctcagg aggagctagt tatagaggaa gcttagcgtt

4680

ggcattttca aaattcaagg tgataacgct ttcttcttcc tttctgtttt agaatagatt

4740

gctgtctgat ttgaaaaagg gaaatagatt tgatctcaaa tgaatctgtg cccagaagcc

4800

aggctcaggg tattcagaga tttgtatagt gccctcaaaa aataacaaaa ttttagcttt

4860

ccttttttct tcttttctcc atcaaattct tttttctcta gtttacaaat gacatggaaa

4920

aggaatttcc cctgagtttt gtatgccttt ttttttttgg cttagactat agataggcgt

4980

gttgagctcc taagaaaata caagggaggaa ctctttgttg tgcagagcac tttatgagta

5040

gtttgtgtgg ataatatgtg actgcttccc tgacgagctt gtgaggctgt acttatgtct

5100

ttcctgtaag gcagcttcag tgccttctgt agtgtatata aggaaagatt acgccttctg

5160

aaaaatctca gagcaaccat aagattattt taaaatatgt agtatgactg atggactttt

5220

tcatcattaa attagtctag catctaaact tttaccactg aaataatatt gaccaaaaag

5280

caatttataa aaggtatttg tgaatagaaa atacaatgtg atcatttgta cttatgtgca

5340

ccttaaaaga ggaattctgt ctagctgtca aattctggtt ccttaacatc cagtccttga

5400

ttgtgattga gatctggtag gacgtgctgg ggcacgctag cagataaaat cccgtatact

5460

ttaggataga tgttacattt atgtcagtgt tggcaaagag cattgtgtag taataaagaa

5520

ttcaagactt cagcaatgtc aacctgaaac tttgtaaata tttcctagat tgttatttga

5580

tgcagtcaca gctctttatc acacaatgtt gtctttccct catcaggcaa ttttagaact

5640

gctgcacacc cctcctcaga tctcacctgc ccctcctgta cattcacctc tccagccttg

5700

tgcacacctc atttagcttt agtttgaaac acattgcagg gttcaggtga cctcttcaaa

5760

aactacctcc tcagaatgag gtaatgaata gttatttatt ttaaaatatg aaaagtcagg

5820

agctctagaa tatgaagatg atctaagatt ttaactttta tgtatacttg ttgagcactc

5880

tccttttgtc ctaaagggca ttatacattt aagcagtaat actgaaaaat gtagctcaga

5940

gtaactgaat gttgttgaaa gtggtgccag aatctgtttt aggggtacgt atcagaatct

6000

taatcttaaa tcggttacat gaaattaaat agttaatggt aacacttgac taacagatat

6060

aattttaatt ttcggtaggc ttttagcaag acagtaagta catcttcata atgagttagc

6120

cacagcttca tcacatgcac agattttcct gttgagagac tgcccagtta agaggtaga

6180

atgatgaacc atttttcagg attctcttct ttgtccaaac tggcattgtg agtgctagaa

6240

tatcagcact ttcaaactag tgattccaac tattaggcta ttaaaaagca aaacaaacca

6300

aacaaaccat agccagacat gggaagttta ctatgagtat aaacagcaaa tagcttacag

6360

gtcatacatt gaaatggtgt aggtaaggcg ttagaaaaat accttgacaa tttgccaaat

6420

gatcttactg tgccttcatg atgcaataaa aaaaaaaaaa atttagcata aatcagtgat

6480

ttgtgaagag agcagccacc ctggtctaac tcagctgtgt taatattttt tagcgtgcaa

6540

tttagactgc aaagataaat gcactaaaga gtttatagcc aaaatcacat ttaaaaaatg

6600

agagaaaaca caggtaaatt ttcagtgaac aaaattattt ttttaaagta cataatccct

6660

agtatagtca gatatattta tcacatagag caaataggtt gaaatcacaa ttcagtgaca

6720

tttctagaga aactttttct actcccatag gttcttcaaa gcatggaact tttatataac

6780

agaaatgtgt gacggtcatt ttaaattgct gtagtttggg gctgaagtac tgtgtgctgg

6840

gcagcaatca catgtattaa ctagtgagaa aggagaaatt aagatatagg acagaatttg

6900

attttcttgt tccgatta ctgctgccaa cctagacact gagtttccag aggctgaaac

6960

gtaaacttgc agctcagcaa ctgttttgca aagttagtgg gactgtcctg cttatgctgt

7020

tcaaaaatgc tctgaggggcc aggtggggcc tccaggggct cctctctgag gggacatcag

7080

actagctaac gacctggcgg gcggatgtga accggacaca ctccatggtg tgcttcttgt

7140

atcggtccct cgccaccctc aagaaaggct tcagcgggtt ctctagacgt ctccactaag

7200

gtgtgttact aacagccatg ggttgttgag cacccgagga gtgcaatagc atctctgcat

7260

gattgtatat tggcccgaag agaatgaagt ggccagtgta ctcatgttcc atgttgctag

7320

ctctggtaaa ctgaaaatac tggtaagatt tttgttttat cagtacacta gagagtaagc

7380

tttgttttgt tgtttttaga taatgttttc acttccattt ggaaagacat ttaaattgag

7440

tttcagtcct aaattttgcc agtcatggta attagcagtt tctatcaggt atttttaagg

7500

tagaagagga tagaaacata agttctaaaa gcttaaggta accgtggttt attttaaaat

7560

gtttaggggt ggttagtctc tacctcaaaa aaagtgagtg aatcttttat ttcagcattc

7620

acaagttcgg ctgttgtttt tgtaatacat ttttttttta accttttgac ccccctttac

7680

ctaagtgtca atgtagtttt attaattact aagtcagttt cattaaaatg tttatttagc

7740

agttttgact aattgcaatg attaatatag ccagttgtgc atgaggacac agccagtgag

7800

tatatctggg ttttttttgt gatgcttttt ttcttaagac ttctgtagat ttatgaagta

7860

ctcattgaaa acaactaaaa tacgtttatt cgtgttaata tggaaaaaaa aaaa

7914

<210> 24

<211> 766

<212> PROTEIN

<213> Bos taurus

<400> 24

Met Ala Ala Leu Ser Gly Gly Gly Gly Gly Gly Gly Gly Gly Ala Glu

1 5 10 15

Gln Gly Gln Ala Leu Phe Asn Gly Asp Met Glu Pro Glu Ala Gly Ala

20 25 30

Ala Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp Asn

35 40 45

Ile Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu

50 55 60

Asp Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala

65 70 75 80

Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln

85 90 95

Gln Leu Leu Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser

100 105 110

Ser Ala Ser Thr Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser

115 120 125

Val Leu Pro Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val Ser

130 135 140

Arg Ser Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu

145 150 155 160

Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val

165 170 175

Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu

180 185 190

Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly

195 200 205

Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu

210 215 220

Val Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr

225 230 235 240

Phe Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln

245 250 255

Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser

260 265 270

Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu Leu

275 280 285

Phe Val Ser Lys Phe Phe Glu His His Pro Ile Pro Gln Glu Glu Ala

290 295 300

Ser Leu Ala Glu Thr Thr Leu Pro Cys Gly Ser Ser Pro Ser Ala Pro

305 310 315 320

Pro Ser Asp Ser Ile Gly Pro Pro Ile Leu Thr Ser Pro Ser Pro Ser

325 330 335

Lys Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His

340 345 350

Arg Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val

355 360 365

His Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg Asp

370 375 380

Gln Gly Phe Arg Ser Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala Thr

385 390 395 400

Pro Pro Ala Ser Leu Pro Gly Ser Leu Ser Asn Val Lys Ala Leu Gln

405 410 415

Lys Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser Glu

420 425 430

Asp Arg Asn Arg Met Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp Asp

435 440 445

Trp Glu Ile Pro Asp Gly Gln Ile Thr Val Gly Gln Arg Ile Gly Ser

450 455 460

Gly Ser Phe Gly Thr Val Tyr Lys Gly Lys Trp His Gly Asp Val Ala

465 470 475 480

Val Lys Met Leu Asn Val Thr Ala Pro Thr Pro Gln Gln Leu Gln Ala

485 490 495

Phe Lys Asn Glu Val Gly Val Leu Arg Lys Thr Arg His Val Asn Ile

500 505 510

Leu Leu Phe Met Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val Thr

515 520 525

Gln Trp Cys Glu Gly Ser Ser Leu Tyr His His Leu His Ile Ile Glu

530 535 540

Thr Lys Phe Glu Met Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr Ala

545 550 555 560

Gln Gly Met Asp Tyr Leu His Ala Lys Ser Ile Ile His Arg Asp Leu

565 570 575

Lys Ser Asn Asn Ile Phe Leu His Glu Asp Leu Thr Val Lys Ile Gly

580 585 590

Asp Phe Gly Leu Ala Thr Val Lys Ser Arg Trp Ser Gly Ser His Gln

595 600 605

Phe Glu Gln Leu Ser Gly Ser Ile Leu Trp Met Ala Pro Glu Val Ile

610 615 620

Arg Met Gln Asp Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr Ala

625 630 635 640

Phe Gly Ile Val Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr Ser

645 650 655

Asn Ile Asn Asn Arg Asp Gln Ile Ile Phe Met Val Gly Arg Gly Tyr

660 665 670

Leu Ser Pro Asp Leu Ser Lys Val Arg Ser Asn Cys Pro Lys Ala Met

675 680 685

Lys Arg Leu Met Ala Glu Cys Leu Lys Lys Lys Arg Asp Glu Arg Pro

690 695 700

Leu Phe Pro Gln Ile Leu Ala Ser Ile Glu Leu Leu Ala Arg Ser Leu

705 710 715 720

Pro Lys Ile His Arg Ser Ala Ser Glu Pro Ser Leu Asn Arg Ala Gly

725 730 735

Phe Gln Thr Glu Asp Phe Ser Leu Tyr Ala Cys Ala Ser Pro Lys Thr

740 745 750

Pro Ile Gln Ala Gly Gly Tyr Gly Glu Phe Ala Ala Phe Lys

755 760 765

<210> 25

<211> 4670

<212> DNA

<213> Bos taurus

<400> 25

ggtgtgtcat agtgcagcag attgaatgca gaagatatga aaattcagat gtcttctgtt

60

aaggtgtgga atatcaaaca aatgattaag ttgacacagg agcatataga ggccctattg

120

gacaaatttg gtggggagca taatccacca tcaatatatc tggaggccta tgaagaatac

180

accagcaagc tagatgccct ccaacaaaga gaacaacagt tattggaatc cctggggaat

240

ggaactgatt tttctgtttc tagctctgca tcaacggaca ccgttacatc ttcttcctct

300

tctagccttt cagtgctgcc ttcatctctt tcagtttttc aaaatcccac agatgtgtca

360

cggagcaacc ccaagtcacc acaaaaacct atcgttagag tcttcctgcc caataaacag

420

aggacagtgg tacctgcacg gtgtggagtc acagtccggg acagcctgaa gaaggcactg

480

atgatgagag gtctaatccc agagtgctgt gctgtttaca gaattcagga tggggagaag

540

aaaccaattg gctgggacac tgatatttcc tggcttactg gagaggagtt gcatgtagaa

600

gtgttggaga atgttccact tacaacacac aactttgtac ggaaaacttt tttcacctta

660

gcattttgtg acttctgtag aaagctgctt ttccagggat tccgctgtca aacatgtggt

720

tataaatttc accagcgttg tagtacagag gttccactga tgtgtgttaa ttatgaccaa

780

ctagatttgc tgtttgtctc caagttcttt gaacaccacc caataccaca ggaggaggcc

840

tccttagcag agactaccct tccatgtggc tcatcccctt ctgcaccccc ctccgattct

900

attgggcccc caattctcac cagtccatct ccttcaaaat ccattccaat tccacagcct

960

ttccgaccag cagatgaaga tcatcgaaat cagtttggac aacgagaccg gtcctcatca

1020

gctccaaatg tgcatataaa cacaatagaa cccgtcaata ttgatgactt gattagagac

1080

caagggtttc gtagtgatgg aggatcaacc acaggtttat ccgccacacc ccctgcctca

1140

ttacctggct cactctctaa tgtgaaagca ttgcagaaat ctccaggacc tcagcgagaa

1200

agaaagtcct cttcatcctc agaagacagg aatcgaatga aaacgcttgg tagacgggat

1260

tcaagtgacg attgggagat tcctgatgga cagatcacag tgggacaaag aattggatca

1320

gggtcatttg ggacagtcta caagggaaag tggcatggtg atgtggcagt gaaaatgttg

1380

aatgtgacag cacccacacc tcagcagtta caggccttca aaaatgaagt aggagtactc

1440

aggaaaacgc gacatgtgaa tatcctcctc ttcatgggtt attcaacaaa gccacaactg

1500

gctattgtta cccagtggtg tgagggctcc agtttatatc atcatctcca catcattgag

1560

accaaattcg agatgatcaa acttatagat attgcacggc agactgcaca gggcatggat

1620

tacttacacg ccaagtcaat catccacaga gacctcaaga gtaataatat ttttcttcat

1680

gaagacctca cagtaaaaat aggtgatttt ggtctagcca cagtgaaatc tcgatggagt

1740

gggtcccatc agtttgaaca gttgtctgga tccattttgt ggatggcacc agaagtaatc

1800

agaatgcaag ataaaaaccc atatagcttt cagtcagatg tatatgcatt tgggattgtt

1860

ctgtatgaat tgatgaccgg acagttacct tattcaaata tcaacaacag ggaccagata

1920

atttttatgg tgggacgagg atatctgtct ccagatctca gtaaggtacg gagtaactgt

1980

ccaaaagcca tgaagagatt aatggcagag tgcctaaaaa agaaaagaga tgaaagacca

2040

ctctttcccc aagtaggaaa gactctccta agcaagagac aaaattcaga agttatcagg

2100

gaaaaagata agcagattct cgcctctatt gagctgctgg cccgctcatt gccaaaaatt

2160

caccgcagtg catcagaacc ctccttgaat cgggctggct tccaaacaga ggattttagt

2220

ctatatgctt gtgcttctcc aaaaacaccc attcaggcag ggggatatga agcagatttg

2280

gctcttacat caaataaaaa tagagtagaa gttgggattt agagatttcc tgacatgcaa

2340

gaaggaataa gcaagaaaaa aaggtttgtt ttccccaaat catatctatt gtctttttact

2400

tctatttttt cttaaatttt ttgtgatttc agagacatgt agagttttat tgatacctaa

2460

actatgagtt cttttttttt tttttttttc attattttga tttttttggc caagaggcat

2520

atgggatctt agcttgagaa agcaacaatt ttcttgatgt cattttgggt gagggcacat

2580

attgctgtga acagtgtggt gatagccacc agggaccaaa ctcacacccg ctgcattgaa

2640

aggtgaagtc ttaaacactg gaccagcaga gaaattccta ctctatgagt tctttttgtc

2700

atcccctccc cgcaccctcc acccccaacc taaagtctga tgatgaaatc aacaactatt

2760

ccattagaag cagtagattc tggtagcatg atctttagtt tgttagtaag attttgtgct

2820

ttgtggggtt gtgtcgtttt aaggctaata tttaagtttg tcaaatagaa tgctgttcag

2880

attgtaaaaa tgagtaataa acatctgaag ttttttttaa gttattttta acatggtata

2940

tacagttgag cttagagttt atcattttct gatattctct tacttagtag atgaattcta

3000

gccatttttt ataaagattt ctgttaagca aatcctgttt tcacatgggc ttcctttaag

3060

ggattttaga ttctgctgga tatggtgact gctcataaga ctgttgaaaa ttacttttaa

3120

gatgtattag aatacttctg aaaaaaaata gcaaccttaa aaccataagc aaaagtagta

3180

agggtgttta tacatttcta gagtccctgt ttaggtaata gcctcctatg attgtacttt

3240

aaatgttttg ctctccaagg ttttagtaac ttggcttttt ttctaatcag tgccaaactc

3300

ccccagtttt tttaacttta aatatgaggt aataaatctt ttacccttcc ttgatctttt

3360

gacttataat accttggtca gttgtttctt aaaaggaatc cttaaatgga aagagacaat

3420

atcactgtct gcagttctga ttagtagttt tattcagaat ggaaaaacag attattcatt

3480

tttgaaaatt gttcaggggt atgttcattg ttaggacctt ggactttgga gtcagtgcct

3540

agctatgcat tccaggtctg ccattttctg gctgtgaaat tttggacaag ttacttaacc

3600

actttaaacc ccagctttaa gaagtaaatt aaccccagta aattaagaag taatagcagc

3660

cacttcgtag agttgttatg aggctcagat gcagtgcaaa tgtgtataaa gtattcaggg

3720

agtcacctgg tatactataa tagacactag aatagttgcc aatattatca gcatacaatc

3780

tgaggattct gtcagccaat cattagcaat ctgttgtttg ttgggacatg ccagtgttct

3840

ccagttgaaa tcagtagcaa tctaaaaatg gatagattat tcctcattta aatagtgtgt

3900

tcatataagt gattgcttgg atccttatca gaagttgctg ttactgaaaa atgataaggc

3960

tgactaaatt gtgatagttg tcagttacta accaactccc agaaatgaat aagaggaacc

4020

tatctctagt tcctagtaga aggtatggac aaaatagtag gtgaaaaata atgtcttgaa

4080

cccccaaatt aagtaagctt taaagagtac aatacctcaa agggtctttg cggtttaaaa

4140

tttgtatgct gagaatgatg ttcattgaca tgtgcctata tgtaattttt tgatagttta

4200

aaaggtgaaa tgaactacag atgggagagg tctgaatttt cttgccttca gtcaaatgtg

4260

taatgtggac atattatttg acctgtgaat tttatctttt aaaaaagatt aattcctgct

4320

tcttccttcc taatagttgc attataataa tgaaaatgag ttgataattt ggggggaaag

4380

tattctacaa atcaacctta ttattttacc attggtttct gagaaatttt gttcatttga

4440

accgtttata gcttgattag aatcatagca tgtaaaaccc aactgaggga ttatctgcag

4500

acttaatgta gtattatgta agttgtcttc tttcatttcg accttttttg cttttgttgt

4560

tgctagatct gtagtatgta gctagtcacc tttcagcgag gtttcagcga ggcttttctg

4620

tgtctctagg ttatttgaga taactttttt aaaattagct cttgtcctcc

4670

<210> 26

<211> 761

<212> PROTEIN

<213> Bos taurus

<400> 26

Met Lys Ile Gln Met Ser Ser Val Lys Val Trp Asn Ile Lys Gln Met

1 5 10 15

Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu Asp Lys Phe Gly

20 25 30

Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala Tyr Glu Glu Tyr

35 40 45

Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln Gln Leu Leu Glu

50 55 60

Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser Ser Ala Ser Thr

65 70 75 80

Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser Val Leu Pro Ser

85 90 95

Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val Ser Arg Ser Asn Pro

100 105 110

Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu Pro Asn Lys Gln

115 120 125

Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val Arg Asp Ser Leu

130 135 140

Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu Cys Cys Ala Val

145 150 155 160

Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly Trp Asp Thr Asp

165 170 175

Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu Val Leu Glu Asn

180 185 190

Val Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr Phe Phe Thr Leu

195 200 205

Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln Gly Phe Arg Cys

210 215 220

Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser Thr Glu Val Pro

225 230 235 240

Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu Leu Phe Val Ser Lys

245 250 255

Phe Phe Glu His His Pro Ile Pro Gln Glu Glu Ala Ser Leu Ala Glu

260 265 270

Thr Thr Leu Pro Cys Gly Ser Ser Pro Ser Ala Pro Pro Ser Asp Ser

275 280 285

Ile Gly Pro Pro Ile Leu Thr Ser Pro Ser Pro Ser Lys Ser Ile Pro

290 295 300

Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His Arg Asn Gln Phe

305 310 315 320

Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val His Ile Asn Thr

325 330 335

Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg Asp Gln Gly Phe Arg

340 345 350

Ser Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala Thr Pro Pro Ala Ser

355 360 365

Leu Pro Gly Ser Leu Ser Asn Val Lys Ala Leu Gln Lys Ser Pro Gly

370 375 380

Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser Glu Asp Arg Asn Arg

385 390 395 400

Met Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp Asp Trp Glu Ile Pro

405 410 415

Asp Gly Gln Ile Thr Val Gly Gln Arg Ile Gly Ser Gly Ser Phe Gly

420 425 430

Thr Val Tyr Lys Gly Lys Trp His Gly Asp Val Ala Val Lys Met Leu

435 440 445

Asn Val Thr Ala Pro Thr Pro Gln Gln Leu Gln Ala Phe Lys Asn Glu

450 455 460

Val Gly Val Leu Arg Lys Thr Arg His Val Asn Ile Leu Leu Phe Met

465 470 475 480

Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val Thr Gln Trp Cys Glu

485 490 495

Gly Ser Ser Leu Tyr His His Leu His Ile Ile Glu Thr Lys Phe Glu

500 505 510

Met Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr Ala Gln Gly Met Asp

515 520 525

Tyr Leu His Ala Lys Ser Ile Ile His Arg Asp Leu Lys Ser Asn Asn

530 535 540

Ile Phe Leu His Glu Asp Leu Thr Val Lys Ile Gly Asp Phe Gly Leu

545 550 555 560

Ala Thr Val Lys Ser Arg Trp Ser Gly Ser His Gln Phe Glu Gln Leu

565 570 575

Ser Gly Ser Ile Leu Trp Met Ala Pro Glu Val Ile Arg Met Gln Asp

580 585 590

Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr Ala Phe Gly Ile Val

595 600 605

Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr Ser Asn Ile Asn Asn

610 615 620

Arg Asp Gln Ile Ile Phe Met Val Gly Arg Gly Tyr Leu Ser Pro Asp

625 630 635 640

Leu Ser Lys Val Arg Ser Asn Cys Pro Lys Ala Met Lys Arg Leu Met

645 650 655

Ala Glu Cys Leu Lys Lys Lys Arg Asp Glu Arg Pro Leu Phe Pro Gln

660 665 670

Val Gly Lys Thr Leu Leu Ser Lys Arg Gln Asn Ser Glu Val Ile Arg

675 680 685

Glu Lys Asp Lys Gln Ile Leu Ala Ser Ile Glu Leu Leu Ala Arg Ser

690 695 700

Leu Pro Lys Ile His Arg Ser Ala Ser Glu Pro Ser Leu Asn Arg Ala

705 710 715 720

Gly Phe Gln Thr Glu Asp Phe Ser Leu Tyr Ala Cys Ala Ser Pro Lys

725 730 735

Thr Pro Ile Gln Ala Gly Gly Tyr Glu Ala Asp Leu Ala Leu Thr Ser

740 745 750

Asn Lys Asn Arg Val Glu Val Gly Ile

755 760

<210> 27

<211> 4816

<212> DNA

<213> Bos taurus

<400> 27

ctcagctgcg ccgggtctca caagacggtt cccgaggtgg cccaggcgcc gtcccaccgc

60

cgacgccgcc cgggccgccc gggccgtccc tccccgctgc cccccgtcct ccgcctccgc

120

ctccccccgc cctcagcctc ccttccccct ccccgcccag cagcggtcgc tcgggcccgg

180

ctctcggtta taagatggcg gcgctgagtg gcggcggcgg cggcggcggc ggtggcgcgg

240

agcaggcca ggctctgttc aacggggaca tggagcccga ggccggcgcc gcggcctctt

300

cggctgcgga ccccgccatt cccgaggagg tgtggaatat caaacaaatg attaagttga

360

cacaggagca tatagaggcc ctattggaca aatttggtgg ggagcataat caccatcaa

420

tatatctgga ggcctatgaa gaatacacca gcaagctaga tgccctccaa caaagagaac

480

aacagttatt ggaatccctg gggaatggaa ctgatttttc tgtttctagc tctgcatcaa

540

cggacaccgt tacatcttct tcctcttcta gcctttcagt gctgccttca tctctttcag

600

tttttcaaaa tccccacagat gtgtcacgga gcaaccccaa gtcaccacaa aaacctatcg

660

ttagagtctt cctgcccaat aaacagagga cagtggtacc tgcacggtgt ggagtcacag

720

tccgggacag cctgaagaag gcactgatga tgagaggtct aatcccagag tgctgtgctg

780

tttacagaat tcaggatggg gagaagaaac caattggctg ggacactgat atttcctggc

840

ttactggaga ggagttgcat gtagaagtgt tggagaatgt tccacttaca acacacaact

900

ttgtacggaa aacttttttc accttagcat tttgtgactt ctgtagaaag ctgcttttcc

960

agggattccg ctgtcaaaca tgtggttata aatttcacca gcgttgtagt acagaggttc

1020

cactgatgtg tgttaattat gaccaactag agcccccaat tctcaccagt ccatctcctt

1080

caaaatccat tccaattcca cagcctttcc gaccagcaga tgaagatcat cgaaatcagt

1140

ttggacaacg agaccggtcc tcatcagctc caaatgtgca tataaacaca atagaacccg

1200

tcaatattga tgacttgatt agagaccaag ggtttcgtag tgatggagga tcaaccacag

1260

gtttatccgc cacaccccct gcctcattac ctggctcact ctctaatgtg aaagcattgc

1320

agaaatctcc aggacctcag cgagaaagaa agtcctcttc atcctcagaa gacaggaatc

1380

gaatgaaaac gcttggtaga cgggattcaa gtgacgattg ggagattcct gatggacaga

1440

tcacagtggg acaaagaatt ggatcagggt catttgggac agtctacaag ggaaagtggc

1500

atggtgatgt ggcagtgaaa atgttgaatg tgacagcacc cacacctcag cagttacagg

1560

ccttcaaaaa tgaagtagga gtactcagga aaacgcgaca tgtgaatatc ctcctcttca

1620

tgggttattc aacaaagcca caactggcta ttgttaccca gtggtgtgag ggctccagtt

1680

tatatcatca tctccacatc attgagacca aattcgagat gatcaaactt atagatattg

1740

cacggcagac tgcacagggc atggattact tacacgccaa gtcaatcatc cacagagacc

1800

tcaagagtaa taatattttt cttcatgaag acctcacagt aaaaataggt gattttggtc

1860

tagccacagt gaaatctcga tggagtgggt cccatcagtt tgaacagttg tctggatcca

1920

ttttgtggat ggcaccagaa gtaatcagaa tgcaagataa aaacccatat agctttcagt

1980

cagatgtata tgcatttggg attgttctgt atgaattgat gaccggacag ttaccttatt

2040

caaatatcaa caacagggac cagataattt ttatggtggg acgaggatat ctgtctccag

2100

atctcagtaa ggtacggagt aactgtccaa aagccatgaa gagattaatg gcagagtgcc

2160

taaaaaagaa aagagatgaa agaccactct ttccccaagt aggaaagact ctcctaagca

2220

agagacaaaa ttcagaagtt atcagggaaa aagataagca gattctcgcc tctattgagc

2280

tgctggcccg ctcattgcca aaaattcacc gcagtgcatc agaaccctcc ttgaatcggg

2340

ctggcttcca aacagaggat tttagtctat atgcttgtgc ttctccaaaa acacccattc

2400

aggcaggggg atatgaagca gatttggctc ttacatcaaa taaaaataga gtagaagttg

2460

ggatttagag atttcctgac atgcaagaag gaataagcaa gaaaaaaagg tttgttttcc

2520

ccaaatcata tctattgtct tttacttcta ttttttctta aattttttgt gatttcagag

2580

acatgtagag ttttattgat acctaaacta tgagttcttt tttttttttt tttttcatta

2640

ttttgatttt tttggccaag aggcatatgg gatcttagct tgagaaagca acaattttct

2700

tgatgtcatt ttgggtgagg gcacatattg ctgtgaacag tgtggtgata gccaccaggg

2760

accaaactca cacccgctgc attgaaaggt gaagtcttaa acactggacc agcagagaaa

2820

ttcctactct atgagttctt tttgtcatcc cctccccgca ccctccaccc ccaacctaaa

2880

gtctgatgat gaaatcaaca actattccat tagaagcagt agattctggt agcatgatct

2940

ttagtttgtt agtaagattt tgtgctttgt ggggttgtgt cgttttaagg ctaatattta

3000

agtttgtcaa atagaatgct gttcagattg taaaaatgag taataaacat ctgaagtttt

3060

ttttaagtta tttttaacat ggtatataca gttgagctta gagtttatca ttttctgata

3120

ttctcttact tagtagatga attctagcca ttttttataa agatttctgt taagcaaatc

3180

ctgttttcac atgggcttcc tttaagggat tttagattct gctggatatg gtgactgctc

3240

ataagactgt tgaaaattac ttttaagatg tattagaata cttctgaaaa aaaatagcaa

3300

ccttaaaacc ataagcaaaa gtagtaaggg tgtttataca tttctagagt ccctgtttag

3360

gtaatagcct cctatgattg tactttaaat gttttgctct ccaaggtttt agtaacttgg

3420

ctttttttct aatcagtgcc aaactccccc agttttttta actttaaata tgaggtaata

3480

aatcttttac ccttccttga tcttttgact tataatacct tggtcagttg tttcttaaaa

3540

ggaatcctta aatggaaaga gacaatatca ctgtctgcag ttctgattag tagttttatt

3600

cagaatggaa aaacagatta ttcatttttg aaaattgttc aggggtatgt tcattgttag

3660

gaccttggac tttggagtca gtgcctagct atgcattcca ggtctgccat tttctggctg

3720

tgaaattttg gacaagttac ttaaccactt taaaccccag ctttaagaag taaattaacc

3780

ccagtaaatt aagaagtaat agcagccact tcgtagagtt gttatgaggc tcagatgcag

3840

tgcaaatgtg tataaagtat tcagggagtc acctggtata ctataataga cactagaata

3900

gttgccaata ttatcagcat acaatctgag gattctgtca gccaatcatt agcaatctgt

3960

tgtttgttgg gacatgccag tgttctccag ttgaaatcag tagcaatcta aaaatggata

4020

gattattcct catttaaata gtgtgttcat ataagtgatt gcttggatcc ttatcagaag

4080

ttgctgttac tgaaaaatga taaggctgac taaattgtga tagttgtcag ttactaacca

4140

actcccagaa atgaataaga ggaacctatc tctagttcct agtagaaggt atggacaaaa

4200

tagtaggtga aaaataatgt cttgaacccc caaattaagt aagctttaaa gagtacaata

4260

cctcaaaggg tctttgcggt ttaaaatttg tatgctgaga atgatgttca ttgacatgtg

4320

cctatatgta attttttgat agtttaaaag gtgaaatgaa ctacagatgg gagaggtctg

4380

aattttcttg ccttcagtca aatgtgtaat gtggacatat tatttgacct gtgaatttta

4440

tcttttaaaa aagattaatt cctgcttctt ccttcctaat agttgcatta taataatgaa

4500

aatgagttga taatttgggg ggaaagtatt ctacaaatca accttattat tttaccattg

4560

gtttctgaga aattttgttc atttgaaccg tttatagctt gattagaatc atagcatgta

4620

aaacccaact gagggattat ctgcagactt aatgtagtat tatgtaagtt gtcttctttc

4680

atttcgacct tttttgcttt tgttgttgct agatctgtag tatgtagcta gtcacctttc

4740

agcgaggttt cagcgaggct tttctgtgtc tctaggttat ttgagataac ttttttaaaa

4800

ttagctcttg tcctcc

4816

<210> 28

<211> 757

<212> PROTEIN

<213> Bos taurus

<400> 28

Met Ala Ala Leu Ser Gly Gly Gly Gly Gly Gly Gly Gly Gly Ala Glu

1 5 10 15

Gln Gly Gln Ala Leu Phe Asn Gly Asp Met Glu Pro Glu Ala Gly Ala

20 25 30

Ala Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp Asn

35 40 45

Ile Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu

50 55 60

Asp Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala

65 70 75 80

Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln

85 90 95

Gln Leu Leu Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser

100 105 110

Ser Ala Ser Thr Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser

115 120 125

Val Leu Pro Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val Ser

130 135 140

Arg Ser Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu

145 150 155 160

Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val

165 170 175

Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu

180 185 190

Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly

195 200 205

Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu

210 215 220

Val Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr

225 230 235 240

Phe Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln

245 250 255

Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser

260 265 270

Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Glu Pro Pro

275 280 285

Ile Leu Thr Ser Pro Ser Pro Ser Lys Ser Ile Pro Ile Pro Gln Pro

290 295 300

Phe Arg Pro Ala Asp Glu Asp His Arg Asn Gln Phe Gly Gln Arg Asp

305 310 315 320

Arg Ser Ser Ser Ala Pro Asn Val His Ile Asn Thr Ile Glu Pro Val

325 330 335

Asn Ile Asp Asp Leu Ile Arg Asp Gln Gly Phe Arg Ser Asp Gly Gly

340 345 350

Ser Thr Thr Gly Leu Ser Ala Thr Pro Pro Ala Ser Leu Pro Gly Ser

355 360 365

Leu Ser Asn Val Lys Ala Leu Gln Lys Ser Pro Gly Pro Gln Arg Glu

370 375 380

Arg Lys Ser Ser Ser Ser Ser Glu Asp Arg Asn Arg Met Lys Thr Leu

385 390 395 400

Gly Arg Arg Asp Ser Ser Asp Asp Trp Glu Ile Pro Asp Gly Gln Ile

405 410 415

Thr Val Gly Gln Arg Ile Gly Ser Gly Ser Phe Gly Thr Val Tyr Lys

420 425 430

Gly Lys Trp His Gly Asp Val Ala Val Lys Met Leu Asn Val Thr Ala

435 440 445

Pro Thr Pro Gln Gln Leu Gln Ala Phe Lys Asn Glu Val Gly Val Leu

450 455 460

Arg Lys Thr Arg His Val Asn Ile Leu Leu Phe Met Gly Tyr Ser Thr

465 470 475 480

Lys Pro Gln Leu Ala Ile Val Thr Gln Trp Cys Glu Gly Ser Ser Leu

485 490 495

Tyr His His Leu His Ile Ile Glu Thr Lys Phe Glu Met Ile Lys Leu

500 505 510

Ile Asp Ile Ala Arg Gln Thr Ala Gln Gly Met Asp Tyr Leu His Ala

515 520 525

Lys Ser Ile Ile His Arg Asp Leu Lys Ser Asn Asn Ile Phe Leu His

530 535 540

Glu Asp Leu Thr Val Lys Ile Gly Asp Phe Gly Leu Ala Thr Val Lys

545 550 555 560

Ser Arg Trp Ser Gly Ser His Gln Phe Glu Gln Leu Ser Gly Ser Ile

565 570 575

Leu Trp Met Ala Pro Glu Val Ile Arg Met Gln Asp Lys Asn Pro Tyr

580 585 590

Ser Phe Gln Ser Asp Val Tyr Ala Phe Gly Ile Val Leu Tyr Glu Leu

595 600 605

Met Thr Gly Gln Leu Pro Tyr Ser Asn Ile Asn Asn Arg Asp Gln Ile

610 615 620

Ile Phe Met Val Gly Arg Gly Tyr Leu Ser Pro Asp Leu Ser Lys Val

625 630 635 640

Arg Ser Asn Cys Pro Lys Ala Met Lys Arg Leu Met Ala Glu Cys Leu

645 650 655

Lys Lys Lys Arg Asp Glu Arg Pro Leu Phe Pro Gln Val Gly Lys Thr

660 665 670

Leu Leu Ser Lys Arg Gln Asn Ser Glu Val Ile Arg Glu Lys Asp Lys

675 680 685

Gln Ile Leu Ala Ser Ile Glu Leu Leu Ala Arg Ser Leu Pro Lys Ile

690 695 700

His Arg Ser Ala Ser Glu Pro Ser Leu Asn Arg Ala Gly Phe Gln Thr

705 710 715 720

Glu Asp Phe Ser Leu Tyr Ala Cys Ala Ser Pro Lys Thr Pro Ile Gln

725 730 735

Ala Gly Gly Tyr Glu Ala Asp Leu Ala Leu Thr Ser Asn Lys Asn Arg

740 745 750

Val Glu Val Gly Ile

755

<210> 29

<211> 2499

<212> DNA

<213> Bos taurus

<400> 29

ctcagctgcg ccgggtctca caagacggtt cccgaggtgg cccaggcgcc gtcccaccgc

60

cgacgccgcc cgggccgccc gggccgtccc tccccgctgc cccccgtcct ccgcctccgc

120

ctccccccgc cctcagcctc ccttccccct ccccgcccag cagcggtcgc tcgggcccgg

180

ctctcggtta taagatggcg gcgctgagtg gcggcggcgg cggcggcggc ggtggcgcgg

240

agcaggcca ggctctgttc aacggggaca tggagcccga ggccggcgcc gcggcctctt

300

cggctgcgga ccccgccatt cccgaggagg tgtggaatat caaacaaatg attaagttga

360

cacaggagca tatagaggcc ctattggaca aatttggtgg ggagcataat caccatcaa

420

tatatctgga ggcctatgaa gaatacacca gcaagctaga tgccctccaa caaagagaac

480

aacagttatt ggaatccctg gggaatggaa ctgatttttc tgtttctagc tctgcatcaa

540

cggacaccgt tacatcttct tcctcttcta gcctttcagt gctgccttca tctctttcag

600

tttttcaaaa tccccacagat gtgtcacgga gcaaccccaa gtcaccacaa aaacctatcg

660

ttagagtctt cctgcccaat aaacagagga cagtggtacc tgcacggtgt ggagtcacag

720

tccgggacag cctgaagaag gcactgatga tgagaggtct aatcccagag tgctgtgctg

780

tttacagaat tcaggatggg gagaagaaac caattggctg ggacactgat atttcctggc

840

ttactggaga ggagttgcat gtagaagtgt tggagaatgt tccacttaca acacacaact

900

ttgtacggaa aacttttttc accttagcat tttgtgactt ctgtagaaag ctgcttttcc

960

agggattccg ctgtcaaaca tgtggttata aatttcacca gcgttgtagt acagaggttc

1020

cactgatgtg tgttaattat gaccaactag atttgctgtt tgtctccaag ttctttgaac

1080

accacccaat accacaggag gaggcctcct tagcagagac tacccttcca tgtggctcat

1140

ccccttctgc acccccctcc gattctattg ggcccccaat tctcaccagt ccatctcctt

1200

caaaatccat tccaattcca cagcctttcc gaccagcaga tgaagatcat cgaaatcagt

1260

ttggacaacg agaccggtcc tcatcagctc caaatgtgca tataaacaca atagaacccg

1320

tcaatattga tgacttgatt agagaccaag ggtttcgtag tgatggagga tcaaccacag

1380

gtttatccgc cacaccccct gcctcattac ctggctcact ctctaatgtg aaagcattgc

1440

agaaatctcc aggacctcag cgagaaagaa agtcctcttc atcctcagaa gacaggaatc

1500

gaatgaaaac gcttggtaga cgggattcaa gtgacgattg ggagattcct gatggacaga

1560

tcacagtggg acaaagaatt ggatcagggt catttgggac agtctacaag ggaaagtggc

1620

atggtgatgt ggcagtgaaa atgttgaatg tgacagcacc cacacctcag cagttacagg

1680

ccttcaaaaa tgaagtagga gtactcagga aaacgcgaca tgtgaatatc ctcctcttca

1740

tgggttattc aacaaagcca caactggcta ttgttaccca gtggtgtgag ggctccagtt

1800

tatatcatca tctccacatc attgagacca aattcgagat gatcaaactt atagatattg

1860

cacggcagac tgcacagggc atggattact tacacgccaa gtcaatcatc cacagagacc

1920

tcaagagtaa taatattttt cttcatgaag acctcacagt aaaaataggt gattttggtc

1980

tagccacagt gaaatctcga tggagtgggt cccatcagtt tgaacagttg tctggatcca

2040

ttttgtggat ggcaccagaa gtaatcagaa tgcaagataa aaacccatat agctttcagt

2100

cagatgtata tgcatttggg attgttctgt atgaattgat gaccggacag ttaccttatt

2160

caaatatcaa caacagggac cagataattt ttatggtggg acgaggatat ctgtctccag

2220

atctcagtaa ggtacggagt aactgtccaa aagccatgaa gagattaatg gcagagtgcc

2280

taaaaaagaa aagagatgaa agaccactct ttccccaagt aggaaagact ctcctaagca

2340

agagacaaaa ttcagaagtt atcagggaaa aagataagca ggaaaagtat gtttctttag

2400

tacattccag gcatttggga ttacagtaaa aacaatattc tcgcctctat tgagctgctg

2460

gcccgctcat tgccaaaaat tcaccgcagt gcatcagaa

2499

<210> 30

<211> 744

<212> PROTEIN

<213> Bos taurus

<400> 30

Met Ala Ala Leu Ser Gly Gly Gly Gly Gly Gly Gly Gly Gly Ala Glu

1 5 10 15

Gln Gly Gln Ala Leu Phe Asn Gly Asp Met Glu Pro Glu Ala Gly Ala

20 25 30

Ala Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp Asn

35 40 45

Ile Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu

50 55 60

Asp Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala

65 70 75 80

Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln

85 90 95

Gln Leu Leu Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser

100 105 110

Ser Ala Ser Thr Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser

115 120 125

Val Leu Pro Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val Ser

130 135 140

Arg Ser Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu

145 150 155 160

Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val

165 170 175

Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu

180 185 190

Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly

195 200 205

Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu

210 215 220

Val Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr

225 230 235 240

Phe Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln

245 250 255

Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser

260 265 270

Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu Leu

275 280 285

Phe Val Ser Lys Phe Phe Glu His His Pro Ile Pro Gln Glu Glu Ala

290 295 300

Ser Leu Ala Glu Thr Thr Leu Pro Cys Gly Ser Ser Pro Ser Ala Pro

305 310 315 320

Pro Ser Asp Ser Ile Gly Pro Pro Ile Leu Thr Ser Pro Ser Pro Ser

325 330 335

Lys Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His

340 345 350

Arg Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val

355 360 365

His Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg Asp

370 375 380

Gln Gly Phe Arg Ser Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala Thr

385 390 395 400

Pro Pro Ala Ser Leu Pro Gly Ser Leu Ser Asn Val Lys Ala Leu Gln

405 410 415

Lys Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser Glu

420 425 430

Asp Arg Asn Arg Met Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp Asp

435 440 445

Trp Glu Ile Pro Asp Gly Gln Ile Thr Val Gly Gln Arg Ile Gly Ser

450 455 460

Gly Ser Phe Gly Thr Val Tyr Lys Gly Lys Trp His Gly Asp Val Ala

465 470 475 480

Val Lys Met Leu Asn Val Thr Ala Pro Thr Pro Gln Gln Leu Gln Ala

485 490 495

Phe Lys Asn Glu Val Gly Val Leu Arg Lys Thr Arg His Val Asn Ile

500 505 510

Leu Leu Phe Met Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val Thr

515 520 525

Gln Trp Cys Glu Gly Ser Ser Leu Tyr His His Leu His Ile Ile Glu

530 535 540

Thr Lys Phe Glu Met Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr Ala

545 550 555 560

Gln Gly Met Asp Tyr Leu His Ala Lys Ser Ile Ile His Arg Asp Leu

565 570 575

Lys Ser Asn Asn Ile Phe Leu His Glu Asp Leu Thr Val Lys Ile Gly

580 585 590

Asp Phe Gly Leu Ala Thr Val Lys Ser Arg Trp Ser Gly Ser His Gln

595 600 605

Phe Glu Gln Leu Ser Gly Ser Ile Leu Trp Met Ala Pro Glu Val Ile

610 615 620

Arg Met Gln Asp Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr Ala

625 630 635 640

Phe Gly Ile Val Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr Ser

645 650 655

Asn Ile Asn Asn Arg Asp Gln Ile Ile Phe Met Val Gly Arg Gly Tyr

660 665 670

Leu Ser Pro Asp Leu Ser Lys Val Arg Ser Asn Cys Pro Lys Ala Met

675 680 685

Lys Arg Leu Met Ala Glu Cys Leu Lys Lys Lys Arg Asp Glu Arg Pro

690 695 700

Leu Phe Pro Gln Val Gly Lys Thr Leu Leu Ser Lys Arg Gln Asn Ser

705 710 715 720

Glu Val Ile Arg Glu Lys Asp Lys Gln Glu Lys Tyr Val Ser Leu Val

725 730 735

His Ser Arg His Leu Gly Leu Gln

740

<210> 31

<211> 2404

<212> DNA

<213> Bos taurus

<400> 31

ctcagctgcg ccgggtctca caagacggtt cccgaggtgg cccaggcgcc gtcccaccgc

60

cgacgccgcc cgggccgccc gggccgtccc tccccgctgc cccccgtcct ccgcctccgc

120

ctccccccgc cctcagcctc ccttccccct ccccgcccag cagcggtcgc tcgggcccgg

180

ctctcggtta taagatggcg gcgctgagtg gcggcggcgg cggcggcggc ggtggcgcgg

240

agcaggcca ggctctgttc aacggggaca tggagcccga ggccggcgcc gcggcctctt

300

cggctgcgga ccccgccatt cccgaggagg tgtggaatat caaacaaatg attaagttga

360

cacaggagca tatagaggcc ctattggaca aatttggtgg ggagcataat caccatcaa

420

tatatctgga ggcctatgaa gaatacacca gcaagctaga tgccctccaa caaagagaac

480

aacagttatt ggaatccctg gggaatggaa ctgatttttc tgtttctagc tctgcatcaa

540

cggacaccgt tacatcttct tcctcttcta gcctttcagt gctgccttca tctctttcag

600

tttttcaaaa tccccacagat gtgtcacgga gcaaccccaa gtcaccacaa aaacctatcg

660

ttagagtctt cctgcccaat aaacagagga cagtggtacc tgcacggtgt ggagtcacag

720

tccgggacag cctgaagaag gcactgatga tgagaggtct aatcccagag tgctgtgctg

780

tttacagaat tcaggatggg gagaagaaac caattggctg ggacactgat atttcctggc

840

ttactggaga ggagttgcat gtagaagtgt tggagaatgt tccacttaca acacacaact

900

ttgtacggaa aacttttttc accttagcat tttgtgactt ctgtagaaag ctgcttttcc

960

agggattccg ctgtcaaaca tgtggttata aatttcacca gcgttgtagt acagaggttc

1020

cactgatgtg tgttaattat gaccaactag atttgctgtt tgtctccaag ttctttgaac

1080

accacccaat accacaggag gaggcctcct tagcagagac tacccttcca tgtggctcat

1140

ccccttctgc acccccctcc gattctattg ggcccccaat tctcaccagt ccatctcctt

1200

caaaatccat tccaattcca cagcctttcc gaccagcaga tgaagatcat cgaaatcagt

1260

ttggacaacg agaccggtcc tcatcagctc caaatgtgca tataaacaca atagaacccg

1320

tcaatattga tgacttgatt agagaccaag ggtttcgtag tgatggagga tcaaccacag

1380

gtttatccgc cacaccccct gcctcattac ctggctcact ctctaatgtg aaagcattgc

1440

agaaatctcc aggacctcag cgagaaagaa agtcctcttc atcctcagaa gacaggaatc

1500

gaatgaaaac gcttggtaga cgggattcaa gtgacgattg ggagattcct gatggacaga

1560

tcacagtggg acaaagaatt ggatcagggt catttgggac agtctacaag ggaaagtggc

1620

atggtgatgt ggcagtgaaa atgttgaatg tgacagcacc cacacctcag cagttacagg

1680

ccttcaaaaa tgaagtagga gtactcagga aaacgcgaca tgtgaatatc ctcctcttca

1740

tgggttattc aacaaagcca caactggcta ttgttaccca gtggtgtgag ggctccagtt

1800

tatatcatca tctccacatc attgagacca aattcgagat gatcaaactt atagatattg

1860

cacggcagac tgcacagggc atggattact tacacgccaa gtcaatcatc cacagagacc

1920

tcaagagtaa taatattttt cttcatgaag acctcacagt aaaaataggt gattttggtc

1980

tagccacagt gaaatctcga tggagtgggt cccatcagtt tgaacagttg tctggatcca

2040

ttttgtggat ggcaccagaa gtaatcagaa tgcaagataa aaacccatat agctttcagt

2100

cagatgtata tgcatttggg attgttctgt atgaattgat gaccggacag ttaccttatt

2160

caaatatcaa caacagggac cagataattt ttatggtggg acgaggatat ctgtctccag

2220

atctcagtaa ggtacggagt aactgtccaa aagccatgaa gagattaatg gcagagtgcc

2280

taaaaaagaa aagagatgaa agaccactct ttccccaaga tctctcttcc caccatagac

2340

acaaaaattt cagatggcta caggtttaca tgtaaaaaac agaattataa caaatgattt

2400

ttat

2404

<210> 32

<211> 726

<212> PROTEIN

<213> Bos taurus

<400> 32

Met Ala Ala Leu Ser Gly Gly Gly Gly Gly Gly Gly Gly Gly Ala Glu

1 5 10 15

Gln Gly Gln Ala Leu Phe Asn Gly Asp Met Glu Pro Glu Ala Gly Ala

20 25 30

Ala Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp Asn

35 40 45

Ile Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu

50 55 60

Asp Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala

65 70 75 80

Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln

85 90 95

Gln Leu Leu Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser

100 105 110

Ser Ala Ser Thr Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser

115 120 125

Val Leu Pro Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val Ser

130 135 140

Arg Ser Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu

145 150 155 160

Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val

165 170 175

Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu

180 185 190

Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly

195 200 205

Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu

210 215 220

Val Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr

225 230 235 240

Phe Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln

245 250 255

Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser

260 265 270

Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu Leu

275 280 285

Phe Val Ser Lys Phe Phe Glu His His Pro Ile Pro Gln Glu Glu Ala

290 295 300

Ser Leu Ala Glu Thr Thr Leu Pro Cys Gly Ser Ser Pro Ser Ala Pro

305 310 315 320

Pro Ser Asp Ser Ile Gly Pro Pro Ile Leu Thr Ser Pro Ser Pro Ser

325 330 335

Lys Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His

340 345 350

Arg Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val

355 360 365

His Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg Asp

370 375 380

Gln Gly Phe Arg Ser Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala Thr

385 390 395 400

Pro Pro Ala Ser Leu Pro Gly Ser Leu Ser Asn Val Lys Ala Leu Gln

405 410 415

Lys Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser Glu

420 425 430

Asp Arg Asn Arg Met Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp Asp

435 440 445

Trp Glu Ile Pro Asp Gly Gln Ile Thr Val Gly Gln Arg Ile Gly Ser

450 455 460

Gly Ser Phe Gly Thr Val Tyr Lys Gly Lys Trp His Gly Asp Val Ala

465 470 475 480

Val Lys Met Leu Asn Val Thr Ala Pro Thr Pro Gln Gln Leu Gln Ala

485 490 495

Phe Lys Asn Glu Val Gly Val Leu Arg Lys Thr Arg His Val Asn Ile

500 505 510

Leu Leu Phe Met Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val Thr

515 520 525

Gln Trp Cys Glu Gly Ser Ser Leu Tyr His His Leu His Ile Ile Glu

530 535 540

Thr Lys Phe Glu Met Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr Ala

545 550 555 560

Gln Gly Met Asp Tyr Leu His Ala Lys Ser Ile Ile His Arg Asp Leu

565 570 575

Lys Ser Asn Asn Ile Phe Leu His Glu Asp Leu Thr Val Lys Ile Gly

580 585 590

Asp Phe Gly Leu Ala Thr Val Lys Ser Arg Trp Ser Gly Ser His Gln

595 600 605

Phe Glu Gln Leu Ser Gly Ser Ile Leu Trp Met Ala Pro Glu Val Ile

610 615 620

Arg Met Gln Asp Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr Ala

625 630 635 640

Phe Gly Ile Val Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr Ser

645 650 655

Asn Ile Asn Asn Arg Asp Gln Ile Ile Phe Met Val Gly Arg Gly Tyr

660 665 670

Leu Ser Pro Asp Leu Ser Lys Val Arg Ser Asn Cys Pro Lys Ala Met

675 680 685

Lys Arg Leu Met Ala Glu Cys Leu Lys Lys Lys Arg Asp Glu Arg Pro

690 695 700

Leu Phe Pro Gln Asp Leu Ser Ser His His Arg His Lys Asn Phe Arg

705 710 715 720

Trp Leu Gln Val Tyr Met

725

<210> 33

<211> 2331

<212> DNA

<213> Bos taurus

<400> 33

ctcagctgcg ccgggtctca caagacggtt cccgaggtgg cccaggcgcc gtcccaccgc

60

cgacgccgcc cgggccgccc gggccgtccc tccccgctgc cccccgtcct ccgcctccgc

120

ctccccccgc cctcagcctc ccttccccct ccccgcccag cagcggtcgc tcgggcccgg

180

ctctcggtta taagatggcg gcgctgagtg gcggcggcgg cggcggcggc ggtggcgcgg

240

agcaggcca ggctctgttc aacggggaca tggagcccga ggccggcgcc gcggcctctt

300

cggctgcgga ccccgccatt cccgaggagg tgtggaatat caaacaaatg attaagttga

360

cacaggagca tatagaggcc ctattggaca aatttggtgg ggagcataat caccatcaa

420

tatatctgga ggcctatgaa gaatacacca gcaagctaga tgccctccaa caaagagaac

480

aacagttatt ggaatccctg gggaatggaa ctgatttttc tgtttctagc tctgcatcaa

540

cggacaccgt tacatcttct tcctcttcta gcctttcagt gctgccttca tctctttcag

600

tttttcaaaa tccccacagat gtgtcacgga gcaaccccaa gtcaccacaa aaacctatcg

660

ttagagtctt cctgcccaat aaacagagga cagtggtacc tgcacggtgt ggagtcacag

720

tccgggacag cctgaagaag gcactgatga tgagaggtct aatcccagag tgctgtgctg

780

tttacagaat tcaggatggg gagaagaaac caattggctg ggacactgat atttcctggc

840

ttactggaga ggagttgcat gtagaagtgt tggagaatgt tccacttaca acacacaact

900

ttgtacggaa aacttttttc accttagcat tttgtgactt ctgtagaaag ctgcttttcc

960

agggattccg ctgtcaaaca tgtggttata aatttcacca gcgttgtagt acagaggttc

1020

cactgatgtg tgttaattat gaccaactag atttgctgtt tgtctccaag ttctttgaac

1080

accacccaat accacaggag gaggcctcct tagcagagac tacccttcca tgtggctcat

1140

ccccttctgc acccccctcc gattctattg ggcccccaat tctcaccagt ccatctcctt

1200

caaaatccat tccaattcca cagcctttcc gaccagcaga tgaagatcat cgaaatcagt

1260

ttggacaacg agaccggtcc tcatcagctc caaatgtgca tataaacaca atagaacccg

1320

tcaatattga tgacttgatt agagaccaag ggtttcgtag tgatggagga tcaaccacag

1380

gtttatccgc cacaccccct gcctcattac ctggctcact ctctaatgtg aaagcattgc

1440

agaaatctcc aggacctcag cgagaaagaa agtcctcttc atcctcagaa gacaggaatc

1500

gaatgaaaac gcttggtaga cgggattcaa gtgacgattg ggagattcct gatggacaga

1560

tcacagtggg acaaagaatt ggatcagggt catttgggac agtctacaag ggaaagtggc

1620

atggtgatgt ggcagtgaaa atgttgaatg tgacagcacc cacacctcag cagttacagg

1680

ccttcaaaaa tgaagtagga gtactcagga aaacgcgaca tgtgaatatc ctcctcttca

1740

tgggttattc aacaaagcca caactggcta ttgttaccca gtggtgtgag ggctccagtt

1800

tatatcatca tctccacatc attgagacca aattcgagat gatcaaactt atagatattg

1860

cacggcagac tgcacagggc atggattact tacacgccaa gtcaatcatc cacagagacc

1920

tcaagagtaa taatattttt cttcatgaag acctcacagt aaaaataggt gattttggtc

1980

tagccacagt gaaatctcga tggagtgggt cccatcagtt tgaacagttg tctggatcca

2040

ttttgtggat ggcaccagaa gtaatcagaa tgcaagataa aaacccatat agctttcagt

2100

cagatgtata tgcatttggg attgttctgt atgaattgat gaccggacag ttaccttatt

2160

caaatatcaa caacagggac caggtgcttt gtcctccatg ggagtgtaat aaatgctgtg

2220

caagggctta cttcccatga gagaagtgag tgaccaacag aaggataatt tttatggtgg

2280

gacgaggata tctgtctcca gatctcagta aggtacggag taactgtcca a

2331

<210> 34

<211> 681

<212> PROTEIN

<213> Bos taurus

<400> 34

Met Ala Ala Leu Ser Gly Gly Gly Gly Gly Gly Gly Gly Gly Ala Glu

1 5 10 15

Gln Gly Gln Ala Leu Phe Asn Gly Asp Met Glu Pro Glu Ala Gly Ala

20 25 30

Ala Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp Asn

35 40 45

Ile Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu

50 55 60

Asp Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala

65 70 75 80

Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln

85 90 95

Gln Leu Leu Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser

100 105 110

Ser Ala Ser Thr Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser

115 120 125

Val Leu Pro Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val Ser

130 135 140

Arg Ser Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu

145 150 155 160

Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val

165 170 175

Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu

180 185 190

Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly

195 200 205

Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu

210 215 220

Val Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr

225 230 235 240

Phe Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln

245 250 255

Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser

260 265 270

Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu Leu

275 280 285

Phe Val Ser Lys Phe Phe Glu His His Pro Ile Pro Gln Glu Glu Ala

290 295 300

Ser Leu Ala Glu Thr Thr Leu Pro Cys Gly Ser Ser Pro Ser Ala Pro

305 310 315 320

Pro Ser Asp Ser Ile Gly Pro Pro Ile Leu Thr Ser Pro Ser Pro Ser

325 330 335

Lys Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His

340 345 350

Arg Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val

355 360 365

His Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg Asp

370 375 380

Gln Gly Phe Arg Ser Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala Thr

385 390 395 400

Pro Pro Ala Ser Leu Pro Gly Ser Leu Ser Asn Val Lys Ala Leu Gln

405 410 415

Lys Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser Glu

420 425 430

Asp Arg Asn Arg Met Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp Asp

435 440 445

Trp Glu Ile Pro Asp Gly Gln Ile Thr Val Gly Gln Arg Ile Gly Ser

450 455 460

Gly Ser Phe Gly Thr Val Tyr Lys Gly Lys Trp His Gly Asp Val Ala

465 470 475 480

Val Lys Met Leu Asn Val Thr Ala Pro Thr Pro Gln Gln Leu Gln Ala

485 490 495

Phe Lys Asn Glu Val Gly Val Leu Arg Lys Thr Arg His Val Asn Ile

500 505 510

Leu Leu Phe Met Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val Thr

515 520 525

Gln Trp Cys Glu Gly Ser Ser Leu Tyr His His Leu His Ile Ile Glu

530 535 540

Thr Lys Phe Glu Met Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr Ala

545 550 555 560

Gln Gly Met Asp Tyr Leu His Ala Lys Ser Ile Ile His Arg Asp Leu

565 570 575

Lys Ser Asn Asn Ile Phe Leu His Glu Asp Leu Thr Val Lys Ile Gly

580 585 590

Asp Phe Gly Leu Ala Thr Val Lys Ser Arg Trp Ser Gly Ser His Gln

595 600 605

Phe Glu Gln Leu Ser Gly Ser Ile Leu Trp Met Ala Pro Glu Val Ile

610 615 620

Arg Met Gln Asp Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr Ala

625 630 635 640

Phe Gly Ile Val Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr Ser

645 650 655

Asn Ile Asn Asn Arg Asp Gln Val Leu Cys Pro Pro Trp Glu Cys Asn

660 665 670

Lys Cys Cys Ala Arg Ala Tyr Phe Pro

675 680

<210> 35

<211> 2319

<212> DNA

<213> Bos taurus

<400> 35

ctcagctgcg ccgggtctca caagacggtt cccgaggtgg cccaggcgcc gtcccaccgc

60

cgacgccgcc cgggccgccc gggccgtccc tccccgctgc cccccgtcct ccgcctccgc

120

ctccccccgc cctcagcctc ccttccccct ccccgcccag cagcggtcgc tcgggcccgg

180

ctctcggtta taagatggcg gcgctgagtg gcggcggcgg cggcggcggc ggtggcgcgg

240

agcaggcca ggctctgttc aacggggaca tggagcccga ggccggcgcc gcggcctctt

300

cggctgcgga ccccgccatt cccgaggagg tgtggaatat caaacaaatg attaagttga

360

cacaggagca tatagaggcc ctattggaca aatttggtgg ggagcataat caccatcaa

420

tatatctgga ggcctatgaa gaatacacca gcaagctaga tgccctccaa caaagagaac

480

aacagttatt ggaatccctg gggaatggaa ctgatttttc tgtttctagc tctgcatcaa

540

cggacaccgt tacatcttct tcctcttcta gcctttcagt gctgccttca tctctttcag

600

tttttcaaaa tccccacagat gtgtcacgga gcaaccccaa gtcaccacaa aaacctatcg

660

ttagagtctt cctgcccaat aaacagagga cagtggtacc tgcacggtgt ggagtcacag

720

tccgggacag cctgaagaag gcactgatga tgagaggtct aatcccagag tgctgtgctg

780

tttacagaat tcaggatggg gagaagaaac caattggctg ggacactgat atttcctggc

840

ttactggaga ggagttgcat gtagaagtgt tggagaatgt tccacttaca acacacaact

900

ttgtacggaa aacttttttc accttagcat tttgtgactt ctgtagaaag ctgcttttcc

960

agggattccg ctgtcaaaca tgtggttata aatttcacca gcgttgtagt acagaggttc

1020

cactgatgtg tgttaattat gaccaactag atttgctgtt tgtctccaag ttctttgaac

1080

accacccaat accacaggag gaggcctcct tagcagagac tacccttcca tgtggctcat

1140

ccccttctgc acccccctcc gattctattg ggcccccaat tctcaccagt ccatctcctt

1200

caaaatccat tccaattcca cagcctttcc gaccagcaga tgaagatcat cgaaatcagt

1260

ttggacaacg agaccggtcc tcatcagctc caaatgtgca tataaacaca atagaacccg

1320

tcaatattga tgacttgatt agagaccaag ggtttcgtag tgatggagga tcaaccacag

1380

gtttatccgc cacaccccct gcctcattac ctggctcact ctctaatgtg aaagcattgc

1440

agaaatctcc aggacctcag cgagaaagaa agtcctcttc atcctcagaa gacaggaatc

1500

gaatgaaaac gcttggtaga cgggattcaa gtgacgattg ggagattcct gatggacaga

1560

tcacagtggg acaaagaatt ggatcagggt catttgggac agtctacaag ggaaagtggc

1620

atggtgatgt ggcagtgaaa atgttgaatg tgacagcacc cacacctcag cagttacagg

1680

ccttcaaaaa tgaagtagga gtactcagga aaacgcgaca tgtgaatatc ctcctcttca

1740

tgggttattc aacaaagcca caactggcta ttgttaccca gtggtgtgag ggctccagtt

1800

tatatcatca tctccacatc attgagacca aattcgagat gatcaaactt atagatattg

1860

cacggcagac tgcacagggc atggattact tacacgccaa gtcaatcatc cacagagacc

1920

tcaagagtaa taatattttt cttcatgaag acctcacagt aaaaataggt gattttggtc

1980

tagccacagt gaaatctcga tggagtgggt cccatcagtt tgaacagttg tctggatcca

2040

ttttgtggat ggcaccagaa gtaatcagaa tgcaagataa aaacccatat agctttcagt

2100

cagatgtata tgcatttggg attgttctgt atgaattgat gaccggacag ttaccttatt

2160

caaatatcaa caacagggac caggtgcttt gtcctccatg ggagtgtaat aaatgctgtg

2220

caagggctta cttcccatga gagaagtgag tgaccaacag aaggtctgtg caaggaaaag

2280

agacaaagcc acggatcaga agcacatggc cataactga

2319

<210> 36

<211> 681

<212> PROTEIN

<213> Bos taurus

<400> 36

Met Ala Ala Leu Ser Gly Gly Gly Gly Gly Gly Gly Gly Gly Ala Glu

1 5 10 15

Gln Gly Gln Ala Leu Phe Asn Gly Asp Met Glu Pro Glu Ala Gly Ala

20 25 30

Ala Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp Asn

35 40 45

Ile Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu

50 55 60

Asp Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala

65 70 75 80

Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln

85 90 95

Gln Leu Leu Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser

100 105 110

Ser Ala Ser Thr Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser

115 120 125

Val Leu Pro Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val Ser

130 135 140

Arg Ser Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu

145 150 155 160

Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val

165 170 175

Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu

180 185 190

Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly

195 200 205

Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu

210 215 220

Val Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr

225 230 235 240

Phe Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln

245 250 255

Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser

260 265 270

Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu Leu

275 280 285

Phe Val Ser Lys Phe Phe Glu His His Pro Ile Pro Gln Glu Glu Ala

290 295 300

Ser Leu Ala Glu Thr Thr Leu Pro Cys Gly Ser Ser Pro Ser Ala Pro

305 310 315 320

Pro Ser Asp Ser Ile Gly Pro Pro Ile Leu Thr Ser Pro Ser Pro Ser

325 330 335

Lys Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His

340 345 350

Arg Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val

355 360 365

His Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg Asp

370 375 380

Gln Gly Phe Arg Ser Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala Thr

385 390 395 400

Pro Pro Ala Ser Leu Pro Gly Ser Leu Ser Asn Val Lys Ala Leu Gln

405 410 415

Lys Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser Glu

420 425 430

Asp Arg Asn Arg Met Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp Asp

435 440 445

Trp Glu Ile Pro Asp Gly Gln Ile Thr Val Gly Gln Arg Ile Gly Ser

450 455 460

Gly Ser Phe Gly Thr Val Tyr Lys Gly Lys Trp His Gly Asp Val Ala

465 470 475 480

Val Lys Met Leu Asn Val Thr Ala Pro Thr Pro Gln Gln Leu Gln Ala

485 490 495

Phe Lys Asn Glu Val Gly Val Leu Arg Lys Thr Arg His Val Asn Ile

500 505 510

Leu Leu Phe Met Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val Thr

515 520 525

Gln Trp Cys Glu Gly Ser Ser Leu Tyr His His Leu His Ile Ile Glu

530 535 540

Thr Lys Phe Glu Met Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr Ala

545 550 555 560

Gln Gly Met Asp Tyr Leu His Ala Lys Ser Ile Ile His Arg Asp Leu

565 570 575

Lys Ser Asn Asn Ile Phe Leu His Glu Asp Leu Thr Val Lys Ile Gly

580 585 590

Asp Phe Gly Leu Ala Thr Val Lys Ser Arg Trp Ser Gly Ser His Gln

595 600 605

Phe Glu Gln Leu Ser Gly Ser Ile Leu Trp Met Ala Pro Glu Val Ile

610 615 620

Arg Met Gln Asp Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr Ala

625 630 635 640

Phe Gly Ile Val Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr Ser

645 650 655

Asn Ile Asn Asn Arg Asp Gln Val Leu Cys Pro Pro Trp Glu Cys Asn

660 665 670

Lys Cys Cys Ala Arg Ala Tyr Phe Pro

675 680

<210> 37

<211> 2661

<212> DNA

<213> Bos taurus

<400> 37

tcagctgcgc cgggtctcac aagacggttc ccgaggtggc ccaggcgccg tcccaccgcc

60

gacgccgccc gggccgcccg ggccgtccct ccccgctgcc ccccgtcctc cgcctccgcc

120

tccccccgcc ctcagcctcc cttccccctc cccgcccagc agcggtcgct cgggcccggc

180

tctcggttat aagatggcgg cgctgagtgg cggcggcggc ggcggcggcg gtggcgcgga

240

gcagggccag gctctgttca acggggacat ggagcccgag gccggcgccg cggcctcttc

300

ggctgcggac cccgccattc ccgaggaggt gtggaatatc aaacaaatga ttaagttgac

360

acaggagcat atagaggccc tattggacaa atttggtggg gagcataatc caccatcaat

420

atatctggag gcctatgaag aatacaccag caagctagat gccctccaac aaagagaaca

480

acagttattg gaatccctgg ggaatggaac tgatttttct gtttctagct ctgcatcaac

540

ggacaccgtt acatcttctt cctcttctag cctttcagtg ctgccttcat ctctttcagt

600

ttttcaaaat cccacagatg tgtcacggag caaccccaag tcaccacaaa aacctatcgt

660

tagagtcttc ctgcccaata aacagaggac agtggtacct gcacggtgtg gagtcacagt

720

ccgggacagc ctgaagaagg cactgatgat gagaggtcta atcccagagt gctgtgctgt

780

ttacagaatt caggatgggg agaagaaacc aattggctgg gacactgata tttcctggct

840

tactggagag gagttgcatg tagaagtgtt ggagaatgtt ccacttacaa cacacaactt

900

tgtacggaaa acttttttca ccttagcatt ttgtgacttc tgtagaaagc tgcttttcca

960

gggattccgc tgtcaaacat gtggttataa atttcaccag cgttgtagta cagaggttcc

1020

actgatgtgt gttaattatg accaactaga tttgctgttt gtctccaagt tctttgaaca

1080

ccacccaata ccacaggagg aggcctcctt agcagagact acccttccat gtggctcatc

1140

cccttctgca cccccctccg attctattgg gcccccaatt ctcaccagtc catctccttc

1200

aaaatccatt ccaattccac agcctttccg accagcagat gaagatcatc gaaatcagtt

1260

tggacaacga gaccggtcct catcagctcc aaatgtgcat ataaacacaa tagaacccgt

1320

caatattgat gacttgatta gagaccaagg gtttcgtagt gatggaggat caaccacagg

1380

tttatccgcc acaccccctg cctcattacc tggctcactc tctaatgtga aagcattgca

1440

gaaatctcca ggacctcagc gagaaagaaa gtcctcttca tcctcagaag acaggaatcg

1500

aatgaaaacg cttggtagac gggattcaag tgacgattgg gagattcctg atggacagat

1560

cacagtggga caaagaattg gatcagggtc atttgggaca gtctacaagg gaaagtggca

1620

tggtgatgtg gcagtgaaaa tgttgaatgt gacagcaccc acacctcagc agttacaggc

1680

cttcaaaaat gaagtaggag tactcaggaa aacgcgacat gtgaatatcc tcctcttcat

1740

gggttattca acaaagccac aactggctat tgttacccag tggtgtgagg gctccagttt

1800

atatcatcat ctccacatca ttgagaccaa attcgagatg atcaaactta tagatattgc

1860

acggcagact gcacagggca tggattactt acacgccaag tcaatcatcc acagacct

1920

caagagtaat aatatttttc ttcatgaaga cctcacagta aaaataggtg attttggtct

1980

agccacagtg aaatctcgat ggagtgggtc ccatcagttt gaacagttgt ctggatccat

2040

tttgtggatg gcaccagaag taatcagaat gcaagataaa aacccatata gctttcagtc

2100

agatgtatat gcatttggga ttgttctgta tgaattgatg accggacagt taccttattc

2160

aaatatcaac aacagggacc agtctgtgca aggaaaagag acaaagccac ggatcagaag

2220

cacatggcca taactgaaga ttttgtgaac tctcacaagg aaaaaatttg ctctttgaac

2280

aataagaagg aactcactaa aatgtaactg agaactgttc aacaggttga aagctgaaag

2340

atgccattgg aactgacaaa atgtttctta aacataaatg atgaaacagt gaaactacat

2400

aatatctcct ctggctgaaa cattcaagaa gtttaaaatg cttaagttaa aaataaaatc

2460

ctagtaaaca atggacttac tgtgcaacat agagaatatc ttacgataac ctgtaatgga

2520

aaagaatctg aaaaagaatg tatataactg aatcactttg ctgtaaacta gaatctgaca

2580

caacactgta aatcactaca cttttctgtt gcatgccaaa gattatttaa taacgtcatt

2640

aaaaaattat tttaataatt a

2661

<210> 38

<211> 679

<212> PROTEIN

<213> Bos taurus

<400> 38

Met Ala Ala Leu Ser Gly Gly Gly Gly Gly Gly Gly Gly Gly Ala Glu

1 5 10 15

Gln Gly Gln Ala Leu Phe Asn Gly Asp Met Glu Pro Glu Ala Gly Ala

20 25 30

Ala Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp Asn

35 40 45

Ile Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu

50 55 60

Asp Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala

65 70 75 80

Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln

85 90 95

Gln Leu Leu Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser

100 105 110

Ser Ala Ser Thr Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser

115 120 125

Val Leu Pro Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val Ser

130 135 140

Arg Ser Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu

145 150 155 160

Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val

165 170 175

Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu

180 185 190

Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly

195 200 205

Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu

210 215 220

Val Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr

225 230 235 240

Phe Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln

245 250 255

Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser

260 265 270

Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu Leu

275 280 285

Phe Val Ser Lys Phe Phe Glu His His Pro Ile Pro Gln Glu Glu Ala

290 295 300

Ser Leu Ala Glu Thr Thr Leu Pro Cys Gly Ser Ser Pro Ser Ala Pro

305 310 315 320

Pro Ser Asp Ser Ile Gly Pro Pro Ile Leu Thr Ser Pro Ser Pro Ser

325 330 335

Lys Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His

340 345 350

Arg Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val

355 360 365

His Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg Asp

370 375 380

Gln Gly Phe Arg Ser Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala Thr

385 390 395 400

Pro Pro Ala Ser Leu Pro Gly Ser Leu Ser Asn Val Lys Ala Leu Gln

405 410 415

Lys Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser Glu

420 425 430

Asp Arg Asn Arg Met Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp Asp

435 440 445

Trp Glu Ile Pro Asp Gly Gln Ile Thr Val Gly Gln Arg Ile Gly Ser

450 455 460

Gly Ser Phe Gly Thr Val Tyr Lys Gly Lys Trp His Gly Asp Val Ala

465 470 475 480

Val Lys Met Leu Asn Val Thr Ala Pro Thr Pro Gln Gln Leu Gln Ala

485 490 495

Phe Lys Asn Glu Val Gly Val Leu Arg Lys Thr Arg His Val Asn Ile

500 505 510

Leu Leu Phe Met Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val Thr

515 520 525

Gln Trp Cys Glu Gly Ser Ser Leu Tyr His His Leu His Ile Ile Glu

530 535 540

Thr Lys Phe Glu Met Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr Ala

545 550 555 560

Gln Gly Met Asp Tyr Leu His Ala Lys Ser Ile Ile His Arg Asp Leu

565 570 575

Lys Ser Asn Asn Ile Phe Leu His Glu Asp Leu Thr Val Lys Ile Gly

580 585 590

Asp Phe Gly Leu Ala Thr Val Lys Ser Arg Trp Ser Gly Ser His Gln

595 600 605

Phe Glu Gln Leu Ser Gly Ser Ile Leu Trp Met Ala Pro Glu Val Ile

610 615 620

Arg Met Gln Asp Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr Ala

625 630 635 640

Phe Gly Ile Val Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr Ser

645 650 655

Asn Ile Asn Asn Arg Asp Gln Ser Val Gln Gly Lys Glu Thr Lys Pro

660 665 670

Arg Ile Arg Ser Thr Trp Pro

675

<210> 39

<211> 7434

<212> DNA

<213> Bos taurus

<400> 39

acaccgttac atcttcttcc tcttctagcc tttcagtgct gccttcatct ctttcagttt

60

ttcaaaatcc cacagatgtg tcacggagca accccaagtc accacaaaaa cctatcgtta

120

gagtcttcct gcccaataaa cagaggacag tggtacctgc acggtgtgga gtcacagtcc

180

gggacagcct gaagaaggca ctgatgatga gaggtctaat cccagagtgc tgtgctgttt

240

acagaattca ggatggggag aagaaaccaa ttggctggga cactgatatt tcctggctta

300

ctggagagga gttgcatgta gaagtgttgg agaatgttcc acttacaaca cacaactttg

360

tacggaaaac ttttttcacc ttagcatttt gtgacttctg tagaaagctg cttttccagg

420

gattccgctg tcaaacatgt ggttataaat ttcaccagcg ttgtagtaca gaggttccac

480

tgatgtgtgt taattatgac caactagatt tgctgtttgt ctccaagttc tttgaacacc

540

acccaatacc acaggaggag gcctccttag cagagactac ccttccatgt ggctcatccc

600

cttctgcacc cccctccgat tctattgggc ccccaattct caccagtcca tctccttcaa

660

aatccattcc aattccacag cctttccgac cagcagatga agatcatcga aatcagtttg

720

gacaacgaga ccggtcctca tcagctccaa atgtgcatat aaacacaata gaacccgtca

780

atattgatga cttgattaga gaccaagggt ttcgtagtga tggaggatca accacaggtt

840

tatccgccac accccctgcc tcattacctg gctcactctc taatgtgaaa gcattgcaga

900

aatctccagg acctcagcga gaaagaaagt cctcttcatc ctcagaagac aggaatcgaa

960

tgaaaacgct tggtagacgg gattcaagtg acgattggga gattcctgat ggacagatca

1020

cagtgggaca aagaattgga tcagggtcat ttgggacagt ctacaaggga aagtggcatg

1080

gtgatgtggc agtgaaaatg ttgaatgtga cagcacccac acctcagcag ttacaggcct

1140

tcaaaaatga agtaggagta ctcaggaaaa cgcgacatgt gaatatcctc ctcttcatgg

1200

gttattcaac aaagccacaa ctggctattg ttacccagtg gtgtgagggc tccagtttat

1260

atcatcatct ccacatcatt gagaccaaat tcgagatgat caaacttata gatattgcac

1320

ggcagactgc acagggcatg gattacttac acgccaagtc aatcatccac agagacctca

1380

agagtaataa tatttttctt catgaagacc tcacagtaaa aataggtgat tttggtctag

1440

ccacagtgaa atctcgatgg agtgggtccc atcagtttga acagttgtct ggatccattt

1500

tgtggatggc accagaagta atcagaatgc aagataaaaa cccatatagc tttcagtcag

1560

atgtatatgc atttgggatt gttctgtatg aattgatgac cggacagtta ccttattcaa

1620

atatcaacaa cagggaccag ataattttta tggtgggacg aggatatctg tctccagatc

1680

tcagtaaggt acggagtaac tgtccaaaag ccatgaagag attaatggca gagtgcctaa

1740

aaaagaaaag agatgaaaga ccactctttc cccaagtagg aaagactctc ctaagcaaga

1800

gacaaaattc agaagttatc agggaaaaag ataagcagat tctcgcctct attgagctgc

1860

tggcccgctc attgccaaaa attcaccgca gtgcatcaga accctccttg aatcgggctg

1920

gcttccaaac agaggatttt agtctatatg cttgtgcttc tccaaaaaca cccattcagg

1980

cagggggata tggagaattt gcagccttca agtagccaca ccatcatgac agcatctact

2040

cttatttctt aagtcttgtg ttcgtacaat ttgttaacat caaaacacag ttctgttcct

2100

caactctttt taaagttaaa atttttcagt gcataagctg gtgtggaaca gaaggaaatt

2160

tcccatccaa caaaagaggg aagaatgttt taggaaccag aattctctgc tgccagtgtt

2220

tcttcttcaa cacaaatatc acaagtctgc ccactcccag gaagaaagag gagagaccct

2280

gagttctgac cttttgatgg tcaggcatga tggaaagaaa ctgctgctac agcttgggag

2340

atttgctctg ggaagtctgc cagtcaactt tgcccttcta accaccagat caatatgtgg

2400

ctgatcatct gatggggcag ttgcaatcac caagccttgt tctctttcct gttctgggat

2460

tgtgttgtgg aacccttttc cctagccacc accagttcat ttctgaggga tggaacaaaa

2520

atgcagcatg cccttcctgt gtggtgcatg ttcagtcctt gacaaatttt taccaaaatg

2580

aagctacttt atttaaaagg agggtgagag gtgaggaggt cactttgggt gtggcggaaa

2640

gggaatgctg catctttttc ctgggctgct ggggctctgg ccttggcttg ccagccggaa

2700

gcgctggcac gcatcgcctt cttttcccat tgggtccagc aatgaagacg agtgtttggg

2760

gttttttttt tctccaccat gtagcaagtt ctcaggaaaa tacaattgat atcttcctcc

2820

taagctcttc caatcagtca ccaagtactt atgtggttac tttgtccagg gcacaaaatg

2880

cctgtatcta attaaaagcc tacaaaactg cttgataaca gttttgaatg tgagacattt

2940

atgtaattta aatgtaaggt acaagtttta atttctgagt ttcttctatt atatttttat

3000

taaaaaaaga aaataatttt cagattgaat tggagtaaaa taatattact tcccactaga

3060

attatatatc ctggaaaatt gtatttttgt tacataagca gcttttaaag aaagatcatt

3120

acccttttct ctacataaat atatggggag tcttagccta atgacaaata tttataattt

3180

ttaaattaat ggtacttgct ggatccatac taacatcttt actaatacct cattgtttct

3240

tccaacttac tcctacacta catcctacat cttcttccta gtcttttatc tagaatatgc

3300

aacctcaaat aaaaatggtg gtgtcctcat tcattctcct ccttcctttt ttcccaagcc

3360

tgatcttcaa aaggttggtt aatttggcag ctgagttcct ccccaggcag agaatagacc

3420

aattttaggt gtattgggac tgagggagga tgtgtaaaga ttaacatcag taaagaaccg

3480

ctgtggagta attaagaact ttgttcttta taactggaga atataaccta accctaacat

3540

ccctcagcct ttactaaagt gtggcgtaaa tcacagtagt agcaaagaaa gtgactctgg

3600

atgtgttcct ggccagtacc tcccttatca tgaatgtaga ctctctcatc aagatttagg

3660

aatataaatc aaatcaaatg tgcccagcca agctatgtag taagggactt gaacaatatt

3720

aggcagaacc tataaaataa atcagggaat tagaaattat ttaaagtttt caaattgtaa

3780

attgccccgg tgtctttcag cctactgcca ttatttttgc tacaatacct acatttcaga

3840

ggagggccta ctgaaaattc catgcaagtg gaaaataatc ctcaagttat taatgagttt

3900

gaaaagcaat gagttcttaa gtctttgtga gtagagcaag atcctacaaa attcagaaat

3960

agtaaaaatg gattcatgct gatttgaaga gcatctgtgt gcataatata atgctgcatc

4020

tcttttaaaa gcagtctatt tttcttttta aatttgtccc catagatgct tttgaacatg

4080

aacatgctta tgttaccttt tccgaggttg ggaagagcca ggagctctca ggcagggccc

4140

cctccctcag ctgggcagga gctgctcagg aggagctagt tatagaggaa gcttagcgtt

4200

ggcattttca aaattcaagg tgataacgct ttcttcttcc tttctgtttt agaatagatt

4260

gctgtctgat ttgaaaaagg gaaatagatt tgatctcaaa tgaatctgtg cccagaagcc

4320

aggctcaggg tattcagaga tttgtatagt gccctcaaaa aataacaaaa ttttagcttt

4380

ccttttttct tcttttctcc atcaaattct tttttctcta gtttacaaat gacatggaaa

4440

aggaatttcc cctgagtttt gtatgccttt ttttttttgg cttagactat agataggcgt

4500

gttgagctcc taagaaaata caagggaggaa ctctttgttg tgcagagcac tttatgagta

4560

gtttgtgtgg ataatatgtg actgcttccc tgacgagctt gtgaggctgt acttatgtct

4620

ttcctgtaag gcagcttcag tgccttctgt agtgtatata aggaaagatt acgccttctg

4680

aaaaatctca gagcaaccat aagattattt taaaatatgt agtatgactg atggactttt

4740

tcatcattaa attagtctag catctaaact tttaccactg aaataatatt gaccaaaaag

4800

caatttataa aaggtatttg tgaatagaaa atacaatgtg atcatttgta cttatgtgca

4860

ccttaaaaga ggaattctgt ctagctgtca aattctggtt ccttaacatc cagtccttga

4920

ttgtgattga gatctggtag gacgtgctgg ggcacgctag cagataaaat cccgtatact

4980

ttaggataga tgttacattt atgtcagtgt tggcaaagag cattgtgtag taataaagaa

5040

ttcaagactt cagcaatgtc aacctgaaac tttgtaaata tttcctagat tgttatttga

5100

tgcagtcaca gctctttatc acacaatgtt gtctttccct catcaggcaa ttttagaact

5160

gctgcacacc cctcctcaga tctcacctgc ccctcctgta cattcacctc tccagccttg

5220

tgcacacctc atttagcttt agtttgaaac acattgcagg gttcaggtga cctcttcaaa

5280

aactacctcc tcagaatgag gtaatgaata gttatttatt ttaaaatatg aaaagtcagg

5340

agctctagaa tatgaagatg atctaagatt ttaactttta tgtatacttg ttgagcactc

5400

tccttttgtc ctaaagggca ttatacattt aagcagtaat actgaaaaat gtagctcaga

5460

gtaactgaat gttgttgaaa gtggtgccag aatctgtttt aggggtacgt atcagaatct

5520

taatcttaaa tcggttacat gaaattaaat agttaatggt aacacttgac taacagatat

5580

aattttaatt ttcggtaggc ttttagcaag acagtaagta catcttcata atgagttagc

5640

cacagcttca tcacatgcac agattttcct gttgagagac tgcccagtta agaggtaga

5700

atgatgaacc atttttcagg attctcttct ttgtccaaac tggcattgtg agtgctagaa

5760

tatcagcact ttcaaactag tgattccaac tattaggcta ttaaaaagca aaacaaacca

5820

aacaaaccat agccagacat gggaagttta ctatgagtat aaacagcaaa tagcttacag

5880

gtcatacatt gaaatggtgt aggtaaggcg ttagaaaaat accttgacaa tttgccaaat

5940

gatcttactg tgccttcatg atgcaataaa aaaaaaaaaa atttagcata aatcagtgat

6000

ttgtgaagag agcagccacc ctggtctaac tcagctgtgt taatattttt tagcgtgcaa

6060

tttagactgc aaagataaat gcactaaaga gtttatagcc aaaatcacat ttaaaaaatg

6120

agagaaaaca caggtaaatt ttcagtgaac aaaattattt ttttaaagta cataatccct

6180

agtatagtca gatatattta tcacatagag caaataggtt gaaatcacaa ttcagtgaca

6240

tttctagaga aactttttct actcccatag gttcttcaaa gcatggaact tttatataac

6300

agaaatgtgt gacggtcatt ttaaattgct gtagtttggg gctgaagtac tgtgtgctgg

6360

gcagcaatca catgtattaa ctagtgagaa aggagaaatt aagatatagg acagaatttg

6420

attttcttgt tccgatta ctgctgccaa cctagacact gagtttccag aggctgaaac

6480

gtaaacttgc agctcagcaa ctgttttgca aagttagtgg gactgtcctg cttatgctgt

6540

tcaaaaatgc tctgaggggcc aggtggggcc tccaggggct cctctctgag gggacatcag

6600

actagctaac gacctggcgg gcggatgtga accggacaca ctccatggtg tgcttcttgt

6660

atcggtccct cgccaccctc aagaaaggct tcagcgggtt ctctagacgt ctccactaag

6720

gtgtgttact aacagccatg ggttgttgag cacccgagga gtgcaatagc atctctgcat

6780

gattgtatat tggcccgaag agaatgaagt ggccagtgta ctcatgttcc atgttgctag

6840

ctctggtaaa ctgaaaatac tggtaagatt tttgttttat cagtacacta gagagtaagc

6900

tttgttttgt tgtttttaga taatgttttc acttccattt ggaaagacat ttaaattgag

6960

tttcagtcct aaattttgcc agtcatggta attagcagtt tctatcaggt atttttaagg

7020

tagaagagga tagaaacata agttctaaaa gcttaaggta accgtggttt attttaaaat

7080

gtttaggggt ggttagtctc tacctcaaaa aaagtgagtg aatcttttat ttcagcattc

7140

acaagttcgg ctgttgtttt tgtaatacat ttttttttta accttttgac ccccctttac

7200

ctaagtgtca atgtagtttt attaattact aagtcagttt cattaaaatg tttatttagc

7260

agttttgact aattgcaatg attaatatag ccagttgtgc atgaggacac agccagtgag

7320

tatatctggg ttttttttgt gatgcttttt ttcttaagac ttctgtagat ttatgaagta

7380

ctcattgaaa acaactaaaa tacgtttatt cgtgttaata tggaaaaaaa aaaa

7434

<210> 40

<211> 603

<212> PROTEIN

<213> Bos taurus

<400> 40

Met Met Arg Gly Leu Ile Pro Glu Cys Cys Ala Val Tyr Arg Ile Gln

1 5 10 15

Asp Gly Glu Lys Lys Pro Ile Gly Trp Asp Thr Asp Ile Ser Trp Leu

20 25 30

Thr Gly Glu Glu Leu His Val Glu Val Leu Glu Asn Val Pro Leu Thr

35 40 45

Thr His Asn Phe Val Arg Lys Thr Phe Phe Thr Leu Ala Phe Cys Asp

50 55 60

Phe Cys Arg Lys Leu Leu Phe Gln Gly Phe Arg Cys Gln Thr Cys Gly

65 70 75 80

Tyr Lys Phe His Gln Arg Cys Ser Thr Glu Val Pro Leu Met Cys Val

85 90 95

Asn Tyr Asp Gln Leu Asp Leu Leu Phe Val Ser Lys Phe Phe Glu His

100 105 110

His Pro Ile Pro Gln Glu Glu Ala Ser Leu Ala Glu Thr Thr Leu Pro

115 120 125

Cys Gly Ser Ser Pro Ser Ala Pro Pro Ser Asp Ser Ile Gly Pro Pro

130 135 140

Ile Leu Thr Ser Pro Ser Pro Ser Lys Ser Ile Pro Ile Pro Gln Pro

145 150 155 160

Phe Arg Pro Ala Asp Glu Asp His Arg Asn Gln Phe Gly Gln Arg Asp

165 170 175

Arg Ser Ser Ser Ala Pro Asn Val His Ile Asn Thr Ile Glu Pro Val

180 185 190

Asn Ile Asp Asp Leu Ile Arg Asp Gln Gly Phe Arg Ser Asp Gly Gly

195 200 205

Ser Thr Thr Gly Leu Ser Ala Thr Pro Pro Ala Ser Leu Pro Gly Ser

210 215 220

Leu Ser Asn Val Lys Ala Leu Gln Lys Ser Pro Gly Pro Gln Arg Glu

225 230 235 240

Arg Lys Ser Ser Ser Ser Ser Glu Asp Arg Asn Arg Met Lys Thr Leu

245 250 255

Gly Arg Arg Asp Ser Ser Asp Asp Trp Glu Ile Pro Asp Gly Gln Ile

260 265 270

Thr Val Gly Gln Arg Ile Gly Ser Gly Ser Phe Gly Thr Val Tyr Lys

275 280 285

Gly Lys Trp His Gly Asp Val Ala Val Lys Met Leu Asn Val Thr Ala

290 295 300

Pro Thr Pro Gln Gln Leu Gln Ala Phe Lys Asn Glu Val Gly Val Leu

305 310 315 320

Arg Lys Thr Arg His Val Asn Ile Leu Leu Phe Met Gly Tyr Ser Thr

325 330 335

Lys Pro Gln Leu Ala Ile Val Thr Gln Trp Cys Glu Gly Ser Ser Leu

340 345 350

Tyr His His Leu His Ile Ile Glu Thr Lys Phe Glu Met Ile Lys Leu

355 360 365

Ile Asp Ile Ala Arg Gln Thr Ala Gln Gly Met Asp Tyr Leu His Ala

370 375 380

Lys Ser Ile Ile His Arg Asp Leu Lys Ser Asn Asn Ile Phe Leu His

385 390 395 400

Glu Asp Leu Thr Val Lys Ile Gly Asp Phe Gly Leu Ala Thr Val Lys

405 410 415

Ser Arg Trp Ser Gly Ser His Gln Phe Glu Gln Leu Ser Gly Ser Ile

420 425 430

Leu Trp Met Ala Pro Glu Val Ile Arg Met Gln Asp Lys Asn Pro Tyr

435 440 445

Ser Phe Gln Ser Asp Val Tyr Ala Phe Gly Ile Val Leu Tyr Glu Leu

450 455 460

Met Thr Gly Gln Leu Pro Tyr Ser Asn Ile Asn Asn Arg Asp Gln Ile

465 470 475 480

Ile Phe Met Val Gly Arg Gly Tyr Leu Ser Pro Asp Leu Ser Lys Val

485 490 495

Arg Ser Asn Cys Pro Lys Ala Met Lys Arg Leu Met Ala Glu Cys Leu

500 505 510

Lys Lys Lys Arg Asp Glu Arg Pro Leu Phe Pro Gln Val Gly Lys Thr

515 520 525

Leu Leu Ser Lys Arg Gln Asn Ser Glu Val Ile Arg Glu Lys Asp Lys

530 535 540

Gln Ile Leu Ala Ser Ile Glu Leu Leu Ala Arg Ser Leu Pro Lys Ile

545 550 555 560

His Arg Ser Ala Ser Glu Pro Ser Leu Asn Arg Ala Gly Phe Gln Thr

565 570 575

Glu Asp Phe Ser Leu Tyr Ala Cys Ala Ser Pro Lys Thr Pro Ile Gln

580 585 590

Ala Gly Gly Tyr Gly Glu Phe Ala Ala Phe Lys

595 600

<210> 41

<211> 2295

<212> DNA

<213> Equus caballus

<220>

<221> additional feature

<222> (79)..(79)

<223> n represents a, c, g or t

<400> 41

atgaagacgc tgagcggcgg cggcggcggc gcggagcagg gccaggctct gttcaacggg

60

gacatggaac ccggaggcnc cgcgccggcg cccgcggcct cgtcggccgc ggaccctgcc

120

attcccgagg aggtatggaa tatcaaacaa atgattaaat tgacacagga acatatagag

180

gccctattgg acaaatttgg tggggagcat aatccaccat caatatatct ggaggcctat

240

gaagaataca ccagcaagct agatgccctc caacaaagag aacaacagtt attggaatcc

300

ctggggaatg gaactgattt ttctgtttct agttctgcat caacggacac cgttacatct

360

tcttcctctt ctagcctttc agtgctacct tcatctcttt cagtttttca aaatcccaca

420

gatgtgtcac ggagcaaccc taagtcacca caaaaaccta tcgttagagt cttcctgccc

480

aacaaacaga ggacagtggt acctgcaagg tgtggcgtta cagtccggga cagtctaaag

540

aaagcactga tgatgagagg tctaatccca gagtgctgtg ctgtttacag aattcaggat

600

ggagagaaga aaccaattgg ctgggacact gatatttcct ggctcactgg agaggaattg

660

catgtagaag tgttggagaa tgttccactt acaacacaca actttgtacg gaaaactttt

720

ttcaccttag cattttgtga cttttgtcga aagctgcttt tccagggttt ccgctgtcaa

780

acatgtggtt ataaatttca ccagcgttgt agtacagagg ttccactgat gtgtgttaat

840

tatgaccaac ttgatttgct gtttgtctcc aagttctttg aacaccaccc agtatcacag

900

gaggaggcct ccttagcaga gactgccctt acatctggat catccccttc tgcacccccc

960

tccgattcca ttgggcccca aattctcacc agtccatctc cttcaaaatc cattccaatt

1020

ccacagcctt tccgaccagc agatgaagat catcgaaatc agtttggaca acgagaccgg

1080

tcctcatcag ctccaaatgt acatataaac acaatagaac ctgtcaatat tgatgacttg

1140

attagagacc aagggtttcg tagtgatgga ggatcaacca caggtttatc tgccaccccc

1200

cctgcctcat tacctggctc actcactaat gtgaaggcat tacagaaatc tccaggacct

1260

caacgggaaa ggaaatcatc ttcatcctca gaagacagga atcgaatgaa aactcttggt

1320

agacgggatt caagtgacga ttgggagatt cctgatgggc agatcacagt gggacaaaga

1380

attggatctg ggtcatttgg gacagtctac aagggaaagt ggcatggtga tgtggcagtg

1440

aaaatgttga atgtgacagc acccacacct cagcagttac aggccttcaa aaatgaagta

1500

ggagtactca ggaaaactcg acatgtgaat atcctactct tcatgggcta ttcaacaaag

1560

ccacaactgg ctattgttac ccagtggtgt gagggctcca gcttatatca ccatctccac

1620

atcattgaga ccaaatttga gatgatcaaa cttatagata ttgctcggca aactgcacag

1680

ggcatggatt acttacacgc caagtcaatc atccacagag acctcaagag taataatatt

1740

tttcttcatg aagacctcac agtaaaaata ggtgattttg gtctagccac agtgaaatct

1800

cgatggagtg ggtcccatca gtttgaacag ttgtctggat ccattttgtg gatggcacca

1860

gaagtaatca gaatgcaaga taaaaacccg tatagctttc aatcagatgt atatgccttt

1920

gggattgttc tgtatgaatt gatgactgga cagttacctt attcaaacat caacaacagg

1980

gaccagataa tttttatggt gggaagagga tatctatctc cagatctcag taaggtacgg

2040

agtaactgtc caaaagccat gaagagatta atggcagagt gcctaaaaaa gaaaagagac

2100

gagagaccac tcttccccca aattctcgcc tctattgagc tgctggcccg ctcattgcca

2160

aaaattcacc gcagtgcatc agagccctcc ttgaatcggg ctggcttcca gacagaggat

2220

tttagtctat atgcttgtgc ttctccgaaa acacccatcc aggcaggggg atatggtgcg

2280

tttcctgtcc actga

2295

<210> 42

<211> 764

<212> PROTEIN

<213> Equus caballus

<220>

<221> additional feature

<222> (27)..(27)

<223> Xaa can be any naturally occurring

amino acid

<400> 42

Met Lys Thr Leu Ser Gly Gly Gly Gly Gly Ala Glu Gln Gly Gln Ala

1 5 10 15

Leu Phe Asn Gly Asp Met Glu Pro Gly Gly Xaa Ala Pro Ala Pro Ala

20 25 30

Ala Ser Ser Ala Ala Asp Pro Ala Ile Pro Glu Glu Val Trp Asn Ile

35 40 45

Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu Leu Asp

50 55 60

Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu Ala Tyr

65 70 75 80

Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu Gln Gln

85 90 95

Leu Leu Glu Ser Leu Gly Asn Gly Thr Asp Phe Ser Val Ser Ser Ser

100 105 110

Ala Ser Thr Asp Thr Val Thr Ser Ser Ser Ser Ser Ser Leu Ser Val

115 120 125

Leu Pro Ser Ser Leu Ser Val Phe Gln Asn Pro Thr Asp Val Ser Arg

130 135 140

Ser Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe Leu Pro

145 150 155 160

Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr Val Arg

165 170 175

Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro Glu Cys

180 185 190

Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile Gly Trp

195 200 205

Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val Glu Val

210 215 220

Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys Thr Phe

225 230 235 240

Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe Gln Gly

245 250 255

Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys Ser Thr

260 265 270

Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu Leu Phe

275 280 285

Val Ser Lys Phe Phe Glu His His Pro Val Ser Gln Glu Glu Ala Ser

290 295 300

Leu Ala Glu Thr Ala Leu Thr Ser Gly Ser Ser Pro Ser Ala Pro Pro

305 310 315 320

Ser Asp Ser Ile Gly Pro Gln Ile Leu Thr Ser Pro Ser Pro Ser Lys

325 330 335

Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp His Arg

340 345 350

Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn Val His

355 360 365

Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg Asp Gln

370 375 380

Gly Phe Arg Ser Asp Gly Gly Ser Thr Thr Gly Leu Ser Ala Thr Pro

385 390 395 400

Pro Ala Ser Leu Pro Gly Ser Leu Thr Asn Val Lys Ala Leu Gln Lys

405 410 415

Ser Pro Gly Pro Gln Arg Glu Arg Lys Ser Ser Ser Ser Ser Glu Asp

420 425 430

Arg Asn Arg Met Lys Thr Leu Gly Arg Arg Asp Ser Ser Asp Asp Trp

435 440 445

Glu Ile Pro Asp Gly Gln Ile Thr Val Gly Gln Arg Ile Gly Ser Gly

450 455 460

Ser Phe Gly Thr Val Tyr Lys Gly Lys Trp His Gly Asp Val Ala Val

465 470 475 480

Lys Met Leu Asn Val Thr Ala Pro Thr Pro Gln Gln Leu Gln Ala Phe

485 490 495

Lys Asn Glu Val Gly Val Leu Arg Lys Thr Arg His Val Asn Ile Leu

500 505 510

Leu Phe Met Gly Tyr Ser Thr Lys Pro Gln Leu Ala Ile Val Thr Gln

515 520 525

Trp Cys Glu Gly Ser Ser Leu Tyr His His Leu His Ile Ile Glu Thr

530 535 540

Lys Phe Glu Met Ile Lys Leu Ile Asp Ile Ala Arg Gln Thr Ala Gln

545 550 555 560

Gly Met Asp Tyr Leu His Ala Lys Ser Ile Ile His Arg Asp Leu Lys

565 570 575

Ser Asn Asn Ile Phe Leu His Glu Asp Leu Thr Val Lys Ile Gly Asp

580 585 590

Phe Gly Leu Ala Thr Val Lys Ser Arg Trp Ser Gly Ser His Gln Phe

595 600 605

Glu Gln Leu Ser Gly Ser Ile Leu Trp Met Ala Pro Glu Val Ile Arg

610 615 620

Met Gln Asp Lys Asn Pro Tyr Ser Phe Gln Ser Asp Val Tyr Ala Phe

625 630 635 640

Gly Ile Val Leu Tyr Glu Leu Met Thr Gly Gln Leu Pro Tyr Ser Asn

645 650 655

Ile Asn Asn Arg Asp Gln Ile Ile Phe Met Val Gly Arg Gly Tyr Leu

660 665 670

Ser Pro Asp Leu Ser Lys Val Arg Ser Asn Cys Pro Lys Ala Met Lys

675 680 685

Arg Leu Met Ala Glu Cys Leu Lys Lys Lys Arg Asp Glu Arg Pro Leu

690 695 700

Phe Pro Gln Ile Leu Ala Ser Ile Glu Leu Leu Ala Arg Ser Leu Pro

705 710 715 720

Lys Ile His Arg Ser Ala Ser Glu Pro Ser Leu Asn Arg Ala Gly Phe

725 730 735

Gln Thr Glu Asp Phe Ser Leu Tyr Ala Cys Ala Ser Pro Lys Thr Pro

740 745 750

Ile Gln Ala Gly Gly Tyr Gly Ala Phe Pro Val His

755 760

<210> 43

<211> 2678

<212> DNA

<213> Gallus gallus

<400> 43

tccccctccc tcgccccagc gcttcgatcc aagatggcgg cgctgagcag cggcagcagc

60

gccgagggg cctcgctctt caacggggac atggagcccg agccgccgcc gcccgtgctg

120

ggcgcctgct acgccgggag cggcggcggc gacccggcca tcccggagga ggtgtggaat

180

atcaaacaga tgattaaatt aacacaagaa catatagaag cgctgttaga caagtttgga

240

ggagagcata acccaccatc aatatattta gaggcctatg aggagtacac cagcaaacta

300

gatgctctac agcagagaga acagcagtta ttggaatcca tgggaaatgg aactgatttc

360

tctgtttcca gttcagcttc aacggacaca gttgcatcat cttcctcctc tagcctctct

420

gtagcacctt catccctttc agtttatcaa aatcctactg atatgtcgcg gaataaccct

480

aagtctccac agaagcctat tgttagagtc ttcctgccca acaagcaaag gactgtggtt

540

ccggcaagat gtggggtgac agtccgagac agcctgaaga aagctctgat gatgagaggt

600

cttattccag aatgctgtgc tgtttacaga atacaggatg gagagaagaa gccaattggc

660

tgggacactg acatttcctg gctaaccgga gaggagttac acgtggaggt cttggagaat

720

gtgccactca caacacacaa ttttgtacga aaaacattct tcacgttagc gttctgcgac

780

ttctgtcgaa agctgctttt ccagggattc cgatgccaga catgtggcta caaatttcac

840

cagcgctgta gcacagaagt gccactgatg tgtgttaact acgaccaact cgatttgctg

900

tttgtctcca agttctttga acatcacccc atatcgcagg aggagaccac cttaggagag

960

accaccccgg catcgggatc gtacccctca gtgcccccat cagattctgt tggaccacca

1020

attctcccta gtccttctcc ttcaaaatcc attccaatcc cacagccctt ccgaccagca

1080

gatgaagacc atcggaatca gtttgggcaa cgcgaccgat cctcttcagc tcccaatgtt

1140

cacatcaata caattgagcc agtcaatatt gatgacttga ttagagacca gggtgtacga

1200

ggagagggag cccctttgaa ccagctgatg cgctgtcttc ggaaatacca atcccggact

1260

cccagtcccc tccttcattc tgtccccagt gaaatagtgt ttgattttga gcctggccca

1320

gtgttcagag gttcaactgc aggtttgtct gcaacacctc ctgcatcttt gcctgggtca

1380

cttaccaatg tgaaagcatt acagaaatca ccaggccccc aacgggaaag gaaatcatcc

1440

tcatcctcag aagacagaaa taggatgaaa acccttggtc gacgagattc aagtgatgat

1500

tgggaaatac cagatgggca gatcacagtt ggacaaagga taggatctgg atcatttgga

1560

acagtctaca aaggaaagtg gcatggtgac gtggcagtga aaatgttgaa tgttacagca

1620

cccacacctc aacagttaca ggctttcaaa aatgaagtag gagtgctcag gaaaacacgg

1680

catgtgaata tcctactttt tatgggttat tcaacaaaac ctcagttggc tattgttaca

1740

cagtggtgtg aggggtccag cttatatcac catctgcaca taattgagac caagtttgaa

1800

atgatcaaac taattgatat tgcacgacag actgcacaag gcatggatta tttgcatgcc

1860

aagtcaatca tccacagaga cctcaagagt aataatattt ttcttcatga agacctcaca

1920

gtaaaaatag gtgacttcgg tctggctaca gtgaaatcac gatggagtgg atctcatcaa

1980

tttgaacagt tatctggatc aattctatgg atggcaccgg aagtgatcag gatgcaagac

2040

aaaaacccat atagctttca gtcagatgtg tatgcattcg ggattgtgct ttatgaactg

2100

atgactggac agttaccata ctcaaacatc aacaacaggg accagataat ttttatggtg

2160

ggacgaggat atctatctcc agacctcagt aaagtaagaa gtaactgtcc aaaagctatg

2220

aagagactaa tggcagaatg cttgaaaaag aaaagagatg agagacctct ttttccacag

2280

attcttgcct ccattgagct tctggcccgg tcgttgccaa aaattcaccg cagtgcatct

2340

gagccgtcac taaaccgggc tggcttccag accgaggatt tcagtctgta tgcttgtgct

2400

tctccaaaaa cgcccatcca agcaggggga tacggtgggt ttccagtaca ctgaaaagaa

2460

atgtgaaagc gtgtgcctgt ttgctcatgt gctggtgtgt tcctgtgtgt gcaacgcata

2520

cgtacgttct cagttcctac cagcgacttt ttaaggttta ctgagggaat gaagactcat

2580

ttcctaacat ggggcattga acgtcctgag cacaagtcag tgctggtaag gaatgtcttg

2640

ggaacagctg gcaagaagaa ttagaaggta cttaaagg

2678

<210> 44

<211> 806

<212> PROTEIN

<213> Gallus gallus

<400> 44

Met Ala Ala Leu Ser Ser Gly Ser Ser Ala Glu Gly Ala Ser Leu Phe

1 5 10 15

Asn Gly Asp Met Glu Pro Glu Pro Pro Pro Pro Val Leu Gly Ala Cys

20 25 30

Tyr Ala Gly Ser Gly Gly Gly Asp Pro Ala Ile Pro Glu Glu Val Trp

35 40 45

Asn Ile Lys Gln Met Ile Lys Leu Thr Gln Glu His Ile Glu Ala Leu

50 55 60

Leu Asp Lys Phe Gly Gly Glu His Asn Pro Pro Ser Ile Tyr Leu Glu

65 70 75 80

Ala Tyr Glu Glu Tyr Thr Ser Lys Leu Asp Ala Leu Gln Gln Arg Glu

85 90 95

Gln Gln Leu Leu Glu Ser Met Gly Asn Gly Thr Asp Phe Ser Val Ser

100 105 110

Ser Ser Ala Ser Thr Asp Thr Val Ala Ser Ser Ser Ser Ser Ser Leu

115 120 125

Ser Val Ala Pro Ser Ser Leu Ser Val Tyr Gln Asn Pro Thr Asp Met

130 135 140

Ser Arg Asn Asn Pro Lys Ser Pro Gln Lys Pro Ile Val Arg Val Phe

145 150 155 160

Leu Pro Asn Lys Gln Arg Thr Val Val Pro Ala Arg Cys Gly Val Thr

165 170 175

Val Arg Asp Ser Leu Lys Lys Ala Leu Met Met Arg Gly Leu Ile Pro

180 185 190

Glu Cys Cys Ala Val Tyr Arg Ile Gln Asp Gly Glu Lys Lys Pro Ile

195 200 205

Gly Trp Asp Thr Asp Ile Ser Trp Leu Thr Gly Glu Glu Leu His Val

210 215 220

Glu Val Leu Glu Asn Val Pro Leu Thr Thr His Asn Phe Val Arg Lys

225 230 235 240

Thr Phe Phe Thr Leu Ala Phe Cys Asp Phe Cys Arg Lys Leu Leu Phe

245 250 255

Gln Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Gln Arg Cys

260 265 270

Ser Thr Glu Val Pro Leu Met Cys Val Asn Tyr Asp Gln Leu Asp Leu

275 280 285

Leu Phe Val Ser Lys Phe Phe Glu His His Pro Ile Ser Gln Glu Glu

290 295 300

Thr Thr Leu Gly Glu Thr Thr Pro Ala Ser Gly Ser Tyr Pro Ser Val

305 310 315 320

Pro Pro Ser Asp Ser Val Gly Pro Pro Ile Leu Pro Ser Pro Ser Pro

325 330 335

Ser Lys Ser Ile Pro Ile Pro Gln Pro Phe Arg Pro Ala Asp Glu Asp

340 345 350

His Arg Asn Gln Phe Gly Gln Arg Asp Arg Ser Ser Ser Ala Pro Asn

355 360 365

Val His Ile Asn Thr Ile Glu Pro Val Asn Ile Asp Asp Leu Ile Arg

370 375 380

Asp Gln Gly Val Arg Gly Glu Gly Ala Pro Leu Asn Gln Leu Met Arg

385 390 395 400

Cys Leu Arg Lys Tyr Gln Ser Arg Thr Pro Ser Pro Leu Leu His Ser

405 410 415

Val Pro Ser Glu Ile Val Phe Asp Phe Glu Pro Gly Pro Val Phe Arg

420 425 430

Gly Ser Thr Ala Gly Leu Ser Ala Thr Pro Pro Ala Ser Leu Pro Gly

435 440 445

Ser Leu Thr Asn Val Lys Ala Leu Gln Lys Ser Pro Gly Pro Gln Arg

450 455 460

Glu Arg Lys Ser Ser Ser Ser Ser Glu Asp Arg Asn Arg Met Lys Thr

465 470 475 480

Leu Gly Arg Arg Asp Ser Ser Asp Asp Trp Glu Ile Pro Asp Gly Gln

485 490 495

Ile Thr Val Gly Gln Arg Ile Gly Ser Gly Ser Phe Gly Thr Val Tyr

500 505 510

Lys Gly Lys Trp His Gly Asp Val Ala Val Lys Met Leu Asn Val Thr

515 520 525

Ala Pro Thr Pro Gln Gln Leu Gln Ala Phe Lys Asn Glu Val Gly Val

530 535 540

Leu Arg Lys Thr Arg His Val Asn Ile Leu Leu Phe Met Gly Tyr Ser

545 550 555 560

Thr Lys Pro Gln Leu Ala Ile Val Thr Gln Trp Cys Glu Gly Ser Ser

565 570 575

Leu Tyr His His Leu His Ile Ile Glu Thr Lys Phe Glu Met Ile Lys

580 585 590

Leu Ile Asp Ile Ala Arg Gln Thr Ala Gln Gly Met Asp Tyr Leu His

595 600 605

Ala Lys Ser Ile Ile His Arg Asp Leu Lys Ser Asn Asn Ile Phe Leu

610 615 620

His Glu Asp Leu Thr Val Lys Ile Gly Asp Phe Gly Leu Ala Thr Val

625 630 635 640

Lys Ser Arg Trp Ser Gly Ser His Gln Phe Glu Gln Leu Ser Gly Ser

645 650 655

Ile Leu Trp Met Ala Pro Glu Val Ile Arg Met Gln Asp Lys Asn Pro

660 665 670

Tyr Ser Phe Gln Ser Asp Val Tyr Ala Phe Gly Ile Val Leu Tyr Glu

675 680 685

Leu Met Thr Gly Gln Leu Pro Tyr Ser Asn Ile Asn Asn Arg Asp Gln

690 695 700

Ile Ile Phe Met Val Gly Arg Gly Tyr Leu Ser Pro Asp Leu Ser Lys

705 710 715 720

Val Arg Ser Asn Cys Pro Lys Ala Met Lys Arg Leu Met Ala Glu Cys

725 730 735

Leu Lys Lys Lys Arg Asp Glu Arg Pro Leu Phe Pro Gln Ile Leu Ala

740 745 750

Ser Ile Glu Leu Leu Ala Arg Ser Leu Pro Lys Ile His Arg Ser Ala

755 760 765

Ser Glu Pro Ser Leu Asn Arg Ala Gly Phe Gln Thr Glu Asp Phe Ser

770 775 780

Leu Tyr Ala Cys Ala Ser Pro Lys Thr Pro Ile Gln Ala Gly Gly Tyr

785 790 795 800

Gly Gly Phe Pro Val His

805

<---

Claims (68)

1. A method of treating or mitigating the effects of a cancer in an individual having a BRAF mutation other than V600E/K, the method comprising administering to the individual an effective amount of an ERK inhibitor or a pharmaceutically acceptable salt thereof. 2. The method according to claim 1, where the ERK inhibitor is selected from the group consisting of BVD-523, SCH-722984 (Merck & Co.), SCH-772984 (Merck & Co.), SCH-900353 (MK-8353) ( Merck & Co.), LY3214996 (Lilly), AEZS–140 (Aeterna Zentaris), AEZS–131 (Aeterna Zentaris), AEZS–136 (Aeterna Zentaris), LTT–462 (Novartis), RG–7842 (Genentech), CC –90003 (Celgene), KIN–4050 (Kinentia) and combinations thereof. 3. The method of claim 1, wherein the ERK inhibitor is BVD-523. 4. The method of claim 1, wherein the BRAF mutation other than V600E/K is a kinase-activating mutation, a kinase-disrupting mutation, or a mutation with an unknown effect on the kinase, and combinations thereof. 5. The method according to claim 4, where the kinase-activating mutation is selected from the group consisting of R462I, I463S, G464E, G464R, G464V, G466A, G469A, N581S, E586K, F595L, L597Q, L597R, L597S, L597V, A598V, T599E, V600R, K601E, S602D, A728V and their combinations. 6. The method of claim 4, wherein the mutation disrupting the kinase function is selected from the group consisting of G466E, G466R, G466V, Y472C, K483M, D594A, D594E, D594G, D594H, D594N, D594V, G596R, T599A, S602A and combinations thereof. 7. The method according to claim 4, where the mutation with an unknown effect on the kinase is selected from the group consisting of T440I, S467L, G469E, G469R, G469S, G469V, L584F, L588F, V600_K601delinsE, S605I, Q609L, E611Q and combinations thereof. 8. The method of claim 1, wherein the BRAF non-V600E/K mutation is selected from the group consisting of D594, G469, K601E, L597, T599 duplication, L485W, F247L, G466V, BRAF fusion, BRAF–AGAP3 rearrangement, exon 15 splice variant BRAF and their combinations. 9. The method according to claim 1, wherein the individual is a mammal. 10. The method of claim 9, wherein the mammal is selected from the group consisting of humans, primates, farm animals and domestic animals. 11. The method of claim 9, wherein the mammal is a human. 12. The method of claim 1, wherein the malignancy is a solid malignancy or a hematologic malignancy. 13. The method according to claim 1, the malignant tumor is selected from the group consisting of glioblastoma, melanoma, cholangiocarcinoma, small cell lung cancer, colorectal cancer, prostate cancer, vaginal cancer, angiosarcoma, non-small cell lung cancer, appendix cancer, squamous cell carcinoma , salivary gland ductal carcinoma, adenoid cystic carcinoma, small intestinal cancer and gallbladder cancer. 14. The method of claim 13, wherein the cancer is selected from the group consisting of small intestinal cancer, non-small cell lung cancer, gallbladder cancer and squamous cell carcinoma. 15. The method of claim 1, further comprising administering to the individual at least one additional drug selected from the group consisting of a MEK inhibitor, an HDAC inhibitor, and combinations thereof. 16. The method of claim 15, wherein the MEK inhibitor is selected from the group consisting of anthrax toxin, anthroquinolol (Golden Biotechnology), ARRY-142886 ((2-hydroxyethoxy)amide 6-(4-bromo-2-chloro-phenylamino) –7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid) (Array BioPharma), ARRY-438162 (Array BioPharma) binimetinib (MEK162, ARRY-1662), AS-1940477 (Astellas), AS-703988 ( Merck KGaA), bentamapimod (Merck KGaA), BI-847325 (Boehringer Ingelheim), E-6201 (Eisai), GDC-0623 (Hoffmann-La Roche), GDC-0973 (cobimetinib) (Hoffmann-La Roche), L783277 ( Merck), part of the lethal anthrax toxin, MEK162 (Array BioPharma), PD 098059 (2-(2'-amino-3'-methoxphenyl)oxanaphthalene-4-one) (Pfizer), PD 184352 (CI-1040 ) (Pfizer), PD–0325901 (Pfizer), PD318088 (Pfizer), PD334581 (Pfizer), 6-methoxy-7-(3-morpholin-4-ylpropoxy)-4-(4-phenoxyphenylamino)quinoline-3-carbonitrile , 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinoline-3-carbonitrile, pimasertib (Santhera Pharmaceuticals), RDEA119 (Ardea Biosciences/Bayer), refametinib (AstraZeneca), RG422 (Chugai Pharmaceutical Co.), R0092210 (Roche), R04987655 (Hoffmann–La Roche), R05126766 (Hoffmann–La Roche), selumetinib (AZD6244) ( AstraZeneca), SL327 (Sigma), TAK-733 (Takeda), trametinib (Japan Tobacco), U0126 (1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene) (Sigma) , WX-554 (Wilex), YopJ polypeptide (Mittal et al., 2010), pharmaceutically acceptable salts thereof, and combinations thereof. 17. The method according to claim 15, where the HDAC inhibitor is selected from the group consisting of Abexinostat (PCI-24781), Givinostat, Entinostat, Vorinostat, CI-994, CUDC-101, Entinostat, BML-210, M344, NVP-LAQ824, Panobinostat, Pracinostat (SB939), Mocetinostat, Resminostat, Romidepsin, Belinostat, their pharmaceutically acceptable salts and combinations thereof. 18. The method of claim 1, further comprising administering to the individual at least one additional drug selected from the group consisting of an antibody, an antibody fragment, an antibody conjugate, a cytotoxic agent, a toxin, a radionuclide, an immunomodulator, a photoactive drug, a radiosensitizing agent, hormone, antiangiogenic agent and combinations thereof. 19. The method according to claim 18, where the antibody, its fragment or a conjugate thereof is selected from the group consisting of rituximab (Rituxan), Brentuximab Vedotin (Adcetriz), Adotrastuzumab emtansine (Kadcyla), Cetuximab (Erbitux), bevacizumab (Avastin), Ibritumomab (Zevalin), vedolizumab (Entyvio), Ipilimumab (Yervoy), Nivolumab (Opdivo), pembrolizumab (Keytruda), Alemtuzumab atezolizumab (Tecentriq), avelumab (Bavenzio), durvalumab (Imfinzi), B-701, Ofatumumab, Obinutuzumab (Gaziva) , Panitumumab, plosalizumab, BI-754091, OREG-103, COM-701, BI-754111 and combinations thereof. 20. The method according to claim 18, where the cytotoxic agent is selected from the group consisting of cyclophosphamide, mechlorethamine, uramustine, melphalan, chlorambucil, ifosfamide, carmustine, lomustine, streptozocin, busulfan, temozolomide, cisplatin, carboplatin, oxaliplatin, nedaplatin, satraplatin, triplatin tetranitrate, doxorubicin, daunorubicin, idarubicin, mitoxantrone, methotrexate, pemetrexed, 6-mercaptopurine, dacarbazine, fludarabine, 5-fluorouracil, arabinosylcytosine, capecitabine, gemcitabine, decitabine, vinca alkaloids, paclitaxel (Taxol), docetaxel ( Taxotere), ixabepilone (Ixempra ), actinomycin, anthracyclines, valrubicin, epirubicin, bleomycin, plicamycin, mitomycin, pharmaceutically acceptable salts thereof, prodrugs and combinations thereof. 21. The method according to claim 18, where the toxin is diphtheria toxin or parts thereof. 22. The method according to claim 18, where the radionuclide is selected from the group consisting of I–125, At–211, Lu–177, Cu–67, I–131, Sm–153, Re–186, P–32, Re– 188, In–114m, Y–90 and their combinations. 23. The method according to claim 18, where the immunomodulator is selected from the group consisting of granulocyte colony-stimulating factor (G-CSF), LAG-3, IMP-321, JCAR-014, ASLAN-002 (BMS-777607), interferons, imiquimod and cell membrane fractions from bacteria, IL-2, IL-7, IL-12, CCL3, CCL26, CXCL7, synthetic cytosine phosphate-guanosine (CpG), immune checkpoint inhibitors and combinations thereof. 24. The method according to claim 18, where the radiosensitizing agent is selected from the group consisting of mizonidazole, metronidazole, tirapazamine, sodium trans-crocetinate and combinations thereof. 25. The method according to claim 18, where the hormone is selected from the group consisting of prostaglandins, leukotrienes, prostacyclin, thromboxane, amylin, anti-Mullerian hormone, adiponectin, adrenocorticotropic hormone, angiotensinogen, angiotensin, vasopressin, atriopeptin, brain natriuretic peptide, calcitonin, cholecystokinin , corticotropin-releasing hormone, encephalin, endothelin, erythropoietin, follicle-stimulating hormone, galanin, gastrin, ghrelin, glucagon, gonadotropin-releasing hormone, growth hormone releasing factor, human chorionic gonadotropin, human placental lactogen, growth hormone, inhibin, insulin, somatomedin , leptin, lipotropin, luteinizing hormone, melanocyte-stimulating hormone, motilin, orexin, oxytocin, pancreatic polypeptide, parathyroid hormone, prolactin, prolactin-releasing hormone, relaxin, renin, secretin, somatostatin, thrombopoietin, thyroid-stimulating hormone, testosterone, dehydroepiandrosterone , androstenedione , dihydrotestosterone, aldosterone, estradiol, estrone, estriol, cortisol, progesterone, calcitriol, calcidiol, tamoxifen (Nolvadex), anastrozole (Arimidex), lectrozole (Femara), fulvestrant (Faslodex) and combinations thereof. 26. The method according to claim 18, where the antiangiogenic agent is selected from the group consisting of 2-methoxyestradiol, angiostatin, bevacizumab, cartilage angiogenesis inhibitory factor, endostatin, IFN-alpha, IL-12, itraconazole, linomide, platelet factor-4, prolactin , SU5416, suramin, tasquinimod, tecogalane, tetrathiomolybdate, thalidomide, thrombospondin, thrombospondin, TNP-470, ziv-aflibercept, pharmaceutically acceptable salts, prodrugs and combinations thereof. 27. The method according to claim 18, wherein the additional drug is an inhibitor of the PI3K/Akt cascade. 28. The method of claim 27, wherein the PI3K/Akt cascade inhibitor is selected from the group consisting of A-674563 (CAS No. 552325-73-2), AGL 2263, AMG-319 (Amgen, Thousand Oaks, CA), AS- 041164 (5-benzo[1,3]dioxol-5-ylmethylenethiazolidine-2,4-dione), AS-604850 (5-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethylene)thiazolidine- 2,4-dione), AS-605240 (5-quinoxyline-6-methylene-1,3-thiazolidine-2,4-dione), AT7867 (CAS No. 857531-00-1), benzimidazoles series, Genentech (Roche Holdings Inc., South San Francisco, CA), BML–257 (CAS No. 32387–96–5), BVD–723, CAL–120 (Gilead Sciences, Foster City, CA), CAL–129 (Gilead Sciences), CAL– 130 (Gilead Sciences), CAL–253 (Gilead Sciences), CAL–263 (Gilead Sciences), CAS No. 612847–09–3, CAS No. 681281–88–9, CAS No. 75747–14–7, CAS No. 925681– 41–0, CAS No. 98510–80–6, CCT128930 (CAS No. 885499–61–6), CH5132799 (CAS No. 1007207–67–1), CHR–4432 (Chroma Therapeutics, Ltd., Abingdon, UK), FPA 124 (CAS No. 902779–59–3), GS–1101 (CAL–101) (Gilead Sciences), GSK 690693 (CAS No. 937174–76–0), H–89 (CAS No. 127243–85–0), Honokiola , IC87114 (Gilead Science), IPI-145 (Intellikine Inc.), KAR-4139 (Karus Therapeutics, Chilworth, UK), KAR-4141 (Karus Therapeutics), KIN-1 (Karus Therapeutics), KT 5720 (CAS No. 108068 –98–0), Miltefosine, MK–2206 dihydrochloride (CAS No. 1032350–13–2), ML–9 (CAS No. 105637–50–1), Naltrindole hydrochloride, OXY–111A (NormOxys Inc., Brighton, MA) , perifosine, PHT-427 (CAS No. 1191951-57-1), PI3-kinase delta inhibitor, Merck KGaA (Merck & Co., Whitehouse Station, NJ), PI3-kinase delta inhibitors, Genentech (Roche Holdings Inc.), PI3-kinase delta inhibitors, Incozen (Incozen Therapeutics, Pvt. Ltd., Hydrabad, India), PI3-kinase inhibitors-2 delta, Incozen (Incozen Therapeutics), PI3-kinase inhibitor, Roche-4 (Roche Holdings Inc.), PI3-kinase inhibitors, Roche (Roche Holdings Inc.), PI3-kinase inhibitors, Roche-5 (Roche Holdings Inc.), PI3-alpha/delta inhibitors, Pathway Therapeutics (Pathway Therapeutics Ltd., South San Francisco, CA), PI3-delta inhibitors, Cellzome (Cellzome AG, Heidelberg, Germany ), PI3-delta inhibitors, Intellikine (Intellikine Inc., La Jolla, CA), PI3-delta inhibitors, Pathway Therapeutics-1 (Pathway Therapeutics Ltd.), PI3-delta inhibitors, Pathway Therapeutics-2 (Pathway Therapeutics Ltd.) , PI3-delta/gamma inhibitors, Cellzome (Cellzome AG), PI3-delta/gamma inhibitors, Intellikine (Intellikine Inc.), PI3-delta/gamma inhibitors, Pathway Therapeutics (Pathway Therapeutics Ltd.), PI3-gamma inhibitor Evotec ( Evotec), PI3-gamma inhibitor, Cellzome (Cellzome AG), PI3-gamma inhibitors, Pathway Therapeutics (Pathway Therapeutics Ltd.), PI3K-delta/gamma inhibitors, Intellikine-1 (Intellikine Inc.), pictilisib (Roche Holdings Inc. ), PIK-90 (CAS No. 677338-12-4), SC-103980 (Pfizer, New York, NY), SF-1126 (Semafore Pharmaceuticals, Indianapolis, IN), SH-5, SH-6, tetrahydrocurcumin, TG100-115 (Targegen Inc., San Diego, CA), Triciribine, X-339 (Xcovery, West Palm Beach, FL), XL-499 (Evotech, Hamburg, Germany), pharmaceutically acceptable salts thereof, and combinations thereof. 29. A pharmaceutical composition for treating or mitigating the effects of cancer in an individual having a non-V600E/K BRAF mutation, the composition comprising a pharmaceutically acceptable carrier or diluent and an effective amount of an ERK inhibitor or a pharmaceutically acceptable salt thereof. 30. The pharmaceutical composition according to claim 29, where the ERK inhibitor is selected from the group consisting of BVD-523, SCH-722984 (Merck & Co.), SCH-772984 (Merck & Co.), SCH-900353 (MK-8353) (Merck & Co.), LY3214996 (Lilly), AEZS–140 (Aeterna Zentaris), AEZS–131 (Aeterna Zentaris), AEZS–136 (Aeterna Zentaris), LTT–462 (Novartis), RG–7842 (Genentech), CC-90003 (Celgene), KIN-4050 (Kinentia) and combinations thereof. 31. The pharmaceutical composition according to claim 29, where the ERK inhibitor is BVD-523. 32. The pharmaceutical composition according to claim 29, wherein the BRAF mutation other than V600E/K is a kinase-activating mutation, a kinase-impairing mutation, or a mutation with an unknown effect on the kinase, and combinations thereof. 33. The pharmaceutical composition according to claim 32, where the kinase-activating mutation is selected from the group consisting of R462I, I463S, G464E, G464R, G464V, G466A, G469A, N581S, E586K, F595L, L597Q, L597R, L597S, L597V, A598V, T599E , V600R, K601E, S602D, A728V and their combinations. 34. The pharmaceutical composition according to claim 32, where the mutation that disrupts the function of the kinase is selected from the group consisting of G466E, G466R, G466V, Y472C, K483M, D594A, D594E, D594G, D594H, D594N, D594V, G596R, T599A, S602A and combinations thereof . 35. The pharmaceutical composition according to claim 32, where the mutation with an unknown effect on the kinase is selected from the group consisting of T440I, S467L, G469E, G469R, G469S, G469V, L584F, L588F, V600_K601delinsE, S605I, Q609L, E611Q and combinations thereof. 36. The pharmaceutical composition according to claim 29, wherein the individual is a mammal. 37. The pharmaceutical composition according to claim 36, wherein the mammal is selected from the group consisting of humans, primates, farm animals and domestic animals. 38. The pharmaceutical composition according to claim 36, wherein the mammal is a human. 39. The pharmaceutical composition according to claim 29, wherein the malignant tumor is a solid malignant tumor or a hematological malignant tumor. 40. The pharmaceutical composition according to claim 29, where the malignant tumor is selected from the group consisting of glioblastoma, melanoma, cholangiocarcinoma, small cell lung cancer, colorectal cancer, prostate cancer, vaginal cancer, angiosarcoma, non-small cell lung cancer, appendix cancer, squamous cell carcinoma, salivary ductal carcinoma, adenoid cystic carcinoma, small intestinal cancer and gallbladder cancer. 41. The pharmaceutical composition according to claim 40, wherein the malignant tumor is selected from the group consisting of small intestinal cancer, non-small cell lung cancer, gallbladder cancer and squamous cell carcinoma. 42. The pharmaceutical composition according to claim 29, wherein the composition is administered to the individual orally or by injection. 43. The pharmaceutical composition according to claim 29, wherein the composition is administered to an individual as a tablet. 44. The pharmaceutical composition according to claim 29, further containing at least one additional drug selected from the group consisting of a MEK inhibitor, an HDAC inhibitor and combinations thereof. 45. The pharmaceutical composition according to claim 44, where the MEK inhibitor is selected from the group consisting of anthrax toxin, anthroquinonol (Golden Biotechnology), ARRY-142886 ((2-hydroxyethoxy)amide) 6-(4-bromo-2-chlorophenylamino) –7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (Array BioPharma), ARRY-438162 (Array BioPharma), binimetinib (MEK162, ARRY-1662), AS-1940477 (Astellas), AS-703988 ( Merck KGaA), bentamapimod (Merck KGaA), BI-847325 (Boehringer Ingelheim), E-6201 (Eisai), GDC-0623 (Hoffmann-La Roche), GDC-0973 (cobimetinib) (Hoffmann-La Roche), L783277 ( Merck), part of the lethal anthrax toxin, MEK162 (Array BioPharma), PD 098059 (2-(2'-amino-3'-methoxphenyl)oxanaphthalene-4-one) (Pfizer), PD 184352 (CI-1040 ) (Pfizer), PD–0325901 (Pfizer), PD318088 (Pfizer), PD334581 (Pfizer), 6-methoxy-7-(3-morpholin-4-ylpropoxy)-4-(4-phenoxyphenylamino)quinoline-3-carbonitrile , 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinoline-3-carbonitrile, pimasertib (Santhera Pharmaceuticals), RDEA119 (Ardea Biosciences/Bayer), refametinib (AstraZeneca), RG422 (Chugai Pharmaceutical Co.), R0092210 (Roche), R04987655 (Hoffmann–La Roche), R05126766 (Hoffmann–La Roche), selumetinib (AZD6244) ( AstraZeneca), SL327 (Sigma), TAK-733 (Takeda), trametinib (Japan Tobacco), U0126 (1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene) (Sigma) , WX-554 (Wilex), YopJ polypeptide (Mittal et al., 2010), pharmaceutically acceptable salts thereof, and combinations thereof. 46. The pharmaceutical composition according to claim 44, where the HDAC inhibitor is selected from the group consisting of Abexinostat (PCI-24781), Givinostat, Entinostat, Vorinostat, CI-994, CUDC-101, Entinostat, BML-210, M344, NVP-LAQ824 , Panobinostat, Pracinostat (SB939), Mocetinostat, Resminostat, Romidepsin, Belinostat, pharmaceutically acceptable salts thereof and combinations thereof. 47. The pharmaceutical composition according to claim 29, further containing at least one additional drug selected from the group consisting of an antibody, an antibody fragment, an antibody conjugate, a cytotoxic agent, a toxin, a radionuclide, an immunomodulator, a photoactive drug, a radiosensitizing agent, a hormone , antiangiogenic agent and combinations thereof. 48. The pharmaceutical composition according to claim 47, where the antibody, its fragment or their conjugate is selected from the group consisting of rituximab (Rituxan), Brentuximab Vedotin (Adcetriz), Adotrastuzumab emtansine (Kadcyla), Cetuximab (Erbitux), bevacizumab (Avastin), Ibritumomab (Zevalin), vedolizumab (Entyvio), Ipilimumab (Yervoy), Nivolumab (Opdivo), pembrolizumab (Keytruda), Alemtuzumab atezolizumab (Tecentriq), avelumab (Bavenzio), durvalumab (Imfinzi), B-701, Ofatumumab, Obinutuzumab (Gaziva) ), Panitumumab, plosalizumab, BI-754091, OREG-103, COM-701, BI-754111 and combinations thereof. 49. The pharmaceutical composition according to p. 47, where the cytotoxic agent is selected from a group consisting of cyclophosphamide, mehloroetamine, uramustine, melfalan, chlorambucil, ifospamide, carmustine, lomustine, streptozocin, busephin, timosolomide, cisplatin, carboplatin, oxaliplatin, non -platele, satrapetin, satrapetin, satrapetin, satrapetin. triplatin tetranitrate, doxorubicin, daunorubicin, idarubicin, mitoxantrone, methotrexate, pemetrexed, 6-mercaptopurine, dacarbazine, fludarabine, 5-fluorouracil, arabinosylcytosine, capecitabine, gemcitabine, decitabine, vinca alkaloids, paclitaxel (Taxol), docetac village (Taxotere), ixabepilona ( Ixempra), actinomycin, anthracyclines, valrubicin, epirubicin, bleomycin, plicamycin, mitomycin, pharmaceutically acceptable salts thereof, prodrugs and combinations thereof. 50. The pharmaceutical composition according to claim 47, where the toxin is diphtheria toxin or parts thereof. 51. Pharmaceutical composition according to claim 47, where the radionuclide is selected from the group consisting of I-125, At-211, Lu-177, Cu-67, I-131, Sm-153, Re-186, P-32, Re –188, In–114m, Y–90 and their combinations. 52. The pharmaceutical composition according to claim 47, where the immunomodulator is selected from the group consisting of granulocyte colony-stimulating factor (G-CSF), LAG-3, IMP-321, JCAR-014, ASLAN-002 (BMS-777607), interferons, imiquimod and cell membrane fractions from bacteria, IL-2, IL-7, IL-12, CCL3, CCL26, CXCL7, synthetic cytosine phosphate-guanosine (CpG), immune checkpoint inhibitors and combinations thereof. 53. Pharmaceutical composition according to claim 47, where the radiosensitizing agent is selected from the group consisting of misonidazole, metronidazole, tirapazamine, sodium trans-crocetinate and combinations thereof. 54. The pharmaceutical composition according to claim 47, where the hormone is selected from the group consisting of prostaglandins, leukotrienes, prostacyclin, thromboxane, amylin, anti-Mullerian hormone, adiponectin, adrenocorticotropic hormone, angiotensinogen, angiotensin, vasopressin, atriopeptin, brain natriuretic peptide, calcitonin, cholecystokinin, corticotropin-releasing hormone, encephalin, endothelin, erythropoietin, follicle-stimulating hormone, galanin, gastrin, ghrelin, glucagon, gonadotropin-releasing hormone, growth hormone releasing factor, human chorionic gonadotropin, human placental lactogen, growth hormone, inhibin, insulin, somatomedin, leptin, lipotropin, luteinizing hormone, melanocyte-stimulating hormone, motilin, orexin, oxytocin, pancreatic polypeptide, parathyroid hormone, prolactin, prolactin-releasing hormone, relaxin, renin, secretin, somatostatin, thrombopoietin, thyroid-stimulating hormone, testosterone, dehydroep iandrosterone, androstenedione, dihydrotestosterone, aldosterone, estradiol, estrone, estriol, cortisol, progesterone, calcitriol, calcidiol, tamoxifen (Nolvadex), anastrozole (Arimidex), lectrozole (Femara), fulvestrant (Faslodex) and combinations thereof. 55. The pharmaceutical composition according to claim 47, where the antiangiogenic agent is selected from the group consisting of 2-methoxyestradiol, angiostatin, bevacizumab, cartilage angiogenesis inhibitory factor, endostatin, IFN-alpha, IL-12, itraconazole, linomide, platelet factor-4, prolactin, SU5416, suramin, tasquinimod, tecogalane, tetrathiomolybdate, thalidomide, thrombospondin, thrombospondin, TNP-470, ziv-aflibercept, their pharmaceutically acceptable salts, prodrugs and combinations thereof. 56. The pharmaceutical composition according to claim 47, wherein the additional drug is an inhibitor of the PI3K/Akt cascade. 57. The pharmaceutical composition according to claim 56, wherein the PI3K/Akt cascade inhibitor is selected from the group consisting of A-674563 (CAS No. 552325-73-2), AGL 2263, AMG-319 (Amgen, Thousand Oaks, CA), AS –041164 (5-benzo[1,3]dioxol-5-ylmethylenethiazolidin-2,4-dione), AS-604850 (5-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethylene)thiazolidine –2,4-dione), AS-605240 (5-quinoxylin-6-methylene-1,3-thiazolidine-2,4-dione), AT7867 (CAS No. 857531-00-1), benzimidazoles series, Genentech (Roche Holdings Inc., South San Francisco, CA), BML–257 (CAS No. 32387–96–5), BVD–723, CAL–120 (Gilead Sciences, Foster City, CA), CAL–129 (Gilead Sciences), CAL –130 (Gilead Sciences), CAL–253 (Gilead Sciences), CAL–263 (Gilead Sciences), CAS No. 612847–09–3, CAS No. 681281–88–9, CAS No. 75747–14–7, CAS No. 925681 –41–0, CAS No. 98510–80–6, CCT128930 (CAS No. 885499–61–6), CH5132799 (CAS No. 1007207–67–1), CHR–4432 (Chroma Therapeutics, Ltd., Abingdon, UK), FPA 124 (CAS No. 902779–59–3), GS–1101 (CAL–101) (Gilead Sciences), GSK 690693 (CAS No. 937174–76–0), H–89 (CAS No. 127243–85–0), Honokiola, IC87114 (Gilead Science), IPI-145 (Intellikine Inc.), KAR-4139 (Karus Therapeutics, Chilworth, UK), KAR-4141 (Karus Therapeutics), KIN-1 (Karus Therapeutics), KT 5720 (CAS no. 108068-98-0), Miltefosine, MK-2206 dihydrochloride (CAS No. 1032350-13-2), ML-9 (CAS No. 105637-50-1), Naltrindole hydrochloride, OXY-111A (NormOxys Inc., Brighton, MA ), perifosine, PHT-427 (CAS No. 1191951-57-1), PI3-kinase delta inhibitor, Merck KGaA (Merck & Co., Whitehouse Station, NJ), PI3-kinase delta inhibitors, Genentech (Roche Holdings Inc.) , PI3-kinase delta inhibitors, Incozen (Incozen Therapeutics, Pvt. Ltd., Hydrabad, India), PI3-kinase inhibitors-2 delta, Incozen (Incozen Therapeutics), PI3-kinase inhibitor, Roche-4 (Roche Holdings Inc.), PI3-kinase inhibitors, Roche (Roche Holdings Inc.), PI3-kinase inhibitors, Roche-5 (Roche Holdings Inc.), PI3-alpha/delta inhibitors, Pathway Therapeutics (Pathway Therapeutics Ltd., South San Francisco, CA), PI3-delta inhibitors, Cellzome (Cellzome AG, Heidelberg, Germany ), PI3-delta inhibitors, Intellikine (Intellikine Inc., La Jolla, CA), PI3-delta inhibitors, Pathway Therapeutics-1 (Pathway Therapeutics Ltd.), PI3-delta inhibitors, Pathway Therapeutics-2 (Pathway Therapeutics Ltd.) , PI3-delta/gamma inhibitors, Cellzome (Cellzome AG), PI3-delta/gamma inhibitors, Intellikine (Intellikine Inc.), PI3-delta/gamma inhibitors, Pathway Therapeutics (Pathway Therapeutics Ltd.), PI3-gamma inhibitor Evotec ( Evotec), PI3-gamma inhibitor, Cellzome (Cellzome AG), PI3-gamma inhibitors, Pathway Therapeutics (Pathway Therapeutics Ltd.), PI3K-delta/gamma inhibitors, Intellikine-1 (Intellikine Inc.), pictilisib (Roche Holdings Inc. ), PIK-90 (CAS No. 677338-12-4), SC-103980 (Pfizer, New York, NY), SF-1126 (Semafore Pharmaceuticals, Indianapolis, IN), SH-5, SH-6, tetrahydrocurcumin, TG100-115 (Targegen Inc., San Diego, CA), Triciribine, X-339 (Xcovery, West Palm Beach, FL), XL-499 (Evotech, Hamburg, Germany), pharmaceutically acceptable salts thereof, and combinations thereof. 58. The pharmaceutical composition according to claim 44 or 47, which is in a unit dosage form containing both an ERK inhibitor and an additional drug. 59. The pharmaceutical composition according to claim 44 or 47, wherein the ERK inhibitor is in a first unit dosage form and the additional drug is in a second unit dosage form separate from the first. 60. The pharmaceutical composition according to claim 44 or 47, wherein the ERK inhibitor and the additional drug are co-administered to the individual. 61. The pharmaceutical composition according to claim 44 or 47, wherein the ERK inhibitor and the additional drug are administered to the individual sequentially. 62. The pharmaceutical composition according to claim 61, wherein the ERK inhibitor is administered to the individual before or after administration of the additional drug. 63. A method of treating or mitigating the effects of a cancer having a BRAF mutation other than V600E/K, the method comprising administering to an individual an effective amount of BVD-523 or a pharmaceutically acceptable salt thereof. 64. A pharmaceutical composition for treating or mitigating the effects of cancer in an individual having a BRAF mutation other than V600E/K, the composition comprising a pharmaceutically acceptable carrier or diluent and an effective amount of BVD-523 or a pharmaceutically acceptable salt thereof. 65. A kit for the treatment or mitigation of the effects of a malignant tumor in an individual having a BRAF mutation other than V600E/K, wherein the kit contains a pharmaceutical composition according to any one of claims 29, 44 and 47, packaged together with instructions for its use. 66. The method according to claim 15 or the pharmaceutical composition according to claim 44, where the HDAC inhibitor is selected from the group consisting of Vorinostat, Panobinostat, Romidepsin, Belinostat, pharmaceutically acceptable salts thereof and combinations thereof. 67. The method according to claim 18 or the pharmaceutical composition according to claim 47, where the antibody, its fragment or their conjugate is selected from the group consisting of rituximab (Rituxan), Brentuximab Vedotin (Adcetriz), Adotrastuzumab emtansine (Kadcyla), Ipilimumab (Yervoy) , Nivolumab (Opdivo), pembrolizumab (Keytruda), Alemtuzumab atezolizumab (Tecentriq), durvalumab (Imfinzi), Ofatumumab, Obinutuzumab (Gazyva), Panitumumab and combinations thereof. 68. The method according to claim 27 or the pharmaceutical composition according to claim 56, where the inhibitor of the PI3K/Akt cascade is BVD-723.

Images