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 27-MAR-2024, entry version 261. DE RecName: Full=RAF proto-oncogene serine/threonine-protein kinase {ECO:0000305}; DE EC=2.7.11.1 {ECO:0000269|PubMed:17603483}; DE AltName: Full=Proto-oncogene c-RAF; DE Short=cRaf; DE AltName: Full=Raf-1; GN Name=RAF1 {ECO:0000312|HGNC:HGNC:9829}; Synonyms=RAF; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC 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 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., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., 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., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA 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., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., 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 project: RT 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; DOI=10.1128/mcb.5.6.1400-1407.1985; 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 WITH RP PRMT5, METHYLATION AT ARG-563, PHOSPHORYLATION AT SER-289; SER-296; RP 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., Lopez-Fauqued M., RA Bech-Serra J.J., Tenbaum S., Garcia-Trevijano E.R., Canals F., Merlino G., RA Avila M.A., Recio J.A.; RT "Protein arginine methyltransferase 5 regulates ERK1/2 signal transduction RT 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 TISSUE RP 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; DOI=10.1016/s0021-9258(19)85336-x; RA Morrison D.K., Heidecker G., Rapp U.R., Copeland T.D.; RT "Identification of the major phosphorylation sites of the Raf-1 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., Morrice N., RA 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 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 OF PUBMED:9823899. 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, ACTIVITY 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, ACTIVITY REGULATION, AND INTERACTION WITH PPP2CA AND RP 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 kinase RT activation."; RL J. Biol. Chem. 275:22300-22304(2000). RN [16] RP ACTIVITY 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 by RT 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-regulating RT 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 PPP1R12A. RX PubMed=11719507; DOI=10.1074/jbc.m106343200; RA Broustas C.G., Grammatikakis N., Eto M., Dent P., Brautigan D.L., Kasid U.; RT "Phosphorylation of the myosin-binding subunit of myosin phosphatase by RT Raf-1 and inhibition of phosphatase activity."; RL J. Biol. Chem. 277:3053-3059(2002). RN [19] RP PHOSPHORYLATION AT SER-338 BY PAK1, ACTIVITY 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 phosphorylation RT 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 SUBCELLULAR RP 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.22.3.916-926.2001; 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 14-3- RT 3 proteins."; RL Mol. Cell. Biol. 22:916-926(2002). RN [22] RP ACTIVITY 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 binding to RT 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 cells RT through the ERK1/2 pathway."; RL J. Biol. Chem. 279:23151-23157(2004). RN [24] RP ERRATUM OF PUBMED:15047712. 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 WITH RP ADCY2; ADCY5 AND ADCY6. RX PubMed=15385642; DOI=10.1124/mol.66.4.921; 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-oncogene RT 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 SER-339 RP 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 regulates RT its mitochondrial localization, phosphorylation of BAD, and Bcl-2 RT 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 for RT 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 MRAS, RP PHOSPHORYLATION AT SER-259, AND CHARACTERIZATION OF VARIANT 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 subunit RT of PP1 functions as an M-Ras effector to modulate Raf 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, ACTIVITY 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 AND RP 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; DOI=10.4161/cc.6.1.3593; 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 BY RP 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, Hurov K.E., RA Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y., RA 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 ACTIVITY 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 the RT phosphorylated N-region of Raf-1 and inhibits the Raf-1-mediated activated RT 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 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., Yates J.R. III; RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient RT 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 the RT kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [41] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-642, AND IDENTIFICATION BY RP 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., Yen A.; RT "Retinoic acid induces nuclear accumulation of Raf1 during differentiation RT of HL-60 cells."; RL Exp. Cell Res. 315:2241-2248(2009). RN [43] RP ACTIVITY 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., Kanoh H., RA 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., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT 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., Buerckstuemmer T., RA 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 MUTAGENESIS OF LYS-375, AND INTERACTION WITH NEK10 AND MAP2K1. RX PubMed=20956560; DOI=10.1128/mcb.00648-10; RA Moniz L.S., Stambolic V.; RT "Nek10 mediates G2/M cell cycle arrest and MEK autoactivation in response RT to UV irradiation."; RL Mol. Cell. Biol. 31:30-42(2011). RN [50] 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., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [51] 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 [52] RP INTERACTION WITH GLS. RX PubMed=22538822; DOI=10.1073/pnas.1116573109; RA Thangavelu K., Pan C.Q., Karlberg T., Balaji G., Uttamchandani M., RA Suresh V., Schuler H., Low B.C., Sivaraman J.; RT "Structural basis for the allosteric inhibitory mechanism of human kidney- RT type glutaminase (KGA) and its regulation by Raf-Mek-Erk signaling in RT cancer cell metabolism."; RL Proc. Natl. Acad. Sci. U.S.A. 109:7705-7710(2012). RN [53] RP INTERACTION WITH MFHAS1. RX PubMed=23327923; DOI=10.1182/blood-2011-10-385252; RA Kumkhaek C., Aerbajinai W., Liu W., Zhu J., Uchida N., Kurlander R., RA Hsieh M.M., Tisdale J.F., Rodgers G.P.; RT "MASL1 induces erythroid differentiation in human erythropoietin-dependent RT CD34+ cells through the Raf/MEK/ERK pathway."; RL Blood 121:3216-3227(2013). RN [54] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-296; SER-301 AND SER-642, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [55] RP INTERACTION WITH PDE8A. RX PubMed=23509299; DOI=10.1073/pnas.1303004110; RA Brown K.M., Day J.P., Huston E., Zimmermann B., Hampel K., Christian F., RA Romano D., Terhzaz S., Lee L.C., Willis M.J., Morton D.B., Beavo J.A., RA Shimizu-Albergine M., Davies S.A., Kolch W., Houslay M.D., Baillie G.S.; RT "Phosphodiesterase-8A binds to and regulates Raf-1 kinase."; RL Proc. Natl. Acad. Sci. U.S.A. 110:E1533-E1542(2013). RN [56] 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., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [57] RP IDENTIFICATION IN A COMPLEX WITH HSP90; HSP70; CDC37; PPP5C; TSC1; TSC2; RP AKT; CDK4 AND NR3C1. RX PubMed=29127155; DOI=10.15252/embj.201796700; RA Woodford M.R., Sager R.A., Marris E., Dunn D.M., Blanden A.R., Murphy R.L., RA Rensing N., Shapiro O., Panaretou B., Prodromou C., Loh S.N., Gutmann D.H., RA Bourboulia D., Bratslavsky G., Wong M., Mollapour M.; RT "Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates folding RT of kinase and non-kinase clients."; RL EMBO J. 36:3650-3665(2017). RN [58] RP INTERACTION WITH LZTR1. RX PubMed=30368668; DOI=10.1007/s00439-018-1951-7; RA Umeki I., Niihori T., Abe T., Kanno S.I., Okamoto N., Mizuno S., RA Kurosawa K., Nagasaki K., Yoshida M., Ohashi H., Inoue S.I., Matsubara Y., RA Fujiwara I., Kure S., Aoki Y.; RT "Delineation of LZTR1 mutation-positive patients with Noonan syndrome and RT identification of LZTR1 binding to RAF1-PPP1CB complexes."; RL Hum. Genet. 138:21-35(2019). RN [59] RP INTERACTION WITH YWHAZ. RX PubMed=31024343; DOI=10.3389/fphys.2019.00388; RA Popov I.K., Hiatt S.M., Whalen S., Keren B., Ruivenkamp C., RA van Haeringen A., Chen M.J., Cooper G.M., Korf B.R., Chang C.; RT "A YWHAZ variant associated with cardiofaciocutaneous syndrome activates RT the RAF-ERK pathway."; RL Front. Physiol. 10:388-388(2019). RN [60] 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., 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 analogue."; RL Nature 375:554-560(1995). RN [61] 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., Wittinghofer A.; RT "Ras/Rap effector specificity determined by charge reversal."; RL Nat. Struct. Biol. 3:723-729(1996). RN [62] 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 identification RT of its Ras interaction surface."; RL Biochemistry 34:6911-6918(1995). RN [63] 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., Campbell S.L.; RT "The solution structure of the Raf-1 cysteine-rich domain: a novel ras and RT phospholipid binding site."; RL Proc. Natl. Acad. Sci. U.S.A. 93:8312-8317(1996). RN [64] RP VARIANTS NS5 SER-256; PHE-259; ARG-260; LEU-261; SER-261; ASN-486; GLY-486; RP ILE-491; ARG-491 AND THR-612, VARIANT HYPERTROPHIC CARDIOMYOPATHY ILE-260, RP VARIANTS LPRD2 LEU-257 AND VAL-613, VARIANT NS5 LEU-257, CHARACTERIZATION RP OF VARIANTS NS5 SER-261; ASN-486 AND ILE-491, CHARACTERIZATION OF VARIANT RP LPRD2 VAL-613, AND CATALYTIC ACTIVITY. RX PubMed=17603483; DOI=10.1038/ng2073; RA Pandit B., Sarkozy A., Pennacchio L.A., Carta C., Oishi K., Martinelli S., RA Pogna E.A., Schackwitz W., Ustaszewska A., Landstrom A., Bos J.M., RA Ommen S.R., Esposito G., Lepri F., Faul C., Mundel P., Lopez Siguero J.P., RA Tenconi R., Selicorni A., Rossi C., Mazzanti L., Torrente I., Marino B., RA Digilio M.C., Zampino G., Ackerman M.J., Dallapiccola B., Tartaglia M., RA Gelb B.D.; RT "Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with RT hypertrophic cardiomyopathy."; RL Nat. Genet. 39:1007-1012(2007). RN [65] 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 AND RP 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 [66] 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., Bignell G., RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G., RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., RA Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). RN [67] 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 SOS1 RT and a de novo RAF1 mutations."; RL Am. J. Med. Genet. A 152:2176-2184(2010). RN [68] RP INVOLVEMENT IN CMD1NN, VARIANTS CMD1NN THR-237; ALA-310; ALA-332; PRO-603; RP ARG-626 AND MET-641, AND CHARACTERIZATION OF VARIANTS CMD1NN THR-237; RP 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., Edwards J.J., RA Mulero-Navarro S., Riess I., Pardo S., Sheng J., Rani D.S., Rani B., RA Govindaraj P., Flex E., Yokota T., Furutani M., Nishizawa T., Nakanishi T., RA Robbins J., Limongelli G., Hajjar R.J., Lebeche D., Bahl A., Khullar M., RA Rathinavel A., Sadler K.C., Tartaglia M., Matsuoka R., Thangaraj K., RA 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 regulatory CC link between the membrane-associated Ras GTPases and the MAPK/ERK CC cascade, and this critical regulatory link functions as a switch CC determining cell fate decisions including proliferation, CC differentiation, apoptosis, survival and oncogenic transformation. RAF1 CC activation initiates a mitogen-activated protein kinase (MAPK) cascade CC that comprises a sequential phosphorylation of the dual-specific MAPK CC kinases (MAP2K1/MEK1 and MAP2K2/MEK2) and the extracellular signal- CC regulated kinases (MAPK3/ERK1 and MAPK1/ERK2). The phosphorylated form CC of RAF1 (on residues Ser-338 and Ser-339, by PAK1) phosphorylates CC BAD/Bcl2-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 promote CC NF-kB activation and inhibit signal transducers involved in motility CC (ROCK2), apoptosis (MAP3K5/ASK1 and STK3/MST2), proliferation and CC angiogenesis (RB1). Can protect cells from apoptosis also by CC translocating to the mitochondria where it binds BCL2 and displaces CC BAD/Bcl2-antagonist of cell death. Regulates Rho signaling and CC migration, and is required for normal wound healing. Plays a role in CC the oncogenic transformation of epithelial cells via repression of the CC TJ protein, occludin (OCLN) by inducing the up-regulation of a CC transcriptional repressor SNAI2/SLUG, which induces down-regulation of CC OCLN. Restricts caspase activation in response to selected stimuli, CC notably Fas stimulation, pathogen-mediated macrophage apoptosis, and CC erythroid 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: CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; CC Evidence={ECO:0000269|PubMed:17603483}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17990; CC Evidence={ECO:0000269|PubMed:17603483}; CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; CC EC=2.7.11.1; Evidence={ECO:0000269|PubMed:17603483}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46609; CC Evidence={ECO:0000269|PubMed:17603483}; CC -!- COFACTOR: CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; CC Note=Binds 2 Zn(2+) ions per subunit.; CC -!- ACTIVITY REGULATION: Regulation is a highly complex process involving CC membrane recruitment, protein-protein interactions, dimerization, and CC phosphorylation/dephosphorylation events. Ras-GTP recruits RAF1 to the CC membrane, thereby promoting its activation. The inactive conformation CC of RAF1 is maintained by autoinhibitory interactions occurring between CC the N-terminal regulatory and the C-terminal catalytic domains and by CC the binding of a 14-3-3 protein that contacts two phosphorylation CC sites, Ser-259 and Ser-621. Upon mitogenic stimulation, Ras and PPP2R1A CC cooperate to release autoinhibition and the subsequent phosphorylation CC of activating sites: Ser-338, Tyr-341, Thr-491, and Ser-494, yields a CC fully active kinase. Through a negative feedback mechanism involving CC MAPK1/ERK2, RAF1 is phosphorylated on Ser-29, Ser-43, Ser-289, Ser-296, CC Ser-301 and Ser-642 by MAPK1/ERK2, which yields an inactive, CC desensitized kinase. The signaling-competent conformation of RAF1 is CC finally re-established by the coordinated action of PIN1, a prolyl CC isomerase that converts pSer and pThr residues from the cis to the CC trans conformation, which is preferentially recognized and CC dephosphorylated by PPP2R1A. Activated by homodimerization and CC heterodimerization (with BRAF). Also regulated through association with CC other proteins such as KSR2, CNKSR1/CNK1, PEBP1/RKIP, PHB/prohibitin CC and SPRY4. PEBP1/RKIP acts by dissociating RAF1 from its substrates CC MAP2K1/MEK1 and MAP2K2/MEK2. PHB/prohibitin facilitates the CC displacement of 14-3-3 from RAF1 by activated Ras, thereby promoting CC cell membrane localization and phosphorylation of RAF1 at the CC activating Ser-338. SPRY4 inhibits Ras-independent, but not Ras- CC dependent, activation of RAF1. CNKSR1/CNK1 regulates Src-mediated RAF1 CC activation. {ECO:0000269|PubMed:10576742, ECO:0000269|PubMed:10801873, CC ECO:0000269|PubMed:11447113, ECO:0000269|PubMed:11733498, CC ECO:0000269|PubMed:12717443, ECO:0000269|PubMed:16892053, CC ECO:0000269|PubMed:18294816, ECO:0000269|PubMed:19710016}. CC -!- SUBUNIT: Monomer. Homodimer. Heterodimerizes with BRAF and this CC heterodimer possesses a highly increased kinase activity compared to CC the respective homodimers or monomers (PubMed:16508002). CC Heterodimerization is mitogen-regulated and enhanced by 14-3-3 proteins CC (PubMed:16508002). MAPK1/ERK2 activation can induce a negative feedback CC that promotes the dissociation of the heterodimer (PubMed:16508002). CC Forms a multiprotein complex with Ras (M-Ras/MRAS), SHOC2 and protein CC phosphatase 1 (PPP1CA, PPP1CB and PPP1CC) (PubMed:16630891). Interacts CC with LZTR1 (PubMed:30368668). Interacts with Ras proteins; the CC interaction is antagonized by RIN1 (PubMed:11784866). Weakly interacts CC with RIT1. Interacts (via N-terminus) with RGS14 (via RBD domains); the CC interaction mediates the formation of a ternary complex with BRAF, a CC ternary complex inhibited by GNAI1 (By similarity). Probably forms a CC complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37, CC PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this CC complex does not contain co-chaperones STIP1/HOP and PTGES3/p23 CC (PubMed:29127155). Interacts with STK3/MST2; the interaction inhibits CC its pro-apoptotic activity (PubMed:15618521). Interacts (when CC phosphorylated at Ser-259) with YWHAZ (unphosphorylated at 'Thr-232') CC (PubMed:9360956, PubMed:31024343). Interacts with MAP2K1/MEK1 and CC MAP2K2/MEK2 (By similarity). Interacts with MAP3K5/ASF1 (via N- CC terminus) and this interaction inhibits the proapoptotic function of CC MAP3K5/ASK1 (PubMed:11427728). Interacts with PAK1 (via kinase domain) CC (PubMed:11733498). The phosphorylated form interacts with PIN1 (By CC similarity). The Ser-338 and Ser-339 phosphorylated form (by PAK1) CC interacts with BCL2 (PubMed:15849194). Interacts with PEBP1/RKIP and CC this interaction is enhanced if RAF1 is phosphorylated on residues Ser- CC 338, Ser-339, Tyr-340 and Tyr-341 (PubMed:18294816). Interacts with CC ADCY2, ADCY5, ADCY6, DGKH, RCAN1/DSCR1, PPP1R12A, PKB/AKT1, PPP2CA, CC PPP2R1B, SPRY2, SPRY4, CNKSR1/CNK1, KSR2 and PHB/prohibitin CC (PubMed:10801873, PubMed:11719507, PubMed:12717443, PubMed:15385642, CC PubMed:15935327, PubMed:19710016, PubMed:10576742). Interacts with CC ROCK2 (By similarity). In its active form, interacts with PRMT5 CC (PubMed:21917714). Interacts with FAM83B; displaces 14-3-3 proteins CC from RAF1 and activates RAF1 (PubMed:22886302). Interacts with PDE8A; CC the interaction promotes RAF1 activity (PubMed:23509299). Interacts CC with MFHAS1 (PubMed:23327923). Interacts with GLS (PubMed:22538822). CC Interacts with NEK10 and MAP2K1; the interaction is direct with NEK10 CC and required for ERK1/2-signaling pathway activation in response to UV CC irradiation (PubMed:20956560). {ECO:0000250|UniProtKB:P11345, CC ECO:0000250|UniProtKB:Q99N57, 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:11784866, ECO:0000269|PubMed:12717443, CC ECO:0000269|PubMed:15385642, ECO:0000269|PubMed:15618521, CC ECO:0000269|PubMed:15849194, ECO:0000269|PubMed:15935327, CC ECO:0000269|PubMed:16508002, ECO:0000269|PubMed:16630891, CC ECO:0000269|PubMed:18294816, ECO:0000269|PubMed:19710016, CC ECO:0000269|PubMed:20956560, ECO:0000269|PubMed:21917714, CC ECO:0000269|PubMed:22538822, ECO:0000269|PubMed:22886302, CC ECO:0000269|PubMed:23327923, ECO:0000269|PubMed:23509299, CC ECO:0000269|PubMed:29127155, ECO:0000269|PubMed:30368668, CC ECO:0000269|PubMed:9360956}. CC -!- INTERACTION: CC P04049; P05067: APP; NbExp=3; IntAct=EBI-365996, EBI-77613; CC P04049; O95816: BAG2; NbExp=12; IntAct=EBI-365996, EBI-355275; CC P04049; P15056: BRAF; NbExp=71; IntAct=EBI-365996, EBI-365980; CC P04049; Q14790: CASP8; NbExp=3; IntAct=EBI-365996, EBI-78060; CC P04049; P49368: CCT3; NbExp=8; IntAct=EBI-365996, EBI-356673; CC P04049; P30304: CDC25A; NbExp=4; IntAct=EBI-365996, EBI-747671; CC P04049; Q16543: CDC37; NbExp=19; IntAct=EBI-365996, EBI-295634; CC P04049; P31327: CPS1; NbExp=4; IntAct=EBI-365996, EBI-536811; CC P04049; P01112: HRAS; NbExp=27; IntAct=EBI-365996, EBI-350145; CC P04049; P07900: HSP90AA1; NbExp=15; IntAct=EBI-365996, EBI-296047; CC P04049; P08238: HSP90AB1; NbExp=17; IntAct=EBI-365996, EBI-352572; CC P04049; P11021: HSPA5; NbExp=5; IntAct=EBI-365996, EBI-354921; CC P04049; P01116: KRAS; NbExp=6; IntAct=EBI-365996, EBI-367415; CC P04049; P01116-2: KRAS; NbExp=3; IntAct=EBI-365996, EBI-367427; CC P04049; Q8IVT5: KSR1; NbExp=5; IntAct=EBI-365996, EBI-486984; CC P04049; Q02750: MAP2K1; NbExp=38; IntAct=EBI-365996, EBI-492564; CC P04049; P36507: MAP2K2; NbExp=6; IntAct=EBI-365996, EBI-1056930; CC P04049; Q15773: MLF2; NbExp=4; IntAct=EBI-365996, EBI-1051875; CC P04049; Q12968: NFATC3; NbExp=2; IntAct=EBI-365996, EBI-5278441; CC P04049; P01111: NRAS; NbExp=12; IntAct=EBI-365996, EBI-721993; CC P04049; O43482: OIP5; NbExp=4; IntAct=EBI-365996, EBI-536879; CC P04049; Q13177: PAK2; NbExp=2; IntAct=EBI-365996, EBI-1045887; CC P04049; Q6TCH7: PAQR3; NbExp=3; IntAct=EBI-365996, EBI-15654365; CC P04049; P30086: PEBP1; NbExp=10; IntAct=EBI-365996, EBI-716384; CC P04049; Q96S96: PEBP4; NbExp=4; IntAct=EBI-365996, EBI-8563667; CC P04049; Q13526: PIN1; NbExp=2; IntAct=EBI-365996, EBI-714158; CC P04049; P14618: PKM; NbExp=3; IntAct=EBI-365996, EBI-353408; CC P04049; P67775: PPP2CA; NbExp=2; IntAct=EBI-365996, EBI-712311; CC P04049; Q13362: PPP2R5C; NbExp=2; IntAct=EBI-365996, EBI-1266156; CC P04049; P04049: RAF1; NbExp=6; IntAct=EBI-365996, EBI-365996; CC P04049; P62834: RAP1A; NbExp=2; IntAct=EBI-365996, EBI-491414; CC P04049; P06400: RB1; NbExp=3; IntAct=EBI-365996, EBI-491274; CC P04049; P53805-2: RCAN1; NbExp=4; IntAct=EBI-365996, EBI-1541912; CC P04049; P31947: SFN; NbExp=9; IntAct=EBI-365996, EBI-476295; CC P04049; Q13188: STK3; NbExp=6; IntAct=EBI-365996, EBI-992580; CC P04049; Q9UNE7: STUB1; NbExp=8; IntAct=EBI-365996, EBI-357085; CC P04049; Q3ZCQ8: TIMM50; NbExp=7; IntAct=EBI-365996, EBI-355175; CC P04049; P31946: YWHAB; NbExp=35; IntAct=EBI-365996, EBI-359815; CC P04049; P62258: YWHAE; NbExp=22; IntAct=EBI-365996, EBI-356498; CC P04049; P61981: YWHAG; NbExp=21; IntAct=EBI-365996, EBI-359832; CC P04049; Q04917: YWHAH; NbExp=25; IntAct=EBI-365996, EBI-306940; CC P04049; P27348: YWHAQ; NbExp=21; IntAct=EBI-365996, EBI-359854; CC P04049; P63104: YWHAZ; NbExp=30; IntAct=EBI-365996, EBI-347088; CC P04049; P32883: Kras; Xeno; NbExp=2; IntAct=EBI-365996, EBI-644267; CC P04049; P28301: Lox; Xeno; NbExp=2; IntAct=EBI-365996, EBI-642911; CC P04049; Q9ESN9-2: Mapk8ip3; Xeno; NbExp=2; IntAct=EBI-365996, EBI-9549291; CC P04049; P03495: NS; Xeno; NbExp=2; IntAct=EBI-365996, EBI-2548993; CC P04049; O39474: NS5A; Xeno; NbExp=4; IntAct=EBI-365996, EBI-7016711; CC P04049; P01120: RAS2; Xeno; NbExp=2; IntAct=EBI-365996, EBI-14838; CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cell membrane. Mitochondrion. Nucleus. CC Note=Colocalizes with RGS14 and BRAF in both the cytoplasm and CC membranes. Phosphorylation at Ser-259 impairs its membrane CC accumulation. Recruited to the cell membrane by the active Ras protein. CC Phosphorylation at Ser-338 and Ser-339 by PAK1 is required for its CC mitochondrial localization. Retinoic acid-induced Ser-621 CC phosphorylated form of RAF1 is predominantly 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 than CC isoform 2. {ECO:0000269|PubMed:1886707}. CC -!- PTM: Phosphorylation at Thr-269, Ser-338, Tyr-341, Thr-491 and Ser-494 CC results in its activation. Phosphorylation at Ser-29, Ser-43, Ser-289, CC Ser-296, Ser-301 and Ser-642 by MAPK1/ERK2 results in its inactivation. CC Phosphorylation at Ser-259 induces the interaction with YWHAZ and CC inactivates kinase activity. Dephosphorylation of Ser-259 by the CC complex containing protein phosphatase 1, SHOC2 and M-Ras/MRAS relieves CC inactivation, leading to stimulate RAF1 activity. Phosphorylation at CC Ser-338 by PAK1 and PAK5 and Ser-339 by PAK1 is required for its CC mitochondrial localization. Phosphorylation at Ser-621 in response to CC growth factor treatment stabilizes the protein, possibly by preventing CC proteasomal degradation. Phosphorylation at Ser-289, Ser-296, Ser-301, CC Ser-338 and Ser-621 are somehow linked to the methylation potential of CC cells. Treatment of cells with HGF in the presence of the methylation CC inhibitor 5'-methylthioadenosine (MTA) results in increased CC phosphorylation at Ser-338 and Ser-621 and decreased phosphorylation at CC Ser-296, Ser-301 and Ser-338. Dephosphorylation at Ser-338 by PPP5C CC results in an activity decrease. {ECO:0000269|PubMed:10576742, CC ECO:0000269|PubMed:10801873, ECO:0000269|PubMed:11447113, CC ECO:0000269|PubMed:11733498, ECO:0000269|PubMed:11756411, CC ECO:0000269|PubMed:15047712, ECO:0000269|PubMed:15849194, CC ECO:0000269|PubMed:16093354, ECO:0000269|PubMed:16630891, CC ECO:0000269|PubMed:16892053, ECO:0000269|PubMed:18465753, CC ECO:0000269|PubMed:21917714, ECO:0000269|PubMed:7477354, CC ECO:0000269|PubMed:8349614, 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 through CC 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 dysmorphic CC features such as hypertelorism, a downward eyeslant and low-set CC posteriorly rotated ears, and a high incidence of congenital heart CC defects and hypertrophic cardiomyopathy. Other features can include a CC short neck with webbing or redundancy of skin, deafness, motor delay, CC variable intellectual deficits, multiple skeletal defects, CC cryptorchidism, and bleeding diathesis. Individuals with Noonan CC syndrome are at risk of juvenile myelomonocytic leukemia, a CC myeloproliferative disorder characterized by excessive production of CC myelomonocytic cells. {ECO:0000269|PubMed:17603482, CC ECO:0000269|PubMed:17603483, ECO:0000269|PubMed:20683980}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: LEOPARD syndrome 2 (LPRD2) [MIM:611554]: A disorder CC characterized by lentigines, electrocardiographic conduction CC abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities CC of genitalia, retardation of growth, and sensorineural deafness. CC {ECO:0000269|PubMed:17603483}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Cardiomyopathy, dilated, 1NN (CMD1NN) [MIM:615916]: A disorder CC characterized by ventricular dilation and impaired systolic function, CC resulting in congestive heart failure and arrhythmia. Patients are at CC risk of premature death. {ECO:0000269|PubMed:24777450}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr CC protein kinase family. RAF subfamily. {ECO:0000305}. 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 and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/42032/RAF1"; 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 CCDS; CCDS87047.1; -. [P04049-2] DR PIR; A00637; TVHUF6. DR PIR; S60341; S60341. DR RefSeq; NP_002871.1; NM_002880.3. [P04049-1] DR RefSeq; XP_005265412.1; XM_005265355.2. DR RefSeq; XP_011532276.1; XM_011533974.2. [P04049-1] 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 PDB; 6NTC; X-ray; 2.90 A; B=55-131. DR PDB; 6NTD; X-ray; 3.15 A; B=55-131. DR PDB; 6PTS; NMR; -; D=56-187. DR PDB; 6PTW; NMR; -; D=56-187. DR PDB; 6VJJ; X-ray; 1.40 A; B=52-131. DR PDB; 6XGU; X-ray; 2.70 A; B=52-188. DR PDB; 6XGV; X-ray; 2.11 A; B=52-188. DR PDB; 6XHA; X-ray; 2.87 A; B=52-188. DR PDB; 6XHB; X-ray; 2.50 A; B=52-188. DR PDB; 6XI7; X-ray; 1.95 A; B=52-188. DR PDB; 7JHP; X-ray; 2.77 A; C=55-187. DR PDB; 7Z37; EM; 3.67 A; CP1=1-648. DR PDB; 7Z38; EM; 3.16 A; C=1-648. DR PDB; 8A68; X-ray; 1.60 A; B=255-263. DR PDB; 8A6F; X-ray; 1.60 A; P=255-264. DR PDB; 8A6H; X-ray; 1.60 A; P=255-264. DR PDB; 8ATR; X-ray; 1.70 A; P=255-263. DR PDB; 8ATS; X-ray; 1.40 A; P=255-263. DR PDB; 8AV0; X-ray; 1.50 A; P=256-264. DR PDB; 8EPW; X-ray; 2.00 A; B=52-131. DR PDB; 8GAE; EM; 3.30 A; D=404-610. DR PDB; 8GFT; EM; 3.80 A; D=336-618. 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 PDBsum; 6NTC; -. DR PDBsum; 6NTD; -. DR PDBsum; 6PTS; -. DR PDBsum; 6PTW; -. DR PDBsum; 6VJJ; -. DR PDBsum; 6XGU; -. DR PDBsum; 6XGV; -. DR PDBsum; 6XHA; -. DR PDBsum; 6XHB; -. DR PDBsum; 6XI7; -. DR PDBsum; 7JHP; -. DR PDBsum; 7Z37; -. DR PDBsum; 7Z38; -. DR PDBsum; 8A68; -. DR PDBsum; 8A6F; -. DR PDBsum; 8A6H; -. DR PDBsum; 8ATR; -. DR PDBsum; 8ATS; -. DR PDBsum; 8AV0; -. DR PDBsum; 8EPW; -. DR PDBsum; 8GAE; -. DR PDBsum; 8GFT; -. DR AlphaFoldDB; P04049; -. DR BMRB; P04049; -. DR EMDB; EMD-14472; -. DR EMDB; EMD-14473; -. DR EMDB; EMD-29895; -. DR EMDB; EMD-29949; -. DR EMDB; EMD-29957; -. DR EMDB; EMD-29973; -. DR EMDB; EMD-29976; -. DR EMDB; EMD-29984; -. DR SMR; P04049; -. DR BioGRID; 111831; 1651. DR CORUM; P04049; -. DR DIP; DIP-1048N; -. DR IntAct; P04049; 384. DR MINT; P04049; -. DR STRING; 9606.ENSP00000401888; -. DR BindingDB; P04049; -. DR ChEMBL; CHEMBL1906; -. DR DrugBank; DB08862; Cholecystokinin. DR DrugBank; DB08912; Dabrafenib. DR DrugBank; DB12010; Fostamatinib. DR DrugBank; DB05268; iCo-007. DR DrugBank; DB04973; LErafAON. DR DrugBank; DB08896; Regorafenib. DR DrugBank; DB00398; Sorafenib. DR DrugBank; DB05190; XL281. DR DrugCentral; P04049; -. DR GuidetoPHARMACOLOGY; 2184; -. DR MoonDB; P04049; Predicted. DR GlyCosmos; P04049; 1 site, 1 glycan. DR GlyGen; P04049; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P04049; -. DR PhosphoSitePlus; P04049; -. DR BioMuta; RAF1; -. DR DMDM; 125651; -. DR CPTAC; CPTAC-1335; -. DR CPTAC; CPTAC-1336; -. DR CPTAC; CPTAC-1546; -. DR CPTAC; CPTAC-1762; -. DR CPTAC; CPTAC-5778; -. DR CPTAC; CPTAC-5779; -. DR CPTAC; CPTAC-5780; -. DR CPTAC; CPTAC-5828; -. DR CPTAC; CPTAC-5829; -. DR CPTAC; non-CPTAC-5431; -. DR CPTAC; non-CPTAC-5432; -. DR CPTAC; non-CPTAC-5433; -. DR CPTAC; non-CPTAC-5569; -. DR CPTAC; non-CPTAC-5570; -. DR CPTAC; non-CPTAC-5734; -. DR EPD; P04049; -. DR jPOST; P04049; -. DR MassIVE; P04049; -. DR MaxQB; P04049; -. DR PaxDb; 9606-ENSP00000251849; -. DR PeptideAtlas; P04049; -. DR ProteomicsDB; 51637; -. [P04049-1] DR ProteomicsDB; 51638; -. [P04049-2] DR Pumba; P04049; -. DR Antibodypedia; 1131; 3571 antibodies from 50 providers. DR CPTC; P04049; 8 antibodies. DR DNASU; 5894; -. DR Ensembl; ENST00000251849.9; ENSP00000251849.4; ENSG00000132155.14. [P04049-1] DR Ensembl; ENST00000442415.7; ENSP00000401888.2; ENSG00000132155.14. [P04049-2] DR Ensembl; ENST00000685653.1; ENSP00000509968.1; ENSG00000132155.14. [P04049-1] DR Ensembl; ENST00000691899.1; ENSP00000508763.1; ENSG00000132155.14. [P04049-1] DR GeneID; 5894; -. DR KEGG; hsa:5894; -. DR MANE-Select; ENST00000251849.9; ENSP00000251849.4; NM_002880.4; NP_002871.1. DR UCSC; uc003bxf.5; human. [P04049-1] DR AGR; HGNC:9829; -. DR CTD; 5894; -. DR DisGeNET; 5894; -. DR GeneCards; RAF1; -. DR GeneReviews; RAF1; -. DR HGNC; HGNC:9829; RAF1. DR HPA; ENSG00000132155; Low tissue specificity. DR MalaCards; RAF1; -. DR MIM; 164760; gene. DR MIM; 611553; phenotype. DR MIM; 611554; phenotype. DR MIM; 615916; phenotype. DR neXtProt; NX_P04049; -. DR OpenTargets; ENSG00000132155; -. DR Orphanet; 154; Familial isolated dilated cardiomyopathy. DR Orphanet; 626; Large congenital melanocytic nevus. DR Orphanet; 648; Noonan syndrome. DR Orphanet; 500; Noonan syndrome with multiple lentigines. DR Orphanet; 251615; Pilomyxoid astrocytoma. DR PharmGKB; PA34183; -. DR VEuPathDB; HostDB:ENSG00000132155; -. DR eggNOG; KOG0193; Eukaryota. DR GeneTree; ENSGT00940000156084; -. DR InParanoid; P04049; -. DR OMA; SPSSWCH; -. DR OrthoDB; 4560496at2759; -. DR PhylomeDB; P04049; -. DR TreeFam; TF317006; -. DR BRENDA; 2.7.10.2; 2681. DR PathwayCommons; P04049; -. 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-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 Reactome; R-HSA-6802946; Signaling by moderate kinase activity BRAF mutants. DR Reactome; R-HSA-6802948; Signaling by high-kinase activity BRAF mutants. DR Reactome; R-HSA-6802952; Signaling by BRAF and RAF1 fusions. DR Reactome; R-HSA-6802955; Paradoxical activation of RAF signaling by kinase inactive BRAF. DR Reactome; R-HSA-9649948; Signaling downstream of RAS mutants. DR Reactome; R-HSA-9656223; Signaling by RAF1 mutants. DR Reactome; R-HSA-9726840; SHOC2 M1731 mutant abolishes MRAS complex function. DR Reactome; R-HSA-9726842; Gain-of-function MRAS complexes activate RAF signaling. DR Reactome; R-HSA-9732724; IFNG signaling activates MAPKs. DR SignaLink; P04049; -. DR SIGNOR; P04049; -. DR BioGRID-ORCS; 5894; 99 hits in 1206 CRISPR screens. DR ChiTaRS; RAF1; human. DR EvolutionaryTrace; P04049; -. DR GeneWiki; C-Raf; -. DR GenomeRNAi; 5894; -. DR Pharos; P04049; Tclin. DR PRO; PR:P04049; -. DR Proteomes; UP000005640; Chromosome 3. DR RNAct; P04049; Protein. DR Bgee; ENSG00000132155; Expressed in gastrocnemius and 214 other cell types or tissues. DR ExpressionAtlas; P04049; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:MGI. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005794; C:Golgi apparatus; IPI:MGI. DR GO; GO:0005741; C:mitochondrial outer membrane; TAS:ProtInc. DR GO; GO:0005739; C:mitochondrion; IBA:GO_Central. DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell. DR GO; GO:0005886; C:plasma membrane; IDA:HPA. DR GO; GO:0031143; C:pseudopodium; IEA:Ensembl. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0004709; F:MAP kinase kinase kinase activity; IBA:GO_Central. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0004672; F:protein kinase activity; EXP:Reactome. DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB. DR GO; GO:0007190; P:activation of adenylate cyclase activity; IDA:BHF-UCL. DR GO; GO:0006915; P:apoptotic process; TAS:GO_Central. DR GO; GO:0071550; P:death-inducing signaling complex assembly; IEA:Ensembl. DR GO; GO:0038133; P:ERBB2-ERBB3 signaling pathway; IEA:Ensembl. DR GO; GO:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; IEA:Ensembl. DR GO; GO:0060324; P:face development; IEA:Ensembl. DR GO; GO:0008286; P:insulin receptor signaling pathway; IEA:Ensembl. DR GO; GO:0035773; P:insulin secretion involved in cellular response to glucose stimulus; IEA:Ensembl. DR GO; GO:0048009; P:insulin-like growth factor receptor signaling pathway; IEA:Ensembl. DR GO; GO:0045104; P:intermediate filament cytoskeleton organization; IEA:Ensembl. DR GO; GO:0000165; P:MAPK cascade; IBA:GO_Central. DR GO; GO:0042552; P:myelination; IEA:Ensembl. DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB. DR GO; GO:0008285; P:negative regulation of cell population 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-containing complex assembly; IDA:UniProtKB. DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; IEA:Ensembl. DR GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:GO_Central. DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; IDA:UniProtKB. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IEA:Ensembl. DR GO; GO:0006468; P:protein phosphorylation; TAS:ProtInc. 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:0035994; P:response to muscle stretch; IEA:Ensembl. DR GO; GO:0014044; P:Schwann cell development; IEA:Ensembl. DR GO; GO:0007165; P:signal transduction; TAS:ProtInc. DR GO; GO:0035019; P:somatic stem cell population maintenance; IEA:Ensembl. DR GO; GO:0048538; P:thymus development; IEA:Ensembl. DR GO; GO:0030878; P:thyroid gland development; IEA:Ensembl. DR GO; GO:0044342; P:type B pancreatic cell proliferation; IEA:Ensembl. DR GO; GO:0060333; P:type II interferon-mediated signaling pathway; TAS:Reactome. DR GO; GO:0042060; P:wound healing; TAS:UniProtKB. DR CDD; cd20870; C1_A_C-Raf; 1. DR CDD; cd17135; RBD_CRAF; 1. DR CDD; cd14149; STKc_C-Raf; 1. DR Gene3D; 3.30.60.20; -; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR IDEAL; IID00292; -. DR InterPro; IPR046349; C1-like_sf. DR InterPro; IPR020454; DAG/PE-bd. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR002219; PE/DAG-bd. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR003116; RBD_dom. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR InterPro; IPR029071; Ubiquitin-like_domsf. DR PANTHER; PTHR23257:SF763; RAF PROTO-ONCOGENE SERINE_THREONINE-PROTEIN KINASE; 1. DR PANTHER; PTHR23257; SERINE-THREONINE PROTEIN KINASE; 1. DR Pfam; PF00130; C1_1; 1. DR Pfam; PF00069; Pkinase; 1. DR Pfam; PF02196; RBD; 1. DR PRINTS; PR00008; DAGPEDOMAIN. DR SMART; SM00109; C1; 1. DR SMART; SM00455; RBD; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF57889; Cysteine-rich domain; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR SUPFAM; SSF54236; Ubiquitin-like; 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. DR Genevisible; P04049; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; ATP-binding; Cardiomyopathy; KW Cell membrane; Cytoplasm; Deafness; Direct protein sequencing; KW Disease variant; Kinase; Membrane; Metal-binding; Methylation; KW Mitochondrion; Nucleotide-binding; Nucleus; Phosphoprotein; Proto-oncogene; KW Reference proteome; Serine/threonine-protein kinase; Transferase; Zinc; KW Zinc-finger. FT CHAIN 1..648 FT /note="RAF proto-oncogene serine/threonine-protein kinase" FT /id="PRO_0000086596" FT DOMAIN 56..131 FT /note="RBD" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00262" FT DOMAIN 349..609 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT ZN_FING 138..184 FT /note="Phorbol-ester/DAG-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00226" FT REGION 220..334 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 331..349 FT /note="Interaction with PEBP1/RKIP" FT COMPBIAS 222..269 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 284..310 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 468 FT /note="Proton acceptor" FT BINDING 139 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT BINDING 152 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT BINDING 155 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT BINDING 165 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT BINDING 168 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT BINDING 173 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT BINDING 176 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT BINDING 184 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT BINDING 355..363 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 375 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT MOD_RES 29 FT /note="Phosphoserine; by MAPK1" FT /evidence="ECO:0000250|UniProtKB:Q99N57" FT MOD_RES 43 FT /note="Phosphoserine; by PKA and MAPK1" FT /evidence="ECO:0000269|PubMed:8349614" FT MOD_RES 252 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:17525332" FT MOD_RES 259 FT /note="Phosphoserine; by PKA, PKC and PKB/AKT1" FT /evidence="ECO:0000269|PubMed:10576742, FT ECO:0000269|PubMed:10801873, ECO:0000269|PubMed:11756411, FT ECO:0000269|PubMed:15047712, ECO:0000269|PubMed:16630891, FT ECO:0000269|PubMed:16892053, ECO:0000269|PubMed:8349614" FT MOD_RES 268 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:8349614" FT MOD_RES 269 FT /note="Phosphothreonine; by PKA" FT /evidence="ECO:0000269|PubMed:7477354" FT MOD_RES 289 FT /note="Phosphoserine; by MAPK1" FT /evidence="ECO:0000269|PubMed:21917714, FT ECO:0007744|PubMed:19690332" FT MOD_RES 296 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 301 FT /note="Phosphoserine; by MAPK1" FT /evidence="ECO:0000269|PubMed:21917714, FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:23186163" FT MOD_RES 338 FT /note="Phosphoserine; by PAK1, PAK2, PAK3 and PAK5" FT /evidence="ECO:0000269|PubMed:11733498, FT ECO:0000269|PubMed:15849194, ECO:0000269|PubMed:16892053, FT ECO:0000269|PubMed:18465753, ECO:0000269|PubMed:21917714" FT MOD_RES 339 FT /note="Phosphoserine; by PAK1, PAK2 and PAK3" FT /evidence="ECO:0000269|PubMed:15849194" FT MOD_RES 340 FT /note="Phosphotyrosine; by SRC" FT /evidence="ECO:0000269|PubMed:16892053" FT MOD_RES 341 FT /note="Phosphotyrosine; by SRC" FT /evidence="ECO:0000269|PubMed:16892053" FT MOD_RES 471 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:16093354" FT MOD_RES 491 FT /note="Phosphothreonine" FT /evidence="ECO:0000269|PubMed:11447113" FT MOD_RES 494 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:11447113" FT MOD_RES 499 FT /note="Phosphoserine; by PKC" FT /evidence="ECO:0000269|PubMed:8349614" FT MOD_RES 563 FT /note="Symmetric dimethylarginine; by PRMT5" FT /evidence="ECO:0000269|PubMed:21917714" FT MOD_RES 621 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:10801873, FT ECO:0000269|PubMed:16892053, ECO:0000269|PubMed:21917714, FT ECO:0000269|PubMed:8349614" FT MOD_RES 642 FT /note="Phosphoserine; by MAPK1" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT VAR_SEQ 278 FT /note="E -> ENNNLSASPRAWSRRFCLRGR (in isoform 2)" FT /evidence="ECO:0000305" FT /id="VSP_034649" FT VARIANT 237 FT /note="A -> T (in CMD1NN; shows a mild increase in kinase FT activity; dbSNP:rs587777588)" FT /evidence="ECO:0000269|PubMed:24777450" FT /id="VAR_071844" FT VARIANT 256 FT /note="R -> S (in NS5; dbSNP:rs397516826)" FT /evidence="ECO:0000269|PubMed:17603483" FT /id="VAR_037807" FT VARIANT 257 FT /note="S -> L (in NS5 and LPRD2; shows in vitro greater FT kinase activity and enhanced ERK activation than wild-type; FT dbSNP:rs80338796)" FT /evidence="ECO:0000269|PubMed:17603482, FT ECO:0000269|PubMed:17603483" FT /id="VAR_037808" FT VARIANT 259 FT /note="S -> A (in an ovarian serous carcinoma sample; FT somatic mutation; increased ERK activation; FT dbSNP:rs3730271)" FT /evidence="ECO:0000269|PubMed:16630891, FT ECO:0000269|PubMed:17344846" FT /id="VAR_041037" FT VARIANT 259 FT /note="S -> F (in NS5; dbSNP:rs397516827)" FT /evidence="ECO:0000269|PubMed:17603483" FT /id="VAR_037809" FT VARIANT 260 FT /note="T -> I (in hypertrophic cardiomyopathy; uncertain FT significance; dbSNP:rs869025501)" FT /evidence="ECO:0000269|PubMed:17603483" FT /id="VAR_037810" FT VARIANT 260 FT /note="T -> R (in NS5)" FT /evidence="ECO:0000269|PubMed:17603483" FT /id="VAR_037811" FT VARIANT 261 FT /note="P -> A (in NS5; shows in vitro greater kinase FT activity and enhanced MAPK1 activation than wild-type; FT dbSNP:rs121434594)" FT /evidence="ECO:0000269|PubMed:17603482" FT /id="VAR_037812" FT VARIANT 261 FT /note="P -> L (in NS5; shows greater kinase activity and FT enhanced MAPK1 activation than wild-type; FT dbSNP:rs397516828)" FT /evidence="ECO:0000269|PubMed:17603483" FT /id="VAR_037813" FT VARIANT 261 FT /note="P -> S (in NS5; shows in vitro greater kinase FT activity and enhanced MAPK1 activation than wild-type; FT dbSNP:rs121434594)" FT /evidence="ECO:0000269|PubMed:17603482, FT ECO:0000269|PubMed:17603483, ECO:0000269|PubMed:20683980" FT /id="VAR_037814" FT VARIANT 263 FT /note="V -> A (in NS5; shows in vitro greater kinase FT activity and enhanced MAPK1 activation than wild-type; FT dbSNP:rs397516830)" FT /evidence="ECO:0000269|PubMed:17603482" FT /id="VAR_037815" FT VARIANT 308 FT /note="P -> L (in dbSNP:rs5746220)" FT /evidence="ECO:0000269|PubMed:14702039, ECO:0000269|Ref.3" FT /id="VAR_018840" FT VARIANT 310 FT /note="T -> A (in CMD1NN; shows a mild increase in kinase FT activity; dbSNP:rs778155315)" FT /evidence="ECO:0000269|PubMed:24777450" FT /id="VAR_071845" FT VARIANT 332 FT /note="P -> A (in CMD1NN; shows a mild increase in kinase FT activity; dbSNP:rs1057403865)" FT /evidence="ECO:0000269|PubMed:24777450" FT /id="VAR_071846" FT VARIANT 335 FT /note="Q -> H (in a lung adenocarcinoma sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041038" FT VARIANT 486 FT /note="D -> G (in NS5; dbSNP:rs397516815)" FT /evidence="ECO:0000269|PubMed:17603483" FT /id="VAR_037816" FT VARIANT 486 FT /note="D -> N (in NS5; has reduced or absent kinase FT activity; dbSNP:rs80338798)" FT /evidence="ECO:0000269|PubMed:17603483" FT /id="VAR_037817" FT VARIANT 491 FT /note="T -> I (in NS5; has reduced or absent kinase FT activity; dbSNP:rs80338799)" FT /evidence="ECO:0000269|PubMed:17603483" FT /id="VAR_037818" FT VARIANT 491 FT /note="T -> R (in NS5; dbSNP:rs80338799)" FT /evidence="ECO:0000269|PubMed:17603483" FT /id="VAR_037819" FT VARIANT 603 FT /note="L -> P (in CMD1NN; shows impaired kinase activity FT and reduced MAPK3 activation with this mutation; FT dbSNP:rs587777586)" FT /evidence="ECO:0000269|PubMed:24777450" FT /id="VAR_071847" FT VARIANT 612 FT /note="S -> T (in NS5; dbSNP:rs1448392469)" FT /evidence="ECO:0000269|PubMed:17603483" FT /id="VAR_037820" FT VARIANT 613 FT /note="L -> V (in NS5 and LPRD2; shows in vitro greater FT kinase activity and enhanced MAPK1 activation than FT wild-type; dbSNP:rs80338797)" FT /evidence="ECO:0000269|PubMed:17603482, FT ECO:0000269|PubMed:17603483" FT /id="VAR_037821" FT VARIANT 626 FT /note="H -> R (in CMD1NN; shows a mild increase in kinase FT activity; dbSNP:rs1553609795)" FT /evidence="ECO:0000269|PubMed:24777450" FT /id="VAR_071848" FT VARIANT 641 FT /note="T -> M (in CMD1NN; shows a mild increase in kinase FT activity; dbSNP:rs587777587)" FT /evidence="ECO:0000269|PubMed:24777450" FT /id="VAR_071849" FT MUTAGEN 338..339 FT /note="SS->AA: Reduced kinase activity; when associated FT with 340-D-D-341." FT /evidence="ECO:0000269|PubMed:16892053" FT MUTAGEN 338..339 FT /note="SS->DE: Non-inhibited by PPP5C. Constitutively FT active and non-inhibited by PPP5C; when associated with FT 340-D-D-341." FT /evidence="ECO:0000269|PubMed:16892053" FT MUTAGEN 340..341 FT /note="YY->DD: Constitutively active and highly FT phosphorylated on S-338, inhibited by PPP5C. Reduced kinase FT activity; when associated with 338-A-A-339. Constitutively FT active and non-inhibited by PPP5C; when associated with FT 338-D-E-339." FT /evidence="ECO:0000269|PubMed:16892053" FT MUTAGEN 375 FT /note="K->W: Catalytically inactive." FT /evidence="ECO:0000269|PubMed:20956560" FT MUTAGEN 491 FT /note="T->D: Increased kinase activity but can still be FT inhibited by PPP5C; when associated with D-494." FT /evidence="ECO:0000269|PubMed:16892053" FT MUTAGEN 494 FT /note="S->D: Increased kinase activity but can still be FT inhibited by PPP5C; when associated with D-491." FT /evidence="ECO:0000269|PubMed:16892053" FT MUTAGEN 563 FT /note="R->K: Loss of methylation. Increased stability and FT catalytic activity in response to EGF treatment." FT /evidence="ECO:0000269|PubMed:21917714" FT CONFLICT 240 FT /note="F -> L (in Ref. 6; AAA60247)" FT /evidence="ECO:0000305" FT CONFLICT 542 FT /note="M -> I (in Ref. 6; AAA60247)" FT /evidence="ECO:0000305" FT STRAND 57..61 FT /evidence="ECO:0007829|PDB:6VJJ" FT TURN 63..65 FT /evidence="ECO:0007829|PDB:1C1Y" FT STRAND 67..71 FT /evidence="ECO:0007829|PDB:6VJJ" FT HELIX 78..88 FT /evidence="ECO:0007829|PDB:6VJJ" FT HELIX 93..95 FT /evidence="ECO:0007829|PDB:6VJJ" FT STRAND 96..100 FT /evidence="ECO:0007829|PDB:6VJJ" FT STRAND 103..107 FT /evidence="ECO:0007829|PDB:6VJJ" FT STRAND 109..112 FT /evidence="ECO:0007829|PDB:3KUC" FT HELIX 118..121 FT /evidence="ECO:0007829|PDB:6VJJ" FT STRAND 125..130 FT /evidence="ECO:0007829|PDB:6VJJ" FT STRAND 132..134 FT /evidence="ECO:0007829|PDB:6PTW" FT STRAND 135..137 FT /evidence="ECO:0007829|PDB:6XGV" FT STRAND 141..145 FT /evidence="ECO:0007829|PDB:6XI7" FT TURN 153..155 FT /evidence="ECO:0007829|PDB:6XI7" FT STRAND 160..165 FT /evidence="ECO:0007829|PDB:6XI7" FT TURN 166..168 FT /evidence="ECO:0007829|PDB:6XI7" FT STRAND 170..172 FT /evidence="ECO:0007829|PDB:7JHP" FT HELIX 174..179 FT /evidence="ECO:0007829|PDB:6XI7" FT STRAND 182..185 FT /evidence="ECO:0007829|PDB:6XGV" FT STRAND 429..431 FT /evidence="ECO:0007829|PDB:7Z38" FT TURN 434..437 FT /evidence="ECO:0007829|PDB:7Z38" FT HELIX 442..461 FT /evidence="ECO:0007829|PDB:7Z38" FT HELIX 471..473 FT /evidence="ECO:0007829|PDB:7Z38" FT TURN 478..480 FT /evidence="ECO:0007829|PDB:8GAE" FT STRAND 481..484 FT /evidence="ECO:0007829|PDB:8GAE" FT STRAND 510..512 FT /evidence="ECO:0007829|PDB:7Z38" FT HELIX 514..518 FT /evidence="ECO:0007829|PDB:7Z38" FT STRAND 520..522 FT /evidence="ECO:0007829|PDB:7Z38" FT HELIX 527..542 FT /evidence="ECO:0007829|PDB:7Z38" FT TURN 547..550 FT /evidence="ECO:0007829|PDB:7Z38" FT HELIX 554..563 FT /evidence="ECO:0007829|PDB:7Z38" FT HELIX 580..588 FT /evidence="ECO:0007829|PDB:7Z38" FT TURN 593..595 FT /evidence="ECO:0007829|PDB:7Z38" FT HELIX 599..611 FT /evidence="ECO:0007829|PDB:7Z38" FT TURN 612..614 FT /evidence="ECO:0007829|PDB:7Z38" 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 //