ID RAF1_HUMAN Reviewed; 648 AA. AC P04049; B0LPH8; B2R5N3; Q15278; Q9UC20; DT 01-NOV-1986, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1986, sequence version 1. DT 11-NOV-2015, entry version 196. DE RecName: Full=RAF proto-oncogene serine/threonine-protein kinase; DE EC=2.7.11.1; DE AltName: Full=Proto-oncogene c-RAF; DE Short=cRaf; DE AltName: Full=Raf-1; GN Name=RAF1; Synonyms=RAF; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=3003687; DOI=10.1093/nar/14.2.1009; RA Bonner T.I., Oppermann H., Seeburg P., Kerby S.B., Gunnell M.A., RA Young A.C., Rapp U.R.; RT "The complete coding sequence of the human raf oncogene and the RT corresponding structure of the c-raf-1 gene."; RL Nucleic Acids Res. 14:1009-1015(1986). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT RP LEU-308. RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT LEU-308. RG NIEHS SNPs program; RL Submitted (DEC-2007) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R., RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., RA Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Pancreas; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 228-648. RX PubMed=2993863; RA Bonner T.I., Kerby S.B., Sutrave P., Gunnell M.A., Mark G., Rapp U.R.; RT "Structure and biological activity of human homologs of the raf/mil RT oncogene."; RL Mol. Cell. Biol. 5:1400-1407(1985). RN [7] RP PROTEIN SEQUENCE OF 42-53; 60-65; 310-316 AND 564-572, INTERACTION RP WITH PRMT5, METHYLATION AT ARG-563, PHOSPHORYLATION AT SER-289; RP SER-296; SER-301; SER-338 AND SER-621, AND MUTAGENESIS OF ARG-563. RX PubMed=21917714; DOI=10.1126/scisignal.2001936; RA Andreu-Perez P., Esteve-Puig R., de Torre-Minguela C., RA Lopez-Fauqued M., Bech-Serra J.J., Tenbaum S., Garcia-Trevijano E.R., RA Canals F., Merlino G., Avila M.A., Recio J.A.; RT "Protein arginine methyltransferase 5 regulates ERK1/2 signal RT transduction amplitude and cell fate through CRAF."; RL Sci. Signal. 4:RA58-RA58(2011). RN [8] RP PROTEIN SEQUENCE OF 254-278, AND PHOSPHORYLATION AT THR-269. RX PubMed=7477354; DOI=10.1038/378307a0; RA Yao B., Zhang Y., Delikat S., Mathias S., Basu S., Kolesnick R.; RT "Phosphorylation of Raf by ceramide-activated protein kinase."; RL Nature 378:307-310(1995). RN [9] RP PARTIAL NUCLEOTIDE SEQUENCE [GENOMIC DNA], ALTERNATIVE SPLICING, AND RP TISSUE SPECIFICITY. RC TISSUE=Placenta; RX PubMed=1886707; RA Dozier C., Ansieau S., Ferreira E., Coll J., Stehelin D.; RT "An alternatively spliced c-mil/raf mRNA is predominantly expressed in RT chicken muscular tissues and conserved among vertebrate species."; RL Oncogene 6:1307-1311(1991). RN [10] RP PHOSPHORYLATION AT SER-43; SER-259; THR-268; SER-499 AND SER-621. RX PubMed=8349614; RA Morrison D.K., Heidecker G., Rapp U.R., Copeland T.D.; RT "Identification of the major phosphorylation sites of the Raf-1 RT kinase."; RL J. Biol. Chem. 268:17309-17316(1993). RN [11] RP INTERACTION WITH YWHAZ, AND FUNCTION. RX PubMed=9360956; DOI=10.1074/jbc.272.46.28882; RA Dubois T., Rommel C., Howell S., Steinhussen U., Soneji Y., RA Morrice N., Moelling K., Aitken A.; RT "14-3-3 is phosphorylated by casein kinase I on residue 233. RT Phosphorylation at this site in vivo regulates Raf/14-3-3 RT interaction."; RL J. Biol. Chem. 272:28882-28888(1997). RN [12] RP PHOSPHORYLATION. RX PubMed=9823899; DOI=10.1038/24184; RA King A.J., Sun H., Diaz B., Barnard D., Miao W., Bagrodia S., RA Marshall M.S.; RT "The protein kinase Pak3 positively regulates Raf-1 activity through RT phosphorylation of serine 338."; RL Nature 396:180-183(1998). RN [13] RP ERRATUM. RA King A.J., Sun H., Diaz B., Barnard D., Miao W., Bagrodia S., RA Marshall M.S.; RL Nature 406:439-439(2000). RN [14] RP PHOSPHORYLATION AT SER-259 BY PKB/AKT1, ENZYME REGULATION, AND RP INTERACTION WITH PKB/AKT1. RX PubMed=10576742; DOI=10.1126/science.286.5445.1741; RA Zimmermann S., Moelling K.; RT "Phosphorylation and regulation of Raf by Akt (protein kinase B)."; RL Science 286:1741-1744(1999). RN [15] RP PHOSPHORYLATION AT SER-259 AND SER-621, DEPHOSPHORYLATION AT SER-43; RP SER-259 AND SER-621, ENZYME REGULATION, AND INTERACTION WITH PPP2CA RP AND PPP2R1B. RX PubMed=10801873; DOI=10.1074/jbc.M003259200; RA Abraham D., Podar K., Pacher M., Kubicek M., Welzel N., Hemmings B.A., RA Dilworth S.M., Mischak H., Kolch W., Baccarini M.; RT "Raf-1-associated protein phosphatase 2A as a positive regulator of RT kinase activation."; RL J. Biol. Chem. 275:22300-22304(2000). RN [16] RP ENZYME REGULATION, AND PHOSPHORYLATION AT THR-491 AND SER-494. RX PubMed=11447113; DOI=10.1093/emboj/20.14.3716; RA Chong H., Lee J., Guan K.L.; RT "Positive and negative regulation of Raf kinase activity and function RT by phosphorylation."; RL EMBO J. 20:3716-3727(2001). RN [17] RP FUNCTION, AND INTERACTION WITH MAP3K5/ASK1. RX PubMed=11427728; DOI=10.1073/pnas.141224398; RA Chen J., Fujii K., Zhang L., Roberts T., Fu H.; RT "Raf-1 promotes cell survival by antagonizing apoptosis signal- RT regulating kinase 1 through a MEK-ERK independent mechanism."; RL Proc. Natl. Acad. Sci. U.S.A. 98:7783-7788(2001). RN [18] RP FUNCTION IN PHOSPHORYLATION OF PPP1R12A, AND INTERACTION WITH RP PPP1R12A. RX PubMed=11719507; DOI=10.1074/jbc.M106343200; RA Broustas C.G., Grammatikakis N., Eto M., Dent P., Brautigan D.L., RA Kasid U.; RT "Phosphorylation of the myosin-binding subunit of myosin phosphatase RT by Raf-1 and inhibition of phosphatase activity."; RL J. Biol. Chem. 277:3053-3059(2002). RN [19] RP PHOSPHORYLATION AT SER-338 BY PAK1, ENZYME REGULATION, AND INTERACTION RP WITH PAK1. RX PubMed=11733498; DOI=10.1074/jbc.M110000200; RA Zang M., Hayne C., Luo Z.; RT "Interaction between active Pak1 and Raf-1 is necessary for RT phosphorylation and activation of Raf-1."; RL J. Biol. Chem. 277:4395-4405(2002). RN [20] RP PHOSPHORYLATION AT SER-259, DEPHOSPHORYLATION AT SER-259, AND RP SUBCELLULAR LOCATION. RX PubMed=11756411; DOI=10.1074/jbc.M108733200; RA Kubicek M., Pacher M., Abraham D., Podar K., Eulitz M., Baccarini M.; RT "Dephosphorylation of Ser-259 regulates Raf-1 membrane association."; RL J. Biol. Chem. 277:7913-7919(2002). RN [21] RP COMPETITION WITH RIN1. RX PubMed=11784866; DOI=10.1128/MCB.22.13.4638-4651.2002; RA Wang Y., Waldron R.T., Dhaka A., Patel A., Riley M.M., Rozengurt E., RA Colicelli J.; RT "The RAS effector RIN1 directly competes with RAF and is regulated by RT 14-3-3 proteins."; RL Mol. Cell. Biol. 22:916-926(2002). RN [22] RP ENZYME REGULATION, AND INTERACTION WITH SPRY2 AND SPRY4. RX PubMed=12717443; DOI=10.1038/ncb978; RA Sasaki A., Taketomi T., Kato R., Saeki K., Nonami A., Sasaki M., RA Kuriyama M., Saito N., Shibuya M., Yoshimura A.; RT "Mammalian Sprouty4 suppresses Ras-independent ERK activation by RT binding to Raf1."; RL Nat. Cell Biol. 5:427-432(2003). RN [23] RP PHOSPHORYLATION AT SER-259. RX PubMed=15047712; DOI=10.1074/jbc.M314192200; RA Kunapuli P., Kasyapa C.S., Hawthorn L., Cowell J.K.; RT "LGI1, a putative tumor metastasis suppressor gene, controls in vitro RT invasiveness and expression of matrix metalloproteinases in glioma RT cells through the ERK1/2 pathway."; RL J. Biol. Chem. 279:23151-23157(2004). RN [24] RP ERRATUM. RA Kunapuli P., Kasyapa C.S., Hawthorn L., Cowell J.K.; RL J. Biol. Chem. 282:2752-2752(2007). RN [25] RP FUNCTION IN PHOSPHORYLATION OF ADCY2; ADCY5 AND ADCY6, AND INTERACTION RP WITH ADCY2; ADCY5 AND ADCY6. RX PubMed=15385642; DOI=10.1124/mol.66.4.; RA Ding Q., Gros R., Gray I.D., Taussig R., Ferguson S.S., Feldman R.D.; RT "Raf kinase activation of adenylyl cyclases: isoform-selective RT regulation."; RL Mol. Pharmacol. 66:921-928(2004). RN [26] RP INTERACTION WITH STK3/MST2, AND FUNCTION. RX PubMed=15618521; DOI=10.1126/science.1103233; RA O'Neill E., Rushworth L., Baccarini M., Kolch W.; RT "Role of the kinase MST2 in suppression of apoptosis by the proto- RT oncogene product Raf-1."; RL Science 306:2267-2270(2004). RN [27] RP INTERACTION WITH RCAN1/DSCR1. RX PubMed=15935327; DOI=10.1016/j.abb.2005.05.002; RA Cho Y.J., Abe M., Kim S.Y., Sato Y.; RT "Raf-1 is a binding partner of DSCR1."; RL Arch. Biochem. Biophys. 439:121-128(2005). RN [28] RP REVIEW ON FUNCTION. RX PubMed=15943972; DOI=10.1016/j.febslet.2005.03.024; RA Baccarini M.; RT "Second nature: biological functions of the Raf-1 'kinase'."; RL FEBS Lett. 579:3271-3277(2005). RN [29] RP FUNCTION IN PHOSPHORYLATION OF BAD, PHOSPHORYLATION AT SER-338 AND RP SER-339 BY PAK1, SUBCELLULAR LOCATION, AND INTERACTION WITH BCL2. RX PubMed=15849194; DOI=10.1074/jbc.M413374200; RA Jin S., Zhuo Y., Guo W., Field J.; RT "p21-activated Kinase 1 (Pak1)-dependent phosphorylation of Raf-1 RT regulates its mitochondrial localization, phosphorylation of BAD, and RT Bcl-2 association."; RL J. Biol. Chem. 280:24698-24705(2005). RN [30] RP PHOSPHORYLATION AT SER-471. RX PubMed=16093354; DOI=10.1091/mbc.E05-02-0090; RA Zhu J., Balan V., Bronisz A., Balan K., Sun H., Leicht D.T., Luo Z., RA Qin J., Avruch J., Tzivion G.; RT "Identification of Raf-1 S471 as a novel phosphorylation site critical RT for Raf-1 and B-Raf kinase activities and for MEK binding."; RL Mol. Biol. Cell 16:4733-4744(2005). RN [31] RP IDENTIFICATION IN A COMPLEX WITH PP1CA; PPP1CB; PPP1CC; SHOC2 AND RP MRAS, PHOSPHORYLATION AT SER-259, AND CHARACTERIZATION OF VARIANT RP ALA-259. RX PubMed=16630891; DOI=10.1016/j.molcel.2006.03.027; RA Rodriguez-Viciana P., Oses-Prieto J., Burlingame A., Fried M., RA McCormick F.; RT "A phosphatase holoenzyme comprised of Shoc2/Sur8 and the catalytic RT subunit of PP1 functions as an M-Ras effector to modulate Raf RT activity."; RL Mol. Cell 22:217-230(2006). RN [32] RP SUBUNIT. RX PubMed=16508002; DOI=10.1128/MCB.26.6.2262-2272.2006; RA Rushworth L.K., Hindley A.D., O'Neill E., Kolch W.; RT "Regulation and role of Raf-1/B-Raf heterodimerization."; RL Mol. Cell. Biol. 26:2262-2272(2006). RN [33] RP FUNCTION AS KINASE, ENZYME REGULATION, PHOSPHORYLATION AT SER-259; RP SER-338; TYR-340; TYR-341 AND SER-621, DEPHOSPHORYLATION AT SER-338 BY RP PPP5C, AND MUTAGENESIS OF 338-SER-SER-339; 340-TYR-TYR-341; THR-491 RP AND SER-494. RX PubMed=16892053; DOI=10.1038/ncb1465; RA von Kriegsheim A., Pitt A., Grindlay G.J., Kolch W., Dhillon A.S.; RT "Regulation of the Raf-MEK-ERK pathway by protein phosphatase 5."; RL Nat. Cell Biol. 8:1011-1016(2006). RN [34] RP REVIEW ON REGULATION. RX PubMed=17218791; RA Dhillon A.S., von Kriegsheim A., Grindlay J., Kolch W.; RT "Phosphatase and feedback regulation of Raf-1 signaling."; RL Cell Cycle 6:3-7(2007). RN [35] RP FUNCTION. RX PubMed=16924233; DOI=10.1038/sj.onc.1209902; RA Wang Z., Wade P., Mandell K.J., Akyildiz A., Parkos C.A., Mrsny R.J., RA Nusrat A.; RT "Raf 1 represses expression of the tight junction protein occludin via RT activation of the zinc-finger transcription factor slug."; RL Oncogene 26:1222-1230(2007). RN [36] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-252, AND IDENTIFICATION RP BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Embryonic kidney; RX PubMed=17525332; DOI=10.1126/science.1140321; RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, RA Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N., RA Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.; RT "ATM and ATR substrate analysis reveals extensive protein networks RT responsive to DNA damage."; RL Science 316:1160-1166(2007). RN [37] RP ENZYME REGULATION, AND INTERACTION WITH PEBP1/RKIP. RX PubMed=18294816; DOI=10.1016/j.cellsig.2008.01.012; RA Rath O., Park S., Tang H.H., Banfield M.J., Brady R.L., Lee Y.C., RA Dignam J.D., Sedivy J.M., Kolch W., Yeung K.C.; RT "The RKIP (Raf-1 Kinase Inhibitor Protein) conserved pocket binds to RT the phosphorylated N-region of Raf-1 and inhibits the Raf-1-mediated RT activated phosphorylation of MEK."; RL Cell. Signal. 20:935-941(2008). RN [38] RP PHOSPHORYLATION AT SER-338 BY PAK5. RX PubMed=18465753; DOI=10.1002/jcb.21809; RA Wu X., Carr H.S., Dan I., Ruvolo P.P., Frost J.A.; RT "p21 activated kinase 5 activates Raf-1 and targets it to RT mitochondria."; RL J. Cell. Biochem. 105:167-175(2008). RN [39] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18220336; DOI=10.1021/pr0705441; RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., RA Yates J.R. III; RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for RT efficient phosphoproteomic analysis."; RL J. Proteome Res. 7:1346-1351(2008). RN [40] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of RT the kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [41] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-642, AND IDENTIFICATION RP BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [42] RP SUBCELLULAR LOCATION. RX PubMed=19298812; DOI=10.1016/j.yexcr.2009.03.004; RA Smith J., Bunaciu R.P., Reiterer G., Coder D., George T., Asaly M., RA Yen A.; RT "Retinoic acid induces nuclear accumulation of Raf1 during RT differentiation of HL-60 cells."; RL Exp. Cell Res. 315:2241-2248(2009). RN [43] RP ENZYME REGULATION, SUBUNIT, SUBCELLULAR LOCATION, AND INTERACTION WITH RP DGKH. RX PubMed=19710016; DOI=10.1074/jbc.M109.043604; RA Yasuda S., Kai M., Imai S., Takeishi K., Taketomi A., Toyota M., RA Kanoh H., Sakane F.; RT "Diacylglycerol kinase eta augments C-Raf activity and B-Raf/C-Raf RT heterodimerization."; RL J. Biol. Chem. 284:29559-29570(2009). RN [44] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-289 AND SER-301, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [45] RP REVIEW. RX PubMed=20674547; DOI=10.1016/j.bbrc.2010.07.092; RA Roskoski R. Jr.; RT "RAF protein-serine/threonine kinases: structure and regulation."; RL Biochem. Biophys. Res. Commun. 399:313-317(2010). RN [46] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., RA Mann M.; RT "Quantitative phosphoproteomics reveals widespread full RT phosphorylation site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [47] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [48] RP REVIEW. RX PubMed=21779496; DOI=10.1177/1947601911407323; RA Matallanas D., Birtwistle M., Romano D., Zebisch A., Rauch J., RA von Kriegsheim A., Kolch W.; RT "Raf family kinases: old dogs have learned new tricks."; RL Genes Cancer 2:232-260(2011). RN [49] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., RA Blagoev B.; RT "System-wide temporal characterization of the proteome and RT phosphoproteome of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [50] RP INTERACTION WITH FAM83B. RX PubMed=22886302; DOI=10.1172/JCI60517; RA Cipriano R., Graham J., Miskimen K.L., Bryson B.L., Bruntz R.C., RA Scott S.A., Brown H.A., Stark G.R., Jackson M.W.; RT "FAM83B mediates EGFR- and RAS-driven oncogenic transformation."; RL J. Clin. Invest. 122:3197-3210(2012). RN [51] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., RA Wang L., Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human RT liver phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [52] RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 51-131. RX PubMed=7791872; DOI=10.1038/375554a0; RA Nassar N., Horn G., Herrmann C., Scherer A., McCormick F., RA Wittinghofer A.; RT "The 2.2 A crystal structure of the Ras-binding domain of the RT serine/threonine kinase c-Raf1 in complex with Rap1A and a GTP RT analogue."; RL Nature 375:554-560(1995). RN [53] RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 56-131. RX PubMed=8756332; DOI=10.1038/nsb0896-723; RA Nassar N., Horn G., Herrmann C., Block C., Janknecht R., RA Wittinghofer A.; RT "Ras/Rap effector specificity determined by charge reversal."; RL Nat. Struct. Biol. 3:723-729(1996). RN [54] RP STRUCTURE BY NMR OF 55-132. RX PubMed=7766599; DOI=10.1021/bi00021a001; RA Emerson S.D., Madison V.S., Palermo R.E., Waugh D.S., Scheffler J.E., RA Tsao K.L., Kiefer S.E., Liu S.P., Fry D.C.; RT "Solution structure of the Ras-binding domain of c-Raf-1 and RT identification of its Ras interaction surface."; RL Biochemistry 34:6911-6918(1995). RN [55] RP STRUCTURE BY NMR OF 136-187. RX PubMed=8710867; DOI=10.1073/pnas.93.16.8312; RA Mott H.R., Carpenter J.W., Zhong S., Ghosh S., Bell R.M., RA Campbell S.L.; RT "The solution structure of the Raf-1 cysteine-rich domain: a novel ras RT and phospholipid binding site."; RL Proc. Natl. Acad. Sci. U.S.A. 93:8312-8317(1996). RN [56] RP VARIANTS NS5 SER-256; PHE-259; ARG-260; LEU-261; SER-261; ASN-486; RP GLY-486; ILE-491; ARG-491 AND THR-612, VARIANT HYPERTROPHIC RP CARDIOMYOPATHY ILE-260, VARIANTS LPRD2 LEU-257 AND VAL-613, VARIANT RP NS5 LEU-257, CHARACTERIZATION OF VARIANTS NS5 SER-261; ASN-486 AND RP ILE-491, AND CHARACTERIZATION OF VARIANT LPRD2 VAL-613. RX PubMed=17603483; DOI=10.1038/ng2073; RA Pandit B., Sarkozy A., Pennacchio L.A., Carta C., Oishi K., RA Martinelli S., Pogna E.A., Schackwitz W., Ustaszewska A., RA Landstrom A., Bos J.M., Ommen S.R., Esposito G., Lepri F., Faul C., RA Mundel P., Lopez Siguero J.P., Tenconi R., Selicorni A., Rossi C., RA Mazzanti L., Torrente I., Marino B., Digilio M.C., Zampino G., RA Ackerman M.J., Dallapiccola B., Tartaglia M., Gelb B.D.; RT "Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes RT with hypertrophic cardiomyopathy."; RL Nat. Genet. 39:1007-1012(2007). RN [57] RP VARIANTS NS5 LEU-257; ALA-261; SER-261; ALA-263 AND VAL-613, AND RP CHARACTERIZATION OF VARIANTS NS5 LEU-257; ALA-261; SER-261; ALA-263 RP AND VAL-613. RX PubMed=17603482; DOI=10.1038/ng2078; RA Razzaque M.A., Nishizawa T., Komoike Y., Yagi H., Furutani M., Amo R., RA Kamisago M., Momma K., Katayama H., Nakagawa M., Fujiwara Y., RA Matsushima M., Mizuno K., Tokuyama M., Hirota H., Muneuchi J., RA Higashinakagawa T., Matsuoka R.; RT "Germline gain-of-function mutations in RAF1 cause Noonan syndrome."; RL Nat. Genet. 39:1013-1017(2007). RN [58] RP VARIANTS [LARGE SCALE ANALYSIS] ALA-259 AND HIS-335. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E., RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). RN [59] RP VARIANT NS5 SER-261. RX PubMed=20683980; DOI=10.1002/ajmg.a.33564; RA Longoni M., Moncini S., Cisternino M., Morella I.M., Ferraiuolo S., RA Russo S., Mannarino S., Brazzelli V., Coi P., Zippel R., Venturin M., RA Riva P.; RT "Noonan syndrome associated with both a new Jnk-activating familial RT SOS1 and a de novo RAF1 mutations."; RL Am. J. Med. Genet. A 152:2176-2184(2010). RN [60] RP INVOLVEMENT IN CMD1NN, VARIANTS CMD1NN THR-237; ALA-310; ALA-332; RP PRO-603; ARG-626 AND MET-641, AND CHARACTERIZATION OF VARIANTS CMD1NN RP THR-237; ALA-310; ALA-332; PRO-603; ARG-626 AND MET-641. RX PubMed=24777450; DOI=10.1038/ng.2963; RA Dhandapany P.S., Razzaque M.A., Muthusami U., Kunnoth S., RA Edwards J.J., Mulero-Navarro S., Riess I., Pardo S., Sheng J., RA Rani D.S., Rani B., Govindaraj P., Flex E., Yokota T., Furutani M., RA Nishizawa T., Nakanishi T., Robbins J., Limongelli G., Hajjar R.J., RA Lebeche D., Bahl A., Khullar M., Rathinavel A., Sadler K.C., RA Tartaglia M., Matsuoka R., Thangaraj K., Gelb B.D.; RT "RAF1 mutations in childhood-onset dilated cardiomyopathy."; RL Nat. Genet. 46:635-639(2014). CC -!- FUNCTION: Serine/threonine-protein kinase that acts as a CC regulatory link between the membrane-associated Ras GTPases and CC the MAPK/ERK cascade, and this critical regulatory link functions CC as a switch determining cell fate decisions including CC proliferation, differentiation, apoptosis, survival and oncogenic CC transformation. RAF1 activation initiates a mitogen-activated CC protein kinase (MAPK) cascade that comprises a sequential CC phosphorylation of the dual-specific MAPK kinases (MAP2K1/MEK1 and CC MAP2K2/MEK2) and the extracellular signal-regulated kinases CC (MAPK3/ERK1 and MAPK1/ERK2). The phosphorylated form of RAF1 (on CC residues Ser-338 and Ser-339, by PAK1) phosphorylates BAD/Bcl2- CC antagonist of cell death at 'Ser-75'. Phosphorylates adenylyl CC cyclases: ADCY2, ADCY5 and ADCY6, resulting in their activation. CC Phosphorylates PPP1R12A resulting in inhibition of the phosphatase CC activity. Phosphorylates TNNT2/cardiac muscle troponin T. Can CC promote NF-kB activation and inhibit signal transducers involved CC in motility (ROCK2), apoptosis (MAP3K5/ASK1 and STK3/MST2), CC proliferation and angiogenesis (RB1). Can protect cells from CC apoptosis also by translocating to the mitochondria where it binds CC BCL2 and displaces BAD/Bcl2-antagonist of cell death. Regulates CC Rho signaling and migration, and is required for normal wound CC healing. Plays a role in the oncogenic transformation of CC epithelial cells via repression of the TJ protein, occludin (OCLN) CC by inducing the up-regulation of a transcriptional repressor CC SNAI2/SLUG, which induces down-regulation of OCLN. Restricts CC caspase activation in response to selected stimuli, notably Fas CC stimulation, pathogen-mediated macrophage apoptosis, and erythroid CC differentiation. {ECO:0000269|PubMed:11427728, CC ECO:0000269|PubMed:11719507, ECO:0000269|PubMed:15385642, CC ECO:0000269|PubMed:15618521, ECO:0000269|PubMed:15849194, CC ECO:0000269|PubMed:16892053, ECO:0000269|PubMed:16924233, CC ECO:0000269|PubMed:9360956}. CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. CC -!- COFACTOR: CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; CC Note=Binds 2 Zn(2+) ions per subunit.; CC -!- ENZYME REGULATION: Regulation is a highly complex process CC involving membrane recruitment, protein-protein interactions, CC dimerization, and phosphorylation/dephosphorylation events. Ras- CC GTP recruits RAF1 to the membrane, thereby promoting its CC activation. The inactive conformation of RAF1 is maintained by CC autoinhibitory interactions occurring between the N-terminal CC regulatory and the C-terminal catalytic domains and by the binding CC of a 14-3-3 protein that contacts two phosphorylation sites, Ser- CC 259 and Ser-621. Upon mitogenic stimulation, Ras and PPP2R1A CC cooperate to release autoinhibition and the subsequent CC phosphorylation of activating sites: Ser-338, Tyr-341, Thr-491, CC and Ser-494, yields a fully active kinase. Through a negative CC feedback mechanism involving MAPK1/ERK2, RAF1 is phosphorylated on CC Ser-29, Ser-43, Ser-289, Ser-296, Ser-301 and Ser-642 by CC MAPK1/ERK2, which yields an inactive, desensitized kinase. The CC signaling-competent conformation of RAF1 is finally re-established CC by the coordinated action of PIN1, a prolyl isomerase that CC converts pSer and pThr residues from the cis to the trans CC conformation, which is preferentially recognized and CC dephosphorylated by PPP2R1A. Activated by homodimerization and CC heterodimerization (with BRAF). Also regulated through association CC with other proteins such as KSR2, CNKSR1/CNK1, PEBP1/RKIP, CC PHB/prohibitin and SPRY4. PEBP1/RKIP acts by dissociating RAF1 CC from its substrates MAP2K1/MEK1 and MAP2K2/MEK2. PHB/prohibitin CC facilitates the displacement of 14-3-3 from RAF1 by activated Ras, CC thereby promoting cell membrane localization and phosphorylation CC of RAF1 at the activating Ser-338. SPRY4 inhibits Ras-independent, CC but not Ras-dependent, activation of RAF1. CNKSR1/CNK1 regulates CC Src-mediated RAF1 activation. {ECO:0000269|PubMed:10576742, CC ECO:0000269|PubMed:10801873, ECO:0000269|PubMed:11447113, CC ECO:0000269|PubMed:11733498, ECO:0000269|PubMed:12717443, CC ECO:0000269|PubMed:16892053, ECO:0000269|PubMed:18294816, CC ECO:0000269|PubMed:19710016}. CC -!- SUBUNIT: Monomer. Homodimer. Heterodimerizes with BRAF and this CC heterodimer possesses a highly increased kinase activity compared CC to the respective homodimers or monomers. Heterodimerization is CC mitogen-regulated and enhanced by 14-3-3 proteins. MAPK1/ERK2 CC activation can induce a negative feedback that promotes the CC dissociation of the heterodimer. Forms a multiprotein complex with CC Ras (M-Ras/MRAS), SHOC2 and protein phosphatase 1 (PPP1CA, PPP1CB CC and PPP1CC). Interacts with Ras proteins; the interaction is CC antagonized by RIN1. Weakly interacts with RIT1. Interacts (via N- CC terminus) with RGS14 (via RBD domains); the interaction mediates CC the formation of a ternary complex with BRAF, a ternary complex CC inhibited by GNAI1 (By similarity). Interacts with STK3/MST2; the CC interaction inhibits its pro-apoptotic activity. Interacts (when CC phosphorylated at Ser-259) with YWHAZ (unphosphorylated at 'Thr- CC 232'). Interacts with MAP2K1/MEK1 and MAP2K2/MEK2 (By similarity). CC Interacts with MAP3K5/ASF1 (via N-terminus) and this interaction CC inhibits the proapoptotic function of MAP3K5/ASK1. Interacts with CC PAK1 (via kinase domain). The phosphorylated form interacts with CC PIN1. The Ser-338 and Ser-339 phosphorylated form (by PAK1) CC interacts with BCL2. Interacts with PEBP1/RKIP and this CC interaction is enhanced if RAF1 is phosphorylated on residues Ser- CC 338, Ser-339, Tyr-340 and Tyr-341. Interacts with ADCY2, ADCY5, CC ADCY6, DGKH, RCAN1/DSCR1, ROCK2, PPP1R12A, PKB/AKT1, PPP2CA, CC PPP2R1B, SPRY2, SPRY4, CNKSR1/CNK1, KSR2 and PHB/prohibitin. In CC its active form, interacts with PRMT5. Interacts with FAM83B; CC displaces 14-3-3 proteins from RAF1 and activates RAF1 CC (PubMed:22886302). {ECO:0000250, ECO:0000269|PubMed:10576742, CC ECO:0000269|PubMed:10801873, ECO:0000269|PubMed:11427728, CC ECO:0000269|PubMed:11719507, ECO:0000269|PubMed:11733498, CC ECO:0000269|PubMed:12717443, ECO:0000269|PubMed:15385642, CC ECO:0000269|PubMed:15618521, ECO:0000269|PubMed:15849194, CC ECO:0000269|PubMed:15935327, ECO:0000269|PubMed:16508002, CC ECO:0000269|PubMed:16630891, ECO:0000269|PubMed:18294816, CC ECO:0000269|PubMed:19710016, ECO:0000269|PubMed:21917714, CC ECO:0000269|PubMed:22886302, ECO:0000269|PubMed:9360956}. CC -!- INTERACTION: CC Self; NbExp=4; IntAct=EBI-365996, EBI-365996; CC P31749:AKT1; NbExp=2; IntAct=EBI-365996, EBI-296087; CC Q92934:BAD; NbExp=2; IntAct=EBI-365996, EBI-700771; CC P15056:BRAF; NbExp=46; IntAct=EBI-365996, EBI-365980; CC P49368:CCT3; NbExp=3; IntAct=EBI-365996, EBI-356673; CC P30304:CDC25A; NbExp=4; IntAct=EBI-365996, EBI-747671; CC Q16543:CDC37; NbExp=4; IntAct=EBI-365996, EBI-295634; CC P31327:CPS1; NbExp=4; IntAct=EBI-365996, EBI-536811; CC P01112:HRAS; NbExp=14; IntAct=EBI-365996, EBI-350145; CC P08238:HSP90AB1; NbExp=3; IntAct=EBI-365996, EBI-352572; CC P11021:HSPA5; NbExp=4; IntAct=EBI-365996, EBI-354921; CC P01116-2:KRAS; NbExp=2; IntAct=EBI-365996, EBI-367427; CC P28301:Lox (xeno); NbExp=2; IntAct=EBI-365996, EBI-642911; CC Q02750:MAP2K1; NbExp=30; IntAct=EBI-365996, EBI-492564; CC P36507:MAP2K2; NbExp=3; IntAct=EBI-365996, EBI-1056930; CC Q9ESN9-2:Mapk8ip3 (xeno); NbExp=2; IntAct=EBI-365996, EBI-9549291; CC Q12968:NFATC3; NbExp=2; IntAct=EBI-365996, EBI-5278441; CC P03495:NS (xeno); NbExp=2; IntAct=EBI-365996, EBI-2548993; CC O39474:NS5A (xeno); NbExp=4; IntAct=EBI-365996, EBI-7016711; CC O43482:OIP5; NbExp=4; IntAct=EBI-365996, EBI-536879; CC Q13177:PAK2; NbExp=2; IntAct=EBI-365996, EBI-1045887; CC P09619:PDGFRB; NbExp=2; IntAct=EBI-365996, EBI-641237; CC P30086:PEBP1; NbExp=7; IntAct=EBI-365996, EBI-716384; CC Q96S96:PEBP4; NbExp=4; IntAct=EBI-365996, EBI-8563667; CC P14618:PKM; NbExp=3; IntAct=EBI-365996, EBI-353408; CC P62834:RAP1A; NbExp=2; IntAct=EBI-365996, EBI-491414; CC P01120:RAS2 (xeno); NbExp=2; IntAct=EBI-365996, EBI-14838; CC P06400:RB1; NbExp=3; IntAct=EBI-365996, EBI-491274; CC P53805-2:RCAN1; NbExp=4; IntAct=EBI-365996, EBI-1541912; CC P31947:SFN; NbExp=3; IntAct=EBI-365996, EBI-476295; CC Q3ZCQ8:TIMM50; NbExp=4; IntAct=EBI-365996, EBI-355175; CC P31946:YWHAB; NbExp=18; IntAct=EBI-365996, EBI-359815; CC P62258:YWHAE; NbExp=3; IntAct=EBI-365996, EBI-356498; CC Q04917:YWHAH; NbExp=4; IntAct=EBI-365996, EBI-306940; CC P27348:YWHAQ; NbExp=3; IntAct=EBI-365996, EBI-359854; CC P63104:YWHAZ; NbExp=13; IntAct=EBI-365996, EBI-347088; CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cell membrane. Mitochondrion. CC Nucleus. Note=Colocalizes with RGS14 and BRAF in both the CC cytoplasm and membranes. Phosphorylation at Ser-259 impairs its CC membrane accumulation. Recruited to the cell membrane by the CC active Ras protein. Phosphorylation at Ser-338 and Ser-339 by PAK1 CC is required for its mitochondrial localization. Retinoic acid- CC induced Ser-621 phosphorylated form of RAF1 is predominantly CC localized at the nucleus. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; Synonyms=6C; CC IsoId=P04049-1; Sequence=Displayed; CC Name=2; Synonyms=1A; CC IsoId=P04049-2; Sequence=VSP_034649; CC -!- TISSUE SPECIFICITY: In skeletal muscle, isoform 1 is more abundant CC than isoform 2. {ECO:0000269|PubMed:1886707}. CC -!- PTM: Phosphorylation at Thr-269, Ser-338, Tyr-341, Thr-491 and CC Ser-494 results in its activation. Phosphorylation at Ser-29, Ser- CC 43, Ser-289, Ser-296, Ser-301 and Ser-642 by MAPK1/ERK2 results in CC its inactivation. Phosphorylation at Ser-259 induces the CC interaction with YWHAZ and inactivates kinase activity. CC Dephosphorylation of Ser-259 by the complex containing protein CC phosphatase 1, SHOC2 and M-Ras/MRAS relieves inactivation, leading CC to stimulate RAF1 activity. Phosphorylation at Ser-338 by PAK1 and CC PAK7/PAK5 and Ser-339 by PAK1 is required for its mitochondrial CC localization. Phosphorylation at Ser-621 in response to growth CC factor treatment stabilizes the protein, possibly by preventing CC proteasomal degradation. Phosphorylation at Ser-289, Ser-296, Ser- CC 301, Ser-338 and Ser-621 are somehow linked to the methylation CC potential of cells. Treatment of cells with HGF in the presence of CC the methylation inhibitor 5'-methylthioadenosine (MTA) results in CC increased phosphorylation at Ser-338 and Ser-621 and decreased CC phosphorylation at Ser-296, Ser-301 and Ser-338. Dephosphorylation CC at Ser-338 by PPP5C results in a activity decrease. CC {ECO:0000269|PubMed:10576742, ECO:0000269|PubMed:10801873, CC ECO:0000269|PubMed:11447113, ECO:0000269|PubMed:11733498, CC ECO:0000269|PubMed:11756411, ECO:0000269|PubMed:15047712, CC ECO:0000269|PubMed:15849194, ECO:0000269|PubMed:16093354, CC ECO:0000269|PubMed:16630891, ECO:0000269|PubMed:16892053, CC ECO:0000269|PubMed:18465753, ECO:0000269|PubMed:21917714, CC ECO:0000269|PubMed:7477354, ECO:0000269|PubMed:8349614, CC ECO:0000269|PubMed:9823899}. CC -!- PTM: Methylated at Arg-563 in response to EGF treatment. This CC modification leads to destabilization of the protein, possibly CC through proteasomal degradation. {ECO:0000269|PubMed:21917714}. CC -!- DISEASE: Noonan syndrome 5 (NS5) [MIM:611553]: A form of Noonan CC syndrome, a disease characterized by short stature, facial CC dysmorphic features such as hypertelorism, a downward eyeslant and CC low-set posteriorly rotated ears, and a high incidence of CC congenital heart defects and hypertrophic cardiomyopathy. Other CC features can include a short neck with webbing or redundancy of CC skin, deafness, motor delay, variable intellectual deficits, CC multiple skeletal defects, cryptorchidism, and bleeding diathesis. CC Individuals with Noonan syndrome are at risk of juvenile CC myelomonocytic leukemia, a myeloproliferative disorder CC characterized by excessive production of myelomonocytic cells. CC {ECO:0000269|PubMed:17603482, ECO:0000269|PubMed:17603483, CC ECO:0000269|PubMed:20683980}. Note=The disease is caused by CC mutations affecting the gene represented in this entry. CC -!- DISEASE: LEOPARD syndrome 2 (LPRD2) [MIM:611554]: A disorder CC characterized by lentigines, electrocardiographic conduction CC abnormalities, ocular hypertelorism, pulmonic stenosis, CC abnormalities of genitalia, retardation of growth, and CC sensorineural deafness. {ECO:0000269|PubMed:17603483}. Note=The CC disease is caused by mutations affecting the gene represented in CC this entry. CC -!- DISEASE: Cardiomyopathy, dilated 1NN (CMD1NN) [MIM:615916]: A CC disorder characterized by ventricular dilation and impaired CC systolic function, resulting in congestive heart failure and CC arrhythmia. Patients are at risk of premature death. CC {ECO:0000269|PubMed:24777450}. Note=The disease is caused by CC mutations affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr CC protein kinase family. RAF subfamily. {ECO:0000305}. CC -!- SIMILARITY: Contains 1 phorbol-ester/DAG-type zinc finger. CC {ECO:0000255|PROSITE-ProRule:PRU00226}. CC -!- SIMILARITY: Contains 1 protein kinase domain. CC {ECO:0000255|PROSITE-ProRule:PRU00159}. CC -!- SIMILARITY: Contains 1 RBD (Ras-binding) domain. CC {ECO:0000255|PROSITE-ProRule:PRU00262}. CC -!- WEB RESOURCE: Name=NIEHS-SNPs; CC URL="http://egp.gs.washington.edu/data/raf1/"; CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology CC and Haematology; CC URL="http://atlasgeneticsoncology.org/Genes/RAF1ID42032ch3p25.html"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; X03484; CAA27204.1; -; mRNA. DR EMBL; AY271661; AAP03432.1; -; Genomic_DNA. DR EMBL; AK312248; BAG35180.1; -; mRNA. DR EMBL; EU332868; ABY87557.1; -; Genomic_DNA. DR EMBL; CH471055; EAW64134.1; -; Genomic_DNA. DR EMBL; BC018119; AAH18119.1; -; mRNA. DR EMBL; L00212; AAA60247.1; -; Genomic_DNA. DR EMBL; L00206; AAA60247.1; JOINED; Genomic_DNA. DR EMBL; L00207; AAA60247.1; JOINED; Genomic_DNA. DR EMBL; L00208; AAA60247.1; JOINED; Genomic_DNA. DR EMBL; L00209; AAA60247.1; JOINED; Genomic_DNA. DR EMBL; L00210; AAA60247.1; JOINED; Genomic_DNA. DR EMBL; L00211; AAA60247.1; JOINED; Genomic_DNA. DR EMBL; L00213; AAA60247.1; JOINED; Genomic_DNA. DR EMBL; M11376; AAA60247.1; JOINED; Genomic_DNA. DR EMBL; X54851; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR CCDS; CCDS2612.1; -. [P04049-1] DR PIR; A00637; TVHUF6. DR PIR; S60341; S60341. DR RefSeq; NP_002871.1; NM_002880.3. [P04049-1] DR RefSeq; XP_005265412.1; XM_005265355.1. [P04049-1] DR RefSeq; XP_011532276.1; XM_011533974.1. [P04049-1] DR UniGene; Hs.159130; -. DR PDB; 1C1Y; X-ray; 1.90 A; B=55-131. DR PDB; 1FAQ; NMR; -; A=136-187. DR PDB; 1FAR; NMR; -; A=136-187. DR PDB; 1GUA; X-ray; 2.00 A; B=51-131. DR PDB; 1RFA; NMR; -; A=55-132. DR PDB; 3CU8; X-ray; 2.40 A; P/Q=256-264. DR PDB; 3IQJ; X-ray; 1.15 A; P=255-264. DR PDB; 3IQU; X-ray; 1.05 A; P=255-260. DR PDB; 3IQV; X-ray; 1.20 A; P=255-260. DR PDB; 3KUC; X-ray; 1.92 A; B=51-131. DR PDB; 3KUD; X-ray; 2.15 A; B=51-131. DR PDB; 3NKX; X-ray; 2.40 A; P/Q=255-264. DR PDB; 3O8I; X-ray; 2.00 A; B=255-264. DR PDB; 3OMV; X-ray; 4.00 A; A/B=323-618. DR PDB; 4FJ3; X-ray; 1.95 A; P=229-264. DR PDB; 4G0N; X-ray; 2.45 A; B=54-131. DR PDB; 4G3X; X-ray; 3.25 A; B=55-131. DR PDB; 4IEA; X-ray; 1.70 A; P=618-625. DR PDB; 4IHL; X-ray; 2.20 A; P=229-264. DR PDBsum; 1C1Y; -. DR PDBsum; 1FAQ; -. DR PDBsum; 1FAR; -. DR PDBsum; 1GUA; -. DR PDBsum; 1RFA; -. DR PDBsum; 3CU8; -. DR PDBsum; 3IQJ; -. DR PDBsum; 3IQU; -. DR PDBsum; 3IQV; -. DR PDBsum; 3KUC; -. DR PDBsum; 3KUD; -. DR PDBsum; 3NKX; -. DR PDBsum; 3O8I; -. DR PDBsum; 3OMV; -. DR PDBsum; 4FJ3; -. DR PDBsum; 4G0N; -. DR PDBsum; 4G3X; -. DR PDBsum; 4IEA; -. DR PDBsum; 4IHL; -. DR DisProt; DP00171; -. DR ProteinModelPortal; P04049; -. DR SMR; P04049; 55-131, 136-187, 325-615. DR BioGrid; 111831; 140. DR DIP; DIP-1048N; -. DR IntAct; P04049; 95. DR MINT; MINT-86694; -. DR STRING; 9606.ENSP00000251849; -. DR BindingDB; P04049; -. DR ChEMBL; CHEMBL1906; -. DR DrugBank; DB08912; Dabrafenib. DR DrugBank; DB08896; Regorafenib. DR DrugBank; DB00398; Sorafenib. DR GuidetoPHARMACOLOGY; 2184; -. DR PhosphoSite; P04049; -. DR BioMuta; RAF1; -. DR DMDM; 125651; -. DR MaxQB; P04049; -. DR PaxDb; P04049; -. DR PRIDE; P04049; -. DR DNASU; 5894; -. DR Ensembl; ENST00000251849; ENSP00000251849; ENSG00000132155. [P04049-1] DR Ensembl; ENST00000442415; ENSP00000401888; ENSG00000132155. [P04049-2] DR GeneID; 5894; -. DR KEGG; hsa:5894; -. DR UCSC; uc003bxf.4; human. [P04049-1] DR CTD; 5894; -. DR GeneCards; RAF1; -. DR GeneReviews; RAF1; -. DR HGNC; HGNC:9829; RAF1. DR HPA; CAB019291; -. DR HPA; HPA002640; -. DR MIM; 164760; gene. DR MIM; 611553; phenotype. DR MIM; 611554; phenotype. DR MIM; 615916; phenotype. DR neXtProt; NX_P04049; -. DR Orphanet; 154; Familial isolated dilated cardiomyopathy. DR Orphanet; 500; LEOPARD syndrome. DR Orphanet; 648; Noonan syndrome. DR Orphanet; 251612; Pilocytic astrocytoma. DR PharmGKB; PA34183; -. DR eggNOG; KOG0193; Eukaryota. DR eggNOG; ENOG410Y4UP; LUCA. DR GeneTree; ENSGT00760000118807; -. DR HOGENOM; HOG000252972; -. DR HOVERGEN; HBG001886; -. DR InParanoid; P04049; -. DR KO; K04366; -. DR OMA; DGPSCIS; -. DR OrthoDB; EOG7F5128; -. DR PhylomeDB; P04049; -. DR TreeFam; TF317006; -. DR BRENDA; 2.7.10.2; 2681. DR Reactome; R-HSA-2672351; Stimuli-sensing channels. DR Reactome; R-HSA-392517; Rap1 signalling. DR Reactome; R-HSA-430116; GP1b-IX-V activation signalling. DR Reactome; R-HSA-442742; CREB phosphorylation through the activation of Ras. DR Reactome; R-HSA-5621575; CD209 (DC-SIGN) signaling. DR Reactome; R-HSA-5673000; RAF activation. DR Reactome; R-HSA-5674135; MAP2K and MAPK activation. DR Reactome; R-HSA-5674499; Negative feedback regulation of MAPK pathway. DR Reactome; R-HSA-5675221; Negative regulation of MAPK pathway. DR SignaLink; P04049; -. DR ChiTaRS; RAF1; human. DR EvolutionaryTrace; P04049; -. DR GeneWiki; C-Raf; -. DR GenomeRNAi; 5894; -. DR NextBio; 22930; -. DR PMAP-CutDB; P04049; -. DR PRO; PR:P04049; -. DR Proteomes; UP000005640; Chromosome 3. DR Bgee; P04049; -. DR CleanEx; HS_RAF1; -. DR ExpressionAtlas; P04049; baseline and differential. DR Genevisible; P04049; HS. DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0005794; C:Golgi apparatus; IPI:MGI. DR GO; GO:0005741; C:mitochondrial outer membrane; TAS:ProtInc. DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell. DR GO; GO:0005886; C:plasma membrane; IDA:MGI. DR GO; GO:0031143; C:pseudopodium; IEA:Ensembl. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0004709; F:MAP kinase kinase kinase activity; IEA:Ensembl. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0004672; F:protein kinase activity; TAS:ProtInc. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB. DR GO; GO:0007190; P:activation of adenylate cyclase activity; NAS:BHF-UCL. DR GO; GO:0000186; P:activation of MAPKK activity; IDA:AgBase. DR GO; GO:0006915; P:apoptotic process; TAS:ProtInc. DR GO; GO:0007411; P:axon guidance; TAS:Reactome. DR GO; GO:0007596; P:blood coagulation; TAS:Reactome. DR GO; GO:0008283; P:cell proliferation; TAS:ProtInc. DR GO; GO:0071550; P:death-inducing signaling complex assembly; IEA:Ensembl. DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome. DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome. DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome. DR GO; GO:0007507; P:heart development; IEA:Ensembl. DR GO; GO:0045087; P:innate immune response; TAS:Reactome. DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome. DR GO; GO:0035773; P:insulin secretion involved in cellular response to glucose stimulus; IEA:Ensembl. DR GO; GO:0045104; P:intermediate filament cytoskeleton organization; IEA:Ensembl. DR GO; GO:0034220; P:ion transmembrane transport; TAS:Reactome. DR GO; GO:0000165; P:MAPK cascade; TAS:Reactome. DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB. DR GO; GO:0008285; P:negative regulation of cell proliferation; IDA:BHF-UCL. DR GO; GO:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; TAS:UniProtKB. DR GO; GO:1902042; P:negative regulation of extrinsic apoptotic signaling pathway via death domain receptors; IEA:Ensembl. DR GO; GO:0031333; P:negative regulation of protein complex assembly; IDA:UniProtKB. DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome. DR GO; GO:0030168; P:platelet activation; TAS:Reactome. DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; IDA:UniProtKB. DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IEA:Ensembl. DR GO; GO:0006468; P:protein phosphorylation; TAS:ProtInc. DR GO; GO:0007265; P:Ras protein signal transduction; TAS:Reactome. DR GO; GO:0042981; P:regulation of apoptotic process; TAS:UniProtKB. DR GO; GO:0045595; P:regulation of cell differentiation; TAS:UniProtKB. DR GO; GO:2000145; P:regulation of cell motility; TAS:UniProtKB. DR GO; GO:0035023; P:regulation of Rho protein signal transduction; TAS:UniProtKB. DR GO; GO:0001666; P:response to hypoxia; IEA:Ensembl. DR GO; GO:0035994; P:response to muscle stretch; IEA:Ensembl. DR GO; GO:0007165; P:signal transduction; TAS:ProtInc. DR GO; GO:0007264; P:small GTPase mediated signal transduction; TAS:Reactome. DR GO; GO:0035019; P:somatic stem cell population maintenance; IEA:Ensembl. DR GO; GO:0002223; P:stimulatory C-type lectin receptor signaling pathway; TAS:Reactome. DR GO; GO:0007268; P:synaptic transmission; TAS:Reactome. DR GO; GO:0055085; P:transmembrane transport; TAS:Reactome. DR GO; GO:0048010; P:vascular endothelial growth factor receptor signaling pathway; TAS:Reactome. DR GO; GO:0042060; P:wound healing; TAS:UniProtKB. DR InterPro; IPR020454; DAG/PE-bd. DR InterPro; IPR011009; Kinase-like_dom. DR InterPro; IPR002219; PE/DAG-bd. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR003116; Raf-like_ras-bd. DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR InterPro; IPR029071; Ubiquitin-rel_dom. DR Pfam; PF00130; C1_1; 1. DR Pfam; PF07714; Pkinase_Tyr; 1. DR Pfam; PF02196; RBD; 1. DR PRINTS; PR00008; DAGPEDOMAIN. DR SMART; SM00109; C1; 1. DR SMART; SM00455; RBD; 1. DR SUPFAM; SSF54236; SSF54236; 1. DR SUPFAM; SSF56112; SSF56112; 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. DR PROSITE; PS50898; RBD; 1. DR PROSITE; PS00479; ZF_DAG_PE_1; 1. DR PROSITE; PS50081; ZF_DAG_PE_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; ATP-binding; Cardiomyopathy; KW Cell membrane; Complete proteome; Cytoplasm; Deafness; KW Direct protein sequencing; Disease mutation; Kinase; Membrane; KW Metal-binding; Methylation; Mitochondrion; Nucleotide-binding; KW Nucleus; Phosphoprotein; Polymorphism; Proto-oncogene; KW Reference proteome; Serine/threonine-protein kinase; Transferase; KW Zinc; Zinc-finger. FT CHAIN 1 648 RAF proto-oncogene serine/threonine- FT protein kinase. FT /FTId=PRO_0000086596. FT DOMAIN 56 131 RBD. {ECO:0000255|PROSITE- FT ProRule:PRU00262}. FT DOMAIN 349 609 Protein kinase. {ECO:0000255|PROSITE- FT ProRule:PRU00159}. FT ZN_FING 138 184 Phorbol-ester/DAG-type. FT {ECO:0000255|PROSITE-ProRule:PRU00226}. FT NP_BIND 355 363 ATP. {ECO:0000255|PROSITE- FT ProRule:PRU00159}. FT REGION 331 349 Interaction with PEBP1/RKIP. FT ACT_SITE 468 468 Proton acceptor. FT METAL 139 139 Zinc 1. FT METAL 152 152 Zinc 2. FT METAL 155 155 Zinc 2. FT METAL 165 165 Zinc 1. FT METAL 168 168 Zinc 1. FT METAL 173 173 Zinc 2. FT METAL 176 176 Zinc 2. FT METAL 184 184 Zinc 1. FT BINDING 375 375 ATP. {ECO:0000255|PROSITE- FT ProRule:PRU00159}. FT MOD_RES 29 29 Phosphoserine; by MAPK1. {ECO:0000250}. FT MOD_RES 43 43 Phosphoserine; by PKA and MAPK1. FT {ECO:0000269|PubMed:8349614}. FT MOD_RES 233 233 Phosphoserine; by PKA. FT {ECO:0000269|PubMed:9823899}. FT MOD_RES 252 252 Phosphoserine. FT {ECO:0000244|PubMed:17525332}. FT MOD_RES 259 259 Phosphoserine; by PKA, PKC and PKB/AKT1. FT {ECO:0000269|PubMed:10576742, FT ECO:0000269|PubMed:10801873, FT ECO:0000269|PubMed:11756411, FT ECO:0000269|PubMed:15047712, FT ECO:0000269|PubMed:16630891, FT ECO:0000269|PubMed:16892053, FT ECO:0000269|PubMed:8349614}. FT MOD_RES 268 268 Phosphothreonine; by autocatalysis. FT {ECO:0000269|PubMed:8349614}. FT MOD_RES 269 269 Phosphothreonine; by PKA. FT {ECO:0000269|PubMed:7477354}. FT MOD_RES 289 289 Phosphoserine; by MAPK1. FT {ECO:0000244|PubMed:19690332, FT ECO:0000269|PubMed:21917714}. FT MOD_RES 296 296 Phosphoserine; by MAPK1. {ECO:0000250}. FT MOD_RES 301 301 Phosphoserine; by MAPK1. FT {ECO:0000244|PubMed:19690332, FT ECO:0000269|PubMed:21917714}. FT MOD_RES 338 338 Phosphoserine; by PAK1, PAK2, PAK3 and FT PAK7/PAK5. {ECO:0000269|PubMed:11733498, FT ECO:0000269|PubMed:15849194, FT ECO:0000269|PubMed:16892053, FT ECO:0000269|PubMed:18465753, FT ECO:0000269|PubMed:21917714}. FT MOD_RES 339 339 Phosphoserine; by PAK1, PAK2 and PAK3. FT {ECO:0000269|PubMed:15849194}. FT MOD_RES 340 340 Phosphotyrosine; by SRC. FT {ECO:0000269|PubMed:16892053}. FT MOD_RES 341 341 Phosphotyrosine; by SRC. FT {ECO:0000269|PubMed:16892053}. FT MOD_RES 471 471 Phosphoserine. FT {ECO:0000269|PubMed:16093354}. FT MOD_RES 491 491 Phosphothreonine. FT {ECO:0000269|PubMed:11447113}. FT MOD_RES 494 494 Phosphoserine. FT {ECO:0000269|PubMed:11447113}. FT MOD_RES 497 497 Phosphoserine; by PKC. FT {ECO:0000269|PubMed:9823899}. FT MOD_RES 499 499 Phosphoserine; by PKC. FT {ECO:0000269|PubMed:8349614}. FT MOD_RES 563 563 Symmetric dimethylarginine; by PRMT5. FT {ECO:0000269|PubMed:21917714}. FT MOD_RES 621 621 Phosphoserine. FT {ECO:0000269|PubMed:10801873, FT ECO:0000269|PubMed:16892053, FT ECO:0000269|PubMed:21917714, FT ECO:0000269|PubMed:8349614}. FT MOD_RES 642 642 Phosphoserine; by MAPK1. FT {ECO:0000244|PubMed:18669648}. FT VAR_SEQ 278 278 E -> ENNNLSASPRAWSRRFCLRGR (in isoform FT 2). {ECO:0000305}. FT /FTId=VSP_034649. FT VARIANT 237 237 A -> T (in CMD1NN; shows a mild increase FT in kinase activity). FT {ECO:0000269|PubMed:24777450}. FT /FTId=VAR_071844. FT VARIANT 256 256 R -> S (in NS5). FT {ECO:0000269|PubMed:17603483}. FT /FTId=VAR_037807. FT VARIANT 257 257 S -> L (in NS5 and LPRD2; shows in vitro FT greater kinase activity and enhanced ERK FT activation than wild-type). FT {ECO:0000269|PubMed:17603482, FT ECO:0000269|PubMed:17603483}. FT /FTId=VAR_037808. FT VARIANT 259 259 S -> A (in an ovarian serous carcinoma FT sample; somatic mutation; increased ERK FT activation). FT {ECO:0000269|PubMed:16630891, FT ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041037. FT VARIANT 259 259 S -> F (in NS5). FT {ECO:0000269|PubMed:17603483}. FT /FTId=VAR_037809. FT VARIANT 260 260 T -> I (in hypertrophic cardiomyopathy). FT {ECO:0000269|PubMed:17603483}. FT /FTId=VAR_037810. FT VARIANT 260 260 T -> R (in NS5). FT {ECO:0000269|PubMed:17603483}. FT /FTId=VAR_037811. FT VARIANT 261 261 P -> A (in NS5; shows in vitro greater FT kinase activity and enhanced MAPK1 FT activation than wild-type). FT {ECO:0000269|PubMed:17603482}. FT /FTId=VAR_037812. FT VARIANT 261 261 P -> L (in NS5; shows greater kinase FT activity and enhanced MAPK1 activation FT than wild-type). FT {ECO:0000269|PubMed:17603483}. FT /FTId=VAR_037813. FT VARIANT 261 261 P -> S (in NS5; shows in vitro greater FT kinase activity and enhanced MAPK1 FT activation than wild-type). FT {ECO:0000269|PubMed:17603482, FT ECO:0000269|PubMed:17603483, FT ECO:0000269|PubMed:20683980}. FT /FTId=VAR_037814. FT VARIANT 263 263 V -> A (in NS5; shows in vitro greater FT kinase activity and enhanced MAPK1 FT activation than wild-type). FT {ECO:0000269|PubMed:17603482}. FT /FTId=VAR_037815. FT VARIANT 308 308 P -> L (in dbSNP:rs5746220). FT {ECO:0000269|PubMed:14702039, FT ECO:0000269|Ref.3}. FT /FTId=VAR_018840. FT VARIANT 310 310 T -> A (in CMD1NN; shows a mild increase FT in kinase activity). FT {ECO:0000269|PubMed:24777450}. FT /FTId=VAR_071845. FT VARIANT 332 332 P -> A (in CMD1NN; shows a mild increase FT in kinase activity). FT {ECO:0000269|PubMed:24777450}. FT /FTId=VAR_071846. FT VARIANT 335 335 Q -> H (in a lung adenocarcinoma sample; FT somatic mutation). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041038. FT VARIANT 486 486 D -> G (in NS5). FT {ECO:0000269|PubMed:17603483}. FT /FTId=VAR_037816. FT VARIANT 486 486 D -> N (in NS5; has reduced or absent FT kinase activity). FT {ECO:0000269|PubMed:17603483}. FT /FTId=VAR_037817. FT VARIANT 491 491 T -> I (in NS5; has reduced or absent FT kinase activity). FT {ECO:0000269|PubMed:17603483}. FT /FTId=VAR_037818. FT VARIANT 491 491 T -> R (in NS5). FT {ECO:0000269|PubMed:17603483}. FT /FTId=VAR_037819. FT VARIANT 603 603 L -> P (in CMD1NN; shows impaired kinase FT activity and reduced MAPK3 activation FT with this mutation). FT {ECO:0000269|PubMed:24777450}. FT /FTId=VAR_071847. FT VARIANT 612 612 S -> T (in NS5). FT {ECO:0000269|PubMed:17603483}. FT /FTId=VAR_037820. FT VARIANT 613 613 L -> V (in NS5 and LPRD2; shows in vitro FT greater kinase activity and enhanced FT MAPK1 activation than wild-type). FT {ECO:0000269|PubMed:17603482, FT ECO:0000269|PubMed:17603483}. FT /FTId=VAR_037821. FT VARIANT 626 626 H -> R (in CMD1NN; shows a mild increase FT in kinase activity). FT {ECO:0000269|PubMed:24777450}. FT /FTId=VAR_071848. FT VARIANT 641 641 T -> M (in CMD1NN; shows a mild increase FT in kinase activity). FT {ECO:0000269|PubMed:24777450}. FT /FTId=VAR_071849. FT MUTAGEN 338 339 SS->AA: Reduced kinase activity; when FT associated with 340-D-D-341. FT {ECO:0000269|PubMed:16892053}. FT MUTAGEN 338 339 SS->DE: Non-inhibited by PPP5C. FT Constituvely active and non-inhibited by FT PPP5C; when associated with 340-D-D-341. FT {ECO:0000269|PubMed:16892053}. FT MUTAGEN 340 341 YY->DD: Constituvely active and highly FT phosphorylated on S-338, inhibited by FT PPP5C. Reduced kinase activity; when FT associated with 338-A-A-339. Constituvely FT active and non-inhibited by PPP5C; when FT associated with 338-D-E-33. FT {ECO:0000269|PubMed:16892053}. FT MUTAGEN 491 491 T->D: Increased kinase activity but can FT still be inhibited by PPP5C; when FT associated with D-494. FT {ECO:0000269|PubMed:16892053}. FT MUTAGEN 494 494 S->D: Increased kinase activity but can FT still be inhibited by PPP5C; when FT associated with D-491. FT {ECO:0000269|PubMed:16892053}. FT MUTAGEN 563 563 R->K: Loss of methylation. Increased FT stability and catalytic activity in FT response to EGF treatment. FT {ECO:0000269|PubMed:21917714}. FT CONFLICT 240 240 F -> L (in Ref. 6; AAA60247). FT {ECO:0000305}. FT CONFLICT 542 542 M -> I (in Ref. 6; AAA60247). FT {ECO:0000305}. FT STRAND 57 62 {ECO:0000244|PDB:1C1Y}. FT TURN 63 65 {ECO:0000244|PDB:1C1Y}. FT STRAND 66 71 {ECO:0000244|PDB:1C1Y}. FT HELIX 78 87 {ECO:0000244|PDB:1C1Y}. FT TURN 88 90 {ECO:0000244|PDB:1C1Y}. FT HELIX 93 95 {ECO:0000244|PDB:1C1Y}. FT STRAND 96 102 {ECO:0000244|PDB:1C1Y}. FT HELIX 103 105 {ECO:0000244|PDB:1C1Y}. FT STRAND 106 112 {ECO:0000244|PDB:1C1Y}. FT HELIX 118 121 {ECO:0000244|PDB:1C1Y}. FT STRAND 125 130 {ECO:0000244|PDB:1C1Y}. FT STRAND 142 144 {ECO:0000244|PDB:1FAQ}. FT STRAND 155 159 {ECO:0000244|PDB:1FAQ}. FT STRAND 161 164 {ECO:0000244|PDB:1FAQ}. FT TURN 166 169 {ECO:0000244|PDB:1FAQ}. FT HELIX 174 176 {ECO:0000244|PDB:1FAR}. FT STRAND 177 182 {ECO:0000244|PDB:1FAQ}. SQ SEQUENCE 648 AA; 73052 MW; EF821B5349711BC3 CRC64; MEHIQGAWKT ISNGFGFKDA VFDGSSCISP TIVQQFGYQR RASDDGKLTD PSKTSNTIRV FLPNKQRTVV NVRNGMSLHD CLMKALKVRG LQPECCAVFR LLHEHKGKKA RLDWNTDAAS LIGEELQVDF LDHVPLTTHN FARKTFLKLA FCDICQKFLL NGFRCQTCGY KFHEHCSTKV PTMCVDWSNI RQLLLFPNST IGDSGVPALP SLTMRRMRES VSRMPVSSQH RYSTPHAFTF NTSSPSSEGS LSQRQRSTST PNVHMVSTTL PVDSRMIEDA IRSHSESASP SALSSSPNNL SPTGWSQPKT PVPAQRERAP VSGTQEKNKI RPRGQRDSSY YWEIEASEVM LSTRIGSGSF GTVYKGKWHG DVAVKILKVV DPTPEQFQAF RNEVAVLRKT RHVNILLFMG YMTKDNLAIV TQWCEGSSLY KHLHVQETKF QMFQLIDIAR QTAQGMDYLH AKNIIHRDMK SNNIFLHEGL TVKIGDFGLA TVKSRWSGSQ QVEQPTGSVL WMAPEVIRMQ DNNPFSFQSD VYSYGIVLYE LMTGELPYSH INNRDQIIFM VGRGYASPDL SKLYKNCPKA MKRLVADCVK KVKEERPLFP QILSSIELLQ HSLPKINRSA SEPSLHRAAH TEDINACTLT TSPRLPVF //