RAF1_HUMAN
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 03-AUG-2022, entry version 252.
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=3; IntAct=EBI-365996, EBI-355275;
CC P04049; P15056: BRAF; NbExp=57; IntAct=EBI-365996, EBI-365980;
CC P04049; Q14790: CASP8; NbExp=3; IntAct=EBI-365996, EBI-78060;
CC P04049; P49368: CCT3; NbExp=5; IntAct=EBI-365996, EBI-356673;
CC P04049; P30304: CDC25A; NbExp=4; IntAct=EBI-365996, EBI-747671;
CC P04049; Q16543: CDC37; NbExp=7; IntAct=EBI-365996, EBI-295634;
CC P04049; P31327: CPS1; NbExp=4; IntAct=EBI-365996, EBI-536811;
CC P04049; P01112: HRAS; NbExp=23; IntAct=EBI-365996, EBI-350145;
CC P04049; P07900: HSP90AA1; NbExp=4; IntAct=EBI-365996, EBI-296047;
CC P04049; P08238: HSP90AB1; NbExp=6; 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; Q02750: MAP2K1; NbExp=38; IntAct=EBI-365996, EBI-492564;
CC P04049; P36507: MAP2K2; NbExp=6; IntAct=EBI-365996, EBI-1056930;
CC P04049; Q12968: NFATC3; NbExp=2; IntAct=EBI-365996, EBI-5278441;
CC P04049; P01111: NRAS; NbExp=9; 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=6; IntAct=EBI-365996, EBI-476295;
CC P04049; Q13188: STK3; NbExp=6; IntAct=EBI-365996, EBI-992580;
CC P04049; Q3ZCQ8: TIMM50; NbExp=6; IntAct=EBI-365996, EBI-355175;
CC P04049; P31946: YWHAB; NbExp=21; IntAct=EBI-365996, EBI-359815;
CC P04049; P62258: YWHAE; NbExp=6; IntAct=EBI-365996, EBI-356498;
CC P04049; P61981: YWHAG; NbExp=6; IntAct=EBI-365996, EBI-359832;
CC P04049; Q04917: YWHAH; NbExp=10; IntAct=EBI-365996, EBI-306940;
CC P04049; P27348: YWHAQ; NbExp=7; IntAct=EBI-365996, EBI-359854;
CC P04049; P63104: YWHAZ; NbExp=16; 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="http://atlasgeneticsoncology.org/Genes/RAF1ID42032ch3p25.html";
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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 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 AlphaFoldDB; P04049; -.
DR BMRB; P04049; -.
DR SMR; P04049; -.
DR BioGRID; 111831; 316.
DR CORUM; P04049; -.
DR DIP; DIP-1048N; -.
DR IntAct; P04049; 208.
DR MINT; P04049; -.
DR STRING; 9606.ENSP00000251849; -.
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 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 EPD; P04049; -.
DR jPOST; P04049; -.
DR MassIVE; P04049; -.
DR MaxQB; P04049; -.
DR PaxDb; P04049; -.
DR PeptideAtlas; P04049; -.
DR PRIDE; P04049; -.
DR ProteomicsDB; 51637; -. [P04049-1]
DR ProteomicsDB; 51638; -. [P04049-2]
DR Antibodypedia; 1131; 3177 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 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; 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; SWCHRFW; -.
DR OrthoDB; 243095at2759; -.
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 SignaLink; P04049; -.
DR SIGNOR; P04049; -.
DR BioGRID-ORCS; 5894; 93 hits in 1120 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 212 other tissues.
DR ExpressionAtlas; P04049; baseline and differential.
DR Genevisible; P04049; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:MGI.
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: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; TAS:ProtInc.
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:0030154; P:cell differentiation; IEA:Ensembl.
DR GO; GO:0071550; P:death-inducing signaling complex assembly; 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: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:0000165; P:MAPK cascade; IBA:GO_Central.
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: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:0042060; P:wound healing; TAS:UniProtKB.
DR CDD; cd00029; C1; 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; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR InterPro; IPR029071; Ubiquitin-like_domsf.
DR Pfam; PF00130; C1_1; 1.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 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; SSF54236; SSF54236; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR SUPFAM; SSF57889; SSF57889; 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; 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; unknown
FT pathological 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 wild-
FT 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"
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
