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RAF proto-oncogene serine/threonine-protein kinase (EC 2.7.11.1) (Proto-oncogene c-RAF) (cRaf) (Raf-1)

 RAF1_HUMAN              Reviewed;         648 AA.
P04049; B0LPH8; B2R5N3; Q15278; Q9UC20;
01-NOV-1986, integrated into UniProtKB/Swiss-Prot.
01-NOV-1986, sequence version 1.
22-NOV-2017, entry version 217.
RecName: Full=RAF proto-oncogene serine/threonine-protein kinase;
EC=2.7.11.1;
AltName: Full=Proto-oncogene c-RAF;
Short=cRaf;
AltName: Full=Raf-1;
Name=RAF1; Synonyms=RAF;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
PubMed=3003687; DOI=10.1093/nar/14.2.1009;
Bonner T.I., Oppermann H., Seeburg P., Kerby S.B., Gunnell M.A.,
Young A.C., Rapp U.R.;
"The complete coding sequence of the human raf oncogene and the
corresponding structure of the c-raf-1 gene.";
Nucleic Acids Res. 14:1009-1015(1986).
[2]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
LEU-308.
PubMed=14702039; DOI=10.1038/ng1285;
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
"Complete sequencing and characterization of 21,243 full-length human
cDNAs.";
Nat. Genet. 36:40-45(2004).
[3]
NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT LEU-308.
NIEHS SNPs program;
Submitted (DEC-2007) to the EMBL/GenBank/DDBJ databases.
[4]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
Venter J.C.;
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
[5]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
TISSUE=Pancreas;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[6]
NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 228-648.
PubMed=2993863; DOI=10.1128/MCB.5.6.1400;
Bonner T.I., Kerby S.B., Sutrave P., Gunnell M.A., Mark G., Rapp U.R.;
"Structure and biological activity of human homologs of the raf/mil
oncogene.";
Mol. Cell. Biol. 5:1400-1407(1985).
[7]
PROTEIN SEQUENCE OF 42-53; 60-65; 310-316 AND 564-572, INTERACTION
WITH PRMT5, METHYLATION AT ARG-563, PHOSPHORYLATION AT SER-289;
SER-296; SER-301; SER-338 AND SER-621, AND MUTAGENESIS OF ARG-563.
PubMed=21917714; DOI=10.1126/scisignal.2001936;
Andreu-Perez P., Esteve-Puig R., de Torre-Minguela C.,
Lopez-Fauqued M., Bech-Serra J.J., Tenbaum S., Garcia-Trevijano E.R.,
Canals F., Merlino G., Avila M.A., Recio J.A.;
"Protein arginine methyltransferase 5 regulates ERK1/2 signal
transduction amplitude and cell fate through CRAF.";
Sci. Signal. 4:RA58-RA58(2011).
[8]
PROTEIN SEQUENCE OF 254-278, AND PHOSPHORYLATION AT THR-269.
PubMed=7477354; DOI=10.1038/378307a0;
Yao B., Zhang Y., Delikat S., Mathias S., Basu S., Kolesnick R.;
"Phosphorylation of Raf by ceramide-activated protein kinase.";
Nature 378:307-310(1995).
[9]
PARTIAL NUCLEOTIDE SEQUENCE [GENOMIC DNA], ALTERNATIVE SPLICING, AND
TISSUE SPECIFICITY.
TISSUE=Placenta;
PubMed=1886707;
Dozier C., Ansieau S., Ferreira E., Coll J., Stehelin D.;
"An alternatively spliced c-mil/raf mRNA is predominantly expressed in
chicken muscular tissues and conserved among vertebrate species.";
Oncogene 6:1307-1311(1991).
[10]
PHOSPHORYLATION AT SER-43; SER-259; THR-268; SER-499 AND SER-621.
PubMed=8349614;
Morrison D.K., Heidecker G., Rapp U.R., Copeland T.D.;
"Identification of the major phosphorylation sites of the Raf-1
kinase.";
J. Biol. Chem. 268:17309-17316(1993).
[11]
INTERACTION WITH YWHAZ, AND FUNCTION.
PubMed=9360956; DOI=10.1074/jbc.272.46.28882;
Dubois T., Rommel C., Howell S., Steinhussen U., Soneji Y.,
Morrice N., Moelling K., Aitken A.;
"14-3-3 is phosphorylated by casein kinase I on residue 233.
Phosphorylation at this site in vivo regulates Raf/14-3-3
interaction.";
J. Biol. Chem. 272:28882-28888(1997).
[12]
PHOSPHORYLATION.
PubMed=9823899; DOI=10.1038/24184;
King A.J., Sun H., Diaz B., Barnard D., Miao W., Bagrodia S.,
Marshall M.S.;
"The protein kinase Pak3 positively regulates Raf-1 activity through
phosphorylation of serine 338.";
Nature 396:180-183(1998).
[13]
ERRATUM.
King A.J., Sun H., Diaz B., Barnard D., Miao W., Bagrodia S.,
Marshall M.S.;
Nature 406:439-439(2000).
[14]
PHOSPHORYLATION AT SER-259 BY PKB/AKT1, ENZYME REGULATION, AND
INTERACTION WITH PKB/AKT1.
PubMed=10576742; DOI=10.1126/science.286.5445.1741;
Zimmermann S., Moelling K.;
"Phosphorylation and regulation of Raf by Akt (protein kinase B).";
Science 286:1741-1744(1999).
[15]
PHOSPHORYLATION AT SER-259 AND SER-621, DEPHOSPHORYLATION AT SER-43;
SER-259 AND SER-621, ENZYME REGULATION, AND INTERACTION WITH PPP2CA
AND PPP2R1B.
PubMed=10801873; DOI=10.1074/jbc.M003259200;
Abraham D., Podar K., Pacher M., Kubicek M., Welzel N., Hemmings B.A.,
Dilworth S.M., Mischak H., Kolch W., Baccarini M.;
"Raf-1-associated protein phosphatase 2A as a positive regulator of
kinase activation.";
J. Biol. Chem. 275:22300-22304(2000).
[16]
ENZYME REGULATION, AND PHOSPHORYLATION AT THR-491 AND SER-494.
PubMed=11447113; DOI=10.1093/emboj/20.14.3716;
Chong H., Lee J., Guan K.L.;
"Positive and negative regulation of Raf kinase activity and function
by phosphorylation.";
EMBO J. 20:3716-3727(2001).
[17]
FUNCTION, AND INTERACTION WITH MAP3K5/ASK1.
PubMed=11427728; DOI=10.1073/pnas.141224398;
Chen J., Fujii K., Zhang L., Roberts T., Fu H.;
"Raf-1 promotes cell survival by antagonizing apoptosis signal-
regulating kinase 1 through a MEK-ERK independent mechanism.";
Proc. Natl. Acad. Sci. U.S.A. 98:7783-7788(2001).
[18]
FUNCTION IN PHOSPHORYLATION OF PPP1R12A, AND INTERACTION WITH
PPP1R12A.
PubMed=11719507; DOI=10.1074/jbc.M106343200;
Broustas C.G., Grammatikakis N., Eto M., Dent P., Brautigan D.L.,
Kasid U.;
"Phosphorylation of the myosin-binding subunit of myosin phosphatase
by Raf-1 and inhibition of phosphatase activity.";
J. Biol. Chem. 277:3053-3059(2002).
[19]
PHOSPHORYLATION AT SER-338 BY PAK1, ENZYME REGULATION, AND INTERACTION
WITH PAK1.
PubMed=11733498; DOI=10.1074/jbc.M110000200;
Zang M., Hayne C., Luo Z.;
"Interaction between active Pak1 and Raf-1 is necessary for
phosphorylation and activation of Raf-1.";
J. Biol. Chem. 277:4395-4405(2002).
[20]
PHOSPHORYLATION AT SER-259, DEPHOSPHORYLATION AT SER-259, AND
SUBCELLULAR LOCATION.
PubMed=11756411; DOI=10.1074/jbc.M108733200;
Kubicek M., Pacher M., Abraham D., Podar K., Eulitz M., Baccarini M.;
"Dephosphorylation of Ser-259 regulates Raf-1 membrane association.";
J. Biol. Chem. 277:7913-7919(2002).
[21]
COMPETITION WITH RIN1.
PubMed=11784866; DOI=10.1128/MCB.22.13.4638-4651.2002;
Wang Y., Waldron R.T., Dhaka A., Patel A., Riley M.M., Rozengurt E.,
Colicelli J.;
"The RAS effector RIN1 directly competes with RAF and is regulated by
14-3-3 proteins.";
Mol. Cell. Biol. 22:916-926(2002).
[22]
ENZYME REGULATION, AND INTERACTION WITH SPRY2 AND SPRY4.
PubMed=12717443; DOI=10.1038/ncb978;
Sasaki A., Taketomi T., Kato R., Saeki K., Nonami A., Sasaki M.,
Kuriyama M., Saito N., Shibuya M., Yoshimura A.;
"Mammalian Sprouty4 suppresses Ras-independent ERK activation by
binding to Raf1.";
Nat. Cell Biol. 5:427-432(2003).
[23]
PHOSPHORYLATION AT SER-259.
PubMed=15047712; DOI=10.1074/jbc.M314192200;
Kunapuli P., Kasyapa C.S., Hawthorn L., Cowell J.K.;
"LGI1, a putative tumor metastasis suppressor gene, controls in vitro
invasiveness and expression of matrix metalloproteinases in glioma
cells through the ERK1/2 pathway.";
J. Biol. Chem. 279:23151-23157(2004).
[24]
ERRATUM.
Kunapuli P., Kasyapa C.S., Hawthorn L., Cowell J.K.;
J. Biol. Chem. 282:2752-2752(2007).
[25]
FUNCTION IN PHOSPHORYLATION OF ADCY2; ADCY5 AND ADCY6, AND INTERACTION
WITH ADCY2; ADCY5 AND ADCY6.
PubMed=15385642; DOI=10.1124/mol.66.4.;
Ding Q., Gros R., Gray I.D., Taussig R., Ferguson S.S., Feldman R.D.;
"Raf kinase activation of adenylyl cyclases: isoform-selective
regulation.";
Mol. Pharmacol. 66:921-928(2004).
[26]
INTERACTION WITH STK3/MST2, AND FUNCTION.
PubMed=15618521; DOI=10.1126/science.1103233;
O'Neill E., Rushworth L., Baccarini M., Kolch W.;
"Role of the kinase MST2 in suppression of apoptosis by the proto-
oncogene product Raf-1.";
Science 306:2267-2270(2004).
[27]
INTERACTION WITH RCAN1/DSCR1.
PubMed=15935327; DOI=10.1016/j.abb.2005.05.002;
Cho Y.J., Abe M., Kim S.Y., Sato Y.;
"Raf-1 is a binding partner of DSCR1.";
Arch. Biochem. Biophys. 439:121-128(2005).
[28]
REVIEW ON FUNCTION.
PubMed=15943972; DOI=10.1016/j.febslet.2005.03.024;
Baccarini M.;
"Second nature: biological functions of the Raf-1 'kinase'.";
FEBS Lett. 579:3271-3277(2005).
[29]
FUNCTION IN PHOSPHORYLATION OF BAD, PHOSPHORYLATION AT SER-338 AND
SER-339 BY PAK1, SUBCELLULAR LOCATION, AND INTERACTION WITH BCL2.
PubMed=15849194; DOI=10.1074/jbc.M413374200;
Jin S., Zhuo Y., Guo W., Field J.;
"p21-activated Kinase 1 (Pak1)-dependent phosphorylation of Raf-1
regulates its mitochondrial localization, phosphorylation of BAD, and
Bcl-2 association.";
J. Biol. Chem. 280:24698-24705(2005).
[30]
PHOSPHORYLATION AT SER-471.
PubMed=16093354; DOI=10.1091/mbc.E05-02-0090;
Zhu J., Balan V., Bronisz A., Balan K., Sun H., Leicht D.T., Luo Z.,
Qin J., Avruch J., Tzivion G.;
"Identification of Raf-1 S471 as a novel phosphorylation site critical
for Raf-1 and B-Raf kinase activities and for MEK binding.";
Mol. Biol. Cell 16:4733-4744(2005).
[31]
IDENTIFICATION IN A COMPLEX WITH PP1CA; PPP1CB; PPP1CC; SHOC2 AND
MRAS, PHOSPHORYLATION AT SER-259, AND CHARACTERIZATION OF VARIANT
ALA-259.
PubMed=16630891; DOI=10.1016/j.molcel.2006.03.027;
Rodriguez-Viciana P., Oses-Prieto J., Burlingame A., Fried M.,
McCormick F.;
"A phosphatase holoenzyme comprised of Shoc2/Sur8 and the catalytic
subunit of PP1 functions as an M-Ras effector to modulate Raf
activity.";
Mol. Cell 22:217-230(2006).
[32]
SUBUNIT.
PubMed=16508002; DOI=10.1128/MCB.26.6.2262-2272.2006;
Rushworth L.K., Hindley A.D., O'Neill E., Kolch W.;
"Regulation and role of Raf-1/B-Raf heterodimerization.";
Mol. Cell. Biol. 26:2262-2272(2006).
[33]
FUNCTION AS KINASE, ENZYME REGULATION, PHOSPHORYLATION AT SER-259;
SER-338; TYR-340; TYR-341 AND SER-621, DEPHOSPHORYLATION AT SER-338 BY
PPP5C, AND MUTAGENESIS OF 338-SER-SER-339; 340-TYR-TYR-341; THR-491
AND SER-494.
PubMed=16892053; DOI=10.1038/ncb1465;
von Kriegsheim A., Pitt A., Grindlay G.J., Kolch W., Dhillon A.S.;
"Regulation of the Raf-MEK-ERK pathway by protein phosphatase 5.";
Nat. Cell Biol. 8:1011-1016(2006).
[34]
REVIEW ON REGULATION.
PubMed=17218791; DOI=10.4161/cc.6.1.3593;
Dhillon A.S., von Kriegsheim A., Grindlay J., Kolch W.;
"Phosphatase and feedback regulation of Raf-1 signaling.";
Cell Cycle 6:3-7(2007).
[35]
FUNCTION.
PubMed=16924233; DOI=10.1038/sj.onc.1209902;
Wang Z., Wade P., Mandell K.J., Akyildiz A., Parkos C.A., Mrsny R.J.,
Nusrat A.;
"Raf 1 represses expression of the tight junction protein occludin via
activation of the zinc-finger transcription factor slug.";
Oncogene 26:1222-1230(2007).
[36]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-252, AND IDENTIFICATION
BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Embryonic kidney;
PubMed=17525332; DOI=10.1126/science.1140321;
Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III,
Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N.,
Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.;
"ATM and ATR substrate analysis reveals extensive protein networks
responsive to DNA damage.";
Science 316:1160-1166(2007).
[37]
ENZYME REGULATION, AND INTERACTION WITH PEBP1/RKIP.
PubMed=18294816; DOI=10.1016/j.cellsig.2008.01.012;
Rath O., Park S., Tang H.H., Banfield M.J., Brady R.L., Lee Y.C.,
Dignam J.D., Sedivy J.M., Kolch W., Yeung K.C.;
"The RKIP (Raf-1 Kinase Inhibitor Protein) conserved pocket binds to
the phosphorylated N-region of Raf-1 and inhibits the Raf-1-mediated
activated phosphorylation of MEK.";
Cell. Signal. 20:935-941(2008).
[38]
PHOSPHORYLATION AT SER-338 BY PAK5.
PubMed=18465753; DOI=10.1002/jcb.21809;
Wu X., Carr H.S., Dan I., Ruvolo P.P., Frost J.A.;
"p21 activated kinase 5 activates Raf-1 and targets it to
mitochondria.";
J. Cell. Biochem. 105:167-175(2008).
[39]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Cervix carcinoma;
PubMed=18220336; DOI=10.1021/pr0705441;
Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D.,
Yates J.R. III;
"Combining protein-based IMAC, peptide-based IMAC, and MudPIT for
efficient phosphoproteomic analysis.";
J. Proteome Res. 7:1346-1351(2008).
[40]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Cervix carcinoma;
PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
Greff Z., Keri G., Stemmann O., Mann M.;
"Kinase-selective enrichment enables quantitative phosphoproteomics of
the kinome across the cell cycle.";
Mol. Cell 31:438-448(2008).
[41]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-642, AND IDENTIFICATION
BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Cervix carcinoma;
PubMed=18669648; DOI=10.1073/pnas.0805139105;
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
Elledge S.J., Gygi S.P.;
"A quantitative atlas of mitotic phosphorylation.";
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
[42]
SUBCELLULAR LOCATION.
PubMed=19298812; DOI=10.1016/j.yexcr.2009.03.004;
Smith J., Bunaciu R.P., Reiterer G., Coder D., George T., Asaly M.,
Yen A.;
"Retinoic acid induces nuclear accumulation of Raf1 during
differentiation of HL-60 cells.";
Exp. Cell Res. 315:2241-2248(2009).
[43]
ENZYME REGULATION, SUBUNIT, SUBCELLULAR LOCATION, AND INTERACTION WITH
DGKH.
PubMed=19710016; DOI=10.1074/jbc.M109.043604;
Yasuda S., Kai M., Imai S., Takeishi K., Taketomi A., Toyota M.,
Kanoh H., Sakane F.;
"Diacylglycerol kinase eta augments C-Raf activity and B-Raf/C-Raf
heterodimerization.";
J. Biol. Chem. 284:29559-29570(2009).
[44]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-289 AND SER-301, AND
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Leukemic T-cell;
PubMed=19690332; DOI=10.1126/scisignal.2000007;
Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
Rodionov V., Han D.K.;
"Quantitative phosphoproteomic analysis of T cell receptor signaling
reveals system-wide modulation of protein-protein interactions.";
Sci. Signal. 2:RA46-RA46(2009).
[45]
REVIEW.
PubMed=20674547; DOI=10.1016/j.bbrc.2010.07.092;
Roskoski R. Jr.;
"RAF protein-serine/threonine kinases: structure and regulation.";
Biochem. Biophys. Res. Commun. 399:313-317(2010).
[46]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Cervix carcinoma;
PubMed=20068231; DOI=10.1126/scisignal.2000475;
Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
Mann M.;
"Quantitative phosphoproteomics reveals widespread full
phosphorylation site occupancy during mitosis.";
Sci. Signal. 3:RA3-RA3(2010).
[47]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=21269460; DOI=10.1186/1752-0509-5-17;
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
"Initial characterization of the human central proteome.";
BMC Syst. Biol. 5:17-17(2011).
[48]
REVIEW.
PubMed=21779496; DOI=10.1177/1947601911407323;
Matallanas D., Birtwistle M., Romano D., Zebisch A., Rauch J.,
von Kriegsheim A., Kolch W.;
"Raf family kinases: old dogs have learned new tricks.";
Genes Cancer 2:232-260(2011).
[49]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=21406692; DOI=10.1126/scisignal.2001570;
Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
Blagoev B.;
"System-wide temporal characterization of the proteome and
phosphoproteome of human embryonic stem cell differentiation.";
Sci. Signal. 4:RS3-RS3(2011).
[50]
INTERACTION WITH FAM83B.
PubMed=22886302; DOI=10.1172/JCI60517;
Cipriano R., Graham J., Miskimen K.L., Bryson B.L., Bruntz R.C.,
Scott S.A., Brown H.A., Stark G.R., Jackson M.W.;
"FAM83B mediates EGFR- and RAS-driven oncogenic transformation.";
J. Clin. Invest. 122:3197-3210(2012).
[51]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-296; SER-301 AND
SER-642, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
ANALYSIS].
TISSUE=Cervix carcinoma, and Erythroleukemia;
PubMed=23186163; DOI=10.1021/pr300630k;
Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
Mohammed S.;
"Toward a comprehensive characterization of a human cancer cell
phosphoproteome.";
J. Proteome Res. 12:260-271(2013).
[52]
INTERACTION WITH PDE8A.
PubMed=23509299; DOI=10.1073/pnas.1303004110;
Brown K.M., Day J.P., Huston E., Zimmermann B., Hampel K.,
Christian F., Romano D., Terhzaz S., Lee L.C., Willis M.J.,
Morton D.B., Beavo J.A., Shimizu-Albergine M., Davies S.A., Kolch W.,
Houslay M.D., Baillie G.S.;
"Phosphodiesterase-8A binds to and regulates Raf-1 kinase.";
Proc. Natl. Acad. Sci. U.S.A. 110:E1533-E1542(2013).
[53]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Liver;
PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D.,
Wang L., Ye M., Zou H.;
"An enzyme assisted RP-RPLC approach for in-depth analysis of human
liver phosphoproteome.";
J. Proteomics 96:253-262(2014).
[54]
X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 51-131.
PubMed=7791872; DOI=10.1038/375554a0;
Nassar N., Horn G., Herrmann C., Scherer A., McCormick F.,
Wittinghofer A.;
"The 2.2 A crystal structure of the Ras-binding domain of the
serine/threonine kinase c-Raf1 in complex with Rap1A and a GTP
analogue.";
Nature 375:554-560(1995).
[55]
X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 56-131.
PubMed=8756332; DOI=10.1038/nsb0896-723;
Nassar N., Horn G., Herrmann C., Block C., Janknecht R.,
Wittinghofer A.;
"Ras/Rap effector specificity determined by charge reversal.";
Nat. Struct. Biol. 3:723-729(1996).
[56]
STRUCTURE BY NMR OF 55-132.
PubMed=7766599; DOI=10.1021/bi00021a001;
Emerson S.D., Madison V.S., Palermo R.E., Waugh D.S., Scheffler J.E.,
Tsao K.L., Kiefer S.E., Liu S.P., Fry D.C.;
"Solution structure of the Ras-binding domain of c-Raf-1 and
identification of its Ras interaction surface.";
Biochemistry 34:6911-6918(1995).
[57]
STRUCTURE BY NMR OF 136-187.
PubMed=8710867; DOI=10.1073/pnas.93.16.8312;
Mott H.R., Carpenter J.W., Zhong S., Ghosh S., Bell R.M.,
Campbell S.L.;
"The solution structure of the Raf-1 cysteine-rich domain: a novel ras
and phospholipid binding site.";
Proc. Natl. Acad. Sci. U.S.A. 93:8312-8317(1996).
[58]
VARIANTS NS5 SER-256; PHE-259; ARG-260; LEU-261; SER-261; ASN-486;
GLY-486; ILE-491; ARG-491 AND THR-612, VARIANT HYPERTROPHIC
CARDIOMYOPATHY ILE-260, VARIANTS LPRD2 LEU-257 AND VAL-613, VARIANT
NS5 LEU-257, CHARACTERIZATION OF VARIANTS NS5 SER-261; ASN-486 AND
ILE-491, AND CHARACTERIZATION OF VARIANT LPRD2 VAL-613.
PubMed=17603483; DOI=10.1038/ng2073;
Pandit B., Sarkozy A., Pennacchio L.A., Carta C., Oishi K.,
Martinelli S., Pogna E.A., Schackwitz W., Ustaszewska A.,
Landstrom A., Bos J.M., Ommen S.R., Esposito G., Lepri F., Faul C.,
Mundel P., Lopez Siguero J.P., Tenconi R., Selicorni A., Rossi C.,
Mazzanti L., Torrente I., Marino B., Digilio M.C., Zampino G.,
Ackerman M.J., Dallapiccola B., Tartaglia M., Gelb B.D.;
"Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes
with hypertrophic cardiomyopathy.";
Nat. Genet. 39:1007-1012(2007).
[59]
VARIANTS NS5 LEU-257; ALA-261; SER-261; ALA-263 AND VAL-613, AND
CHARACTERIZATION OF VARIANTS NS5 LEU-257; ALA-261; SER-261; ALA-263
AND VAL-613.
PubMed=17603482; DOI=10.1038/ng2078;
Razzaque M.A., Nishizawa T., Komoike Y., Yagi H., Furutani M., Amo R.,
Kamisago M., Momma K., Katayama H., Nakagawa M., Fujiwara Y.,
Matsushima M., Mizuno K., Tokuyama M., Hirota H., Muneuchi J.,
Higashinakagawa T., Matsuoka R.;
"Germline gain-of-function mutations in RAF1 cause Noonan syndrome.";
Nat. Genet. 39:1013-1017(2007).
[60]
VARIANTS [LARGE SCALE ANALYSIS] ALA-259 AND HIS-335.
PubMed=17344846; DOI=10.1038/nature05610;
Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
"Patterns of somatic mutation in human cancer genomes.";
Nature 446:153-158(2007).
[61]
VARIANT NS5 SER-261.
PubMed=20683980; DOI=10.1002/ajmg.a.33564;
Longoni M., Moncini S., Cisternino M., Morella I.M., Ferraiuolo S.,
Russo S., Mannarino S., Brazzelli V., Coi P., Zippel R., Venturin M.,
Riva P.;
"Noonan syndrome associated with both a new Jnk-activating familial
SOS1 and a de novo RAF1 mutations.";
Am. J. Med. Genet. A 152:2176-2184(2010).
[62]
INVOLVEMENT IN CMD1NN, VARIANTS CMD1NN THR-237; ALA-310; ALA-332;
PRO-603; ARG-626 AND MET-641, AND CHARACTERIZATION OF VARIANTS CMD1NN
THR-237; ALA-310; ALA-332; PRO-603; ARG-626 AND MET-641.
PubMed=24777450; DOI=10.1038/ng.2963;
Dhandapany P.S., Razzaque M.A., Muthusami U., Kunnoth S.,
Edwards J.J., Mulero-Navarro S., Riess I., Pardo S., Sheng J.,
Rani D.S., Rani B., Govindaraj P., Flex E., Yokota T., Furutani M.,
Nishizawa T., Nakanishi T., Robbins J., Limongelli G., Hajjar R.J.,
Lebeche D., Bahl A., Khullar M., Rathinavel A., Sadler K.C.,
Tartaglia M., Matsuoka R., Thangaraj K., Gelb B.D.;
"RAF1 mutations in childhood-onset dilated cardiomyopathy.";
Nat. Genet. 46:635-639(2014).
-!- FUNCTION: Serine/threonine-protein kinase that acts as a
regulatory link between the membrane-associated Ras GTPases and
the MAPK/ERK cascade, and this critical regulatory link functions
as a switch determining cell fate decisions including
proliferation, differentiation, apoptosis, survival and oncogenic
transformation. RAF1 activation initiates a mitogen-activated
protein kinase (MAPK) cascade that comprises a sequential
phosphorylation of the dual-specific MAPK kinases (MAP2K1/MEK1 and
MAP2K2/MEK2) and the extracellular signal-regulated kinases
(MAPK3/ERK1 and MAPK1/ERK2). The phosphorylated form of RAF1 (on
residues Ser-338 and Ser-339, by PAK1) phosphorylates BAD/Bcl2-
antagonist of cell death at 'Ser-75'. Phosphorylates adenylyl
cyclases: ADCY2, ADCY5 and ADCY6, resulting in their activation.
Phosphorylates PPP1R12A resulting in inhibition of the phosphatase
activity. Phosphorylates TNNT2/cardiac muscle troponin T. Can
promote NF-kB activation and inhibit signal transducers involved
in motility (ROCK2), apoptosis (MAP3K5/ASK1 and STK3/MST2),
proliferation and angiogenesis (RB1). Can protect cells from
apoptosis also by translocating to the mitochondria where it binds
BCL2 and displaces BAD/Bcl2-antagonist of cell death. Regulates
Rho signaling and migration, and is required for normal wound
healing. Plays a role in the oncogenic transformation of
epithelial cells via repression of the TJ protein, occludin (OCLN)
by inducing the up-regulation of a transcriptional repressor
SNAI2/SLUG, which induces down-regulation of OCLN. Restricts
caspase activation in response to selected stimuli, notably Fas
stimulation, pathogen-mediated macrophage apoptosis, and erythroid
differentiation. {ECO:0000269|PubMed:11427728,
ECO:0000269|PubMed:11719507, ECO:0000269|PubMed:15385642,
ECO:0000269|PubMed:15618521, ECO:0000269|PubMed:15849194,
ECO:0000269|PubMed:16892053, ECO:0000269|PubMed:16924233,
ECO:0000269|PubMed:9360956}.
-!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
-!- COFACTOR:
Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
Note=Binds 2 Zn(2+) ions per subunit.;
-!- ENZYME REGULATION: Regulation is a highly complex process
involving membrane recruitment, protein-protein interactions,
dimerization, and phosphorylation/dephosphorylation events. Ras-
GTP recruits RAF1 to the membrane, thereby promoting its
activation. The inactive conformation of RAF1 is maintained by
autoinhibitory interactions occurring between the N-terminal
regulatory and the C-terminal catalytic domains and by the binding
of a 14-3-3 protein that contacts two phosphorylation sites, Ser-
259 and Ser-621. Upon mitogenic stimulation, Ras and PPP2R1A
cooperate to release autoinhibition and the subsequent
phosphorylation of activating sites: Ser-338, Tyr-341, Thr-491,
and Ser-494, yields a fully active kinase. Through a negative
feedback mechanism involving MAPK1/ERK2, RAF1 is phosphorylated on
Ser-29, Ser-43, Ser-289, Ser-296, Ser-301 and Ser-642 by
MAPK1/ERK2, which yields an inactive, desensitized kinase. The
signaling-competent conformation of RAF1 is finally re-established
by the coordinated action of PIN1, a prolyl isomerase that
converts pSer and pThr residues from the cis to the trans
conformation, which is preferentially recognized and
dephosphorylated by PPP2R1A. Activated by homodimerization and
heterodimerization (with BRAF). Also regulated through association
with other proteins such as KSR2, CNKSR1/CNK1, PEBP1/RKIP,
PHB/prohibitin and SPRY4. PEBP1/RKIP acts by dissociating RAF1
from its substrates MAP2K1/MEK1 and MAP2K2/MEK2. PHB/prohibitin
facilitates the displacement of 14-3-3 from RAF1 by activated Ras,
thereby promoting cell membrane localization and phosphorylation
of RAF1 at the activating Ser-338. SPRY4 inhibits Ras-independent,
but not Ras-dependent, activation of RAF1. CNKSR1/CNK1 regulates
Src-mediated RAF1 activation. {ECO:0000269|PubMed:10576742,
ECO:0000269|PubMed:10801873, ECO:0000269|PubMed:11447113,
ECO:0000269|PubMed:11733498, ECO:0000269|PubMed:12717443,
ECO:0000269|PubMed:16892053, ECO:0000269|PubMed:18294816,
ECO:0000269|PubMed:19710016}.
-!- SUBUNIT: Monomer. Homodimer. Heterodimerizes with BRAF and this
heterodimer possesses a highly increased kinase activity compared
to the respective homodimers or monomers (PubMed:16508002).
Heterodimerization is mitogen-regulated and enhanced by 14-3-3
proteins (PubMed:16508002). MAPK1/ERK2 activation can induce a
negative feedback that promotes the dissociation of the
heterodimer (PubMed:16508002). Forms a multiprotein complex with
Ras (M-Ras/MRAS), SHOC2 and protein phosphatase 1 (PPP1CA, PPP1CB
and PPP1CC) (PubMed:16630891). Interacts with Ras proteins; the
interaction is antagonized by RIN1 (PubMed:11784866). Weakly
interacts with RIT1. Interacts (via N-terminus) with RGS14 (via
RBD domains); the interaction mediates the formation of a ternary
complex with BRAF, a ternary complex inhibited by GNAI1 (By
similarity). Interacts with STK3/MST2; the interaction inhibits
its pro-apoptotic activity (PubMed:15618521). Interacts (when
phosphorylated at Ser-259) with YWHAZ (unphosphorylated at 'Thr-
232') (PubMed:9360956). Interacts with MAP2K1/MEK1 and MAP2K2/MEK2
(By similarity). Interacts with MAP3K5/ASF1 (via N-terminus) and
this interaction inhibits the proapoptotic function of MAP3K5/ASK1
(PubMed:11427728). Interacts with PAK1 (via kinase domain)
(PubMed:11733498). The phosphorylated form interacts with PIN1 (By
similarity). The Ser-338 and Ser-339 phosphorylated form (by PAK1)
interacts with BCL2 (PubMed:15849194). Interacts with PEBP1/RKIP
and this interaction is enhanced if RAF1 is phosphorylated on
residues Ser-338, Ser-339, Tyr-340 and Tyr-341 (PubMed:18294816).
Interacts with ADCY2, ADCY5, ADCY6, DGKH, RCAN1/DSCR1, PPP1R12A,
PKB/AKT1, PPP2CA, PPP2R1B, SPRY2, SPRY4, CNKSR1/CNK1, KSR2 and
PHB/prohibitin (PubMed:10801873, PubMed:11719507, PubMed:12717443,
PubMed:15385642, PubMed:15935327, PubMed:19710016,
PubMed:10576742). Interacts with ROCK2 (By similarity). In its
active form, interacts with PRMT5 (PubMed:21917714). Interacts
with FAM83B; displaces 14-3-3 proteins from RAF1 and activates
RAF1 (PubMed:22886302). Interacts with PDE8A; the interaction
promotes RAF1 activity (PubMed:23509299).
{ECO:0000250|UniProtKB:P11345, ECO:0000250|UniProtKB:Q99N57,
ECO:0000269|PubMed:10576742, ECO:0000269|PubMed:10801873,
ECO:0000269|PubMed:11427728, ECO:0000269|PubMed:11719507,
ECO:0000269|PubMed:11733498, ECO:0000269|PubMed:11784866,
ECO:0000269|PubMed:12717443, ECO:0000269|PubMed:15385642,
ECO:0000269|PubMed:15618521, ECO:0000269|PubMed:15849194,
ECO:0000269|PubMed:15935327, ECO:0000269|PubMed:16508002,
ECO:0000269|PubMed:16630891, ECO:0000269|PubMed:18294816,
ECO:0000269|PubMed:19710016, ECO:0000269|PubMed:21917714,
ECO:0000269|PubMed:22886302, ECO:0000269|PubMed:23509299,
ECO:0000269|PubMed:9360956}.
-!- INTERACTION:
Self; NbExp=6; IntAct=EBI-365996, EBI-365996;
P31749:AKT1; NbExp=2; IntAct=EBI-365996, EBI-296087;
Q92934:BAD; NbExp=2; IntAct=EBI-365996, EBI-700771;
P15056:BRAF; NbExp=55; IntAct=EBI-365996, EBI-365980;
P49368:CCT3; NbExp=3; IntAct=EBI-365996, EBI-356673;
P30304:CDC25A; NbExp=4; IntAct=EBI-365996, EBI-747671;
Q16543:CDC37; NbExp=4; IntAct=EBI-365996, EBI-295634;
P31327:CPS1; NbExp=4; IntAct=EBI-365996, EBI-536811;
P01112:HRAS; NbExp=22; IntAct=EBI-365996, EBI-350145;
P08238:HSP90AB1; NbExp=3; IntAct=EBI-365996, EBI-352572;
P11021:HSPA5; NbExp=4; IntAct=EBI-365996, EBI-354921;
P01116-2:KRAS; NbExp=3; IntAct=EBI-365996, EBI-367427;
P32883:Kras (xeno); NbExp=2; IntAct=EBI-365996, EBI-644267;
P28301:Lox (xeno); NbExp=2; IntAct=EBI-365996, EBI-642911;
Q02750:MAP2K1; NbExp=35; IntAct=EBI-365996, EBI-492564;
P36507:MAP2K2; NbExp=3; IntAct=EBI-365996, EBI-1056930;
Q9ESN9-2:Mapk8ip3 (xeno); NbExp=2; IntAct=EBI-365996, EBI-9549291;
Q12968:NFATC3; NbExp=2; IntAct=EBI-365996, EBI-5278441;
P01111:NRAS; NbExp=3; IntAct=EBI-365996, EBI-721993;
P03495:NS (xeno); NbExp=2; IntAct=EBI-365996, EBI-2548993;
O39474:NS5A (xeno); NbExp=4; IntAct=EBI-365996, EBI-7016711;
O43482:OIP5; NbExp=4; IntAct=EBI-365996, EBI-536879;
Q13177:PAK2; NbExp=2; IntAct=EBI-365996, EBI-1045887;
Q6TCH7:PAQR3; NbExp=3; IntAct=EBI-365996, EBI-15654365;
P09619:PDGFRB; NbExp=2; IntAct=EBI-365996, EBI-641237;
P30086:PEBP1; NbExp=10; IntAct=EBI-365996, EBI-716384;
Q96S96:PEBP4; NbExp=4; IntAct=EBI-365996, EBI-8563667;
P14618:PKM; NbExp=3; IntAct=EBI-365996, EBI-353408;
P62834:RAP1A; NbExp=2; IntAct=EBI-365996, EBI-491414;
P01120:RAS2 (xeno); NbExp=2; IntAct=EBI-365996, EBI-14838;
P06400:RB1; NbExp=3; IntAct=EBI-365996, EBI-491274;
P53805-2:RCAN1; NbExp=4; IntAct=EBI-365996, EBI-1541912;
P31947:SFN; NbExp=3; IntAct=EBI-365996, EBI-476295;
Q13188:STK3; NbExp=6; IntAct=EBI-365996, EBI-992580;
Q3ZCQ8:TIMM50; NbExp=4; IntAct=EBI-365996, EBI-355175;
P31946:YWHAB; NbExp=18; IntAct=EBI-365996, EBI-359815;
P62258:YWHAE; NbExp=3; IntAct=EBI-365996, EBI-356498;
Q04917:YWHAH; NbExp=6; IntAct=EBI-365996, EBI-306940;
P27348:YWHAQ; NbExp=3; IntAct=EBI-365996, EBI-359854;
P63104:YWHAZ; NbExp=13; IntAct=EBI-365996, EBI-347088;
-!- SUBCELLULAR LOCATION: Cytoplasm. Cell membrane. Mitochondrion.
Nucleus. Note=Colocalizes with RGS14 and BRAF in both the
cytoplasm and membranes. Phosphorylation at Ser-259 impairs its
membrane accumulation. Recruited to the cell membrane by the
active Ras protein. Phosphorylation at Ser-338 and Ser-339 by PAK1
is required for its mitochondrial localization. Retinoic acid-
induced Ser-621 phosphorylated form of RAF1 is predominantly
localized at the nucleus.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=2;
Name=1; Synonyms=6C;
IsoId=P04049-1; Sequence=Displayed;
Name=2; Synonyms=1A;
IsoId=P04049-2; Sequence=VSP_034649;
-!- TISSUE SPECIFICITY: In skeletal muscle, isoform 1 is more abundant
than isoform 2. {ECO:0000269|PubMed:1886707}.
-!- PTM: Phosphorylation at Thr-269, Ser-338, Tyr-341, Thr-491 and
Ser-494 results in its activation. Phosphorylation at Ser-29, Ser-
43, Ser-289, Ser-296, Ser-301 and Ser-642 by MAPK1/ERK2 results in
its inactivation. Phosphorylation at Ser-259 induces the
interaction with YWHAZ and inactivates kinase activity.
Dephosphorylation of Ser-259 by the complex containing protein
phosphatase 1, SHOC2 and M-Ras/MRAS relieves inactivation, leading
to stimulate RAF1 activity. Phosphorylation at Ser-338 by PAK1 and
PAK5 and Ser-339 by PAK1 is required for its mitochondrial
localization. Phosphorylation at Ser-621 in response to growth
factor treatment stabilizes the protein, possibly by preventing
proteasomal degradation. Phosphorylation at Ser-289, Ser-296, Ser-
301, Ser-338 and Ser-621 are somehow linked to the methylation
potential of cells. Treatment of cells with HGF in the presence of
the methylation inhibitor 5'-methylthioadenosine (MTA) results in
increased phosphorylation at Ser-338 and Ser-621 and decreased
phosphorylation at Ser-296, Ser-301 and Ser-338. Dephosphorylation
at Ser-338 by PPP5C results in a activity decrease.
{ECO:0000269|PubMed:10576742, ECO:0000269|PubMed:10801873,
ECO:0000269|PubMed:11447113, ECO:0000269|PubMed:11733498,
ECO:0000269|PubMed:11756411, ECO:0000269|PubMed:15047712,
ECO:0000269|PubMed:15849194, ECO:0000269|PubMed:16093354,
ECO:0000269|PubMed:16630891, ECO:0000269|PubMed:16892053,
ECO:0000269|PubMed:18465753, ECO:0000269|PubMed:21917714,
ECO:0000269|PubMed:7477354, ECO:0000269|PubMed:8349614,
ECO:0000269|PubMed:9823899}.
-!- PTM: Methylated at Arg-563 in response to EGF treatment. This
modification leads to destabilization of the protein, possibly
through proteasomal degradation. {ECO:0000269|PubMed:21917714}.
-!- DISEASE: Noonan syndrome 5 (NS5) [MIM:611553]: A form of Noonan
syndrome, a disease characterized by short stature, facial
dysmorphic features such as hypertelorism, a downward eyeslant and
low-set posteriorly rotated ears, and a high incidence of
congenital heart defects and hypertrophic cardiomyopathy. Other
features can include a short neck with webbing or redundancy of
skin, deafness, motor delay, variable intellectual deficits,
multiple skeletal defects, cryptorchidism, and bleeding diathesis.
Individuals with Noonan syndrome are at risk of juvenile
myelomonocytic leukemia, a myeloproliferative disorder
characterized by excessive production of myelomonocytic cells.
{ECO:0000269|PubMed:17603482, ECO:0000269|PubMed:17603483,
ECO:0000269|PubMed:20683980}. Note=The disease is caused by
mutations affecting the gene represented in this entry.
-!- DISEASE: LEOPARD syndrome 2 (LPRD2) [MIM:611554]: A disorder
characterized by lentigines, electrocardiographic conduction
abnormalities, ocular hypertelorism, pulmonic stenosis,
abnormalities of genitalia, retardation of growth, and
sensorineural deafness. {ECO:0000269|PubMed:17603483}. Note=The
disease is caused by mutations affecting the gene represented in
this entry.
-!- DISEASE: Cardiomyopathy, dilated 1NN (CMD1NN) [MIM:615916]: A
disorder characterized by ventricular dilation and impaired
systolic function, resulting in congestive heart failure and
arrhythmia. Patients are at risk of premature death.
{ECO:0000269|PubMed:24777450}. Note=The disease is caused by
mutations affecting the gene represented in this entry.
-!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr
protein kinase family. RAF subfamily. {ECO:0000305}.
-!- WEB RESOURCE: Name=NIEHS-SNPs;
URL="http://egp.gs.washington.edu/data/raf1/";
-!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
and Haematology;
URL="http://atlasgeneticsoncology.org/Genes/RAF1ID42032ch3p25.html";
-----------------------------------------------------------------------
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EMBL; X03484; CAA27204.1; -; mRNA.
EMBL; AY271661; AAP03432.1; -; Genomic_DNA.
EMBL; AK312248; BAG35180.1; -; mRNA.
EMBL; EU332868; ABY87557.1; -; Genomic_DNA.
EMBL; CH471055; EAW64134.1; -; Genomic_DNA.
EMBL; BC018119; AAH18119.1; -; mRNA.
EMBL; L00212; AAA60247.1; -; Genomic_DNA.
EMBL; L00206; AAA60247.1; JOINED; Genomic_DNA.
EMBL; L00207; AAA60247.1; JOINED; Genomic_DNA.
EMBL; L00208; AAA60247.1; JOINED; Genomic_DNA.
EMBL; L00209; AAA60247.1; JOINED; Genomic_DNA.
EMBL; L00210; AAA60247.1; JOINED; Genomic_DNA.
EMBL; L00211; AAA60247.1; JOINED; Genomic_DNA.
EMBL; L00213; AAA60247.1; JOINED; Genomic_DNA.
EMBL; M11376; AAA60247.1; JOINED; Genomic_DNA.
EMBL; X54851; -; NOT_ANNOTATED_CDS; Genomic_DNA.
CCDS; CCDS2612.1; -. [P04049-1]
PIR; A00637; TVHUF6.
PIR; S60341; S60341.
RefSeq; NP_002871.1; NM_002880.3. [P04049-1]
RefSeq; XP_005265412.1; XM_005265355.2. [P04049-1]
RefSeq; XP_011532276.1; XM_011533974.2. [P04049-1]
UniGene; Hs.159130; -.
PDB; 1C1Y; X-ray; 1.90 A; B=55-131.
PDB; 1FAQ; NMR; -; A=136-187.
PDB; 1FAR; NMR; -; A=136-187.
PDB; 1GUA; X-ray; 2.00 A; B=51-131.
PDB; 1RFA; NMR; -; A=55-132.
PDB; 3CU8; X-ray; 2.40 A; P/Q=256-264.
PDB; 3IQJ; X-ray; 1.15 A; P=255-264.
PDB; 3IQU; X-ray; 1.05 A; P=255-260.
PDB; 3IQV; X-ray; 1.20 A; P=255-260.
PDB; 3KUC; X-ray; 1.92 A; B=51-131.
PDB; 3KUD; X-ray; 2.15 A; B=51-131.
PDB; 3NKX; X-ray; 2.40 A; P/Q=255-264.
PDB; 3O8I; X-ray; 2.00 A; B=255-264.
PDB; 3OMV; X-ray; 4.00 A; A/B=323-618.
PDB; 4FJ3; X-ray; 1.95 A; P=229-264.
PDB; 4G0N; X-ray; 2.45 A; B=54-131.
PDB; 4G3X; X-ray; 3.25 A; B=55-131.
PDB; 4IEA; X-ray; 1.70 A; P=618-625.
PDB; 4IHL; X-ray; 2.20 A; P=229-264.
PDBsum; 1C1Y; -.
PDBsum; 1FAQ; -.
PDBsum; 1FAR; -.
PDBsum; 1GUA; -.
PDBsum; 1RFA; -.
PDBsum; 3CU8; -.
PDBsum; 3IQJ; -.
PDBsum; 3IQU; -.
PDBsum; 3IQV; -.
PDBsum; 3KUC; -.
PDBsum; 3KUD; -.
PDBsum; 3NKX; -.
PDBsum; 3O8I; -.
PDBsum; 3OMV; -.
PDBsum; 4FJ3; -.
PDBsum; 4G0N; -.
PDBsum; 4G3X; -.
PDBsum; 4IEA; -.
PDBsum; 4IHL; -.
DisProt; DP00171; -.
ProteinModelPortal; P04049; -.
SMR; P04049; -.
BioGrid; 111831; 174.
CORUM; P04049; -.
DIP; DIP-1048N; -.
IntAct; P04049; 120.
MINT; MINT-86694; -.
STRING; 9606.ENSP00000251849; -.
BindingDB; P04049; -.
ChEMBL; CHEMBL1906; -.
DrugBank; DB08912; Dabrafenib.
DrugBank; DB05268; iCo-007.
DrugBank; DB04973; LErafAON.
DrugBank; DB08896; Regorafenib.
DrugBank; DB00398; Sorafenib.
DrugBank; DB05190; XL281.
GuidetoPHARMACOLOGY; 2184; -.
iPTMnet; P04049; -.
PhosphoSitePlus; P04049; -.
BioMuta; RAF1; -.
DMDM; 125651; -.
EPD; P04049; -.
MaxQB; P04049; -.
PaxDb; P04049; -.
PeptideAtlas; P04049; -.
PRIDE; P04049; -.
DNASU; 5894; -.
Ensembl; ENST00000251849; ENSP00000251849; ENSG00000132155. [P04049-1]
Ensembl; ENST00000442415; ENSP00000401888; ENSG00000132155. [P04049-2]
GeneID; 5894; -.
KEGG; hsa:5894; -.
UCSC; uc003bxf.5; human. [P04049-1]
CTD; 5894; -.
DisGeNET; 5894; -.
EuPathDB; HostDB:ENSG00000132155.11; -.
GeneCards; RAF1; -.
GeneReviews; RAF1; -.
HGNC; HGNC:9829; RAF1.
HPA; CAB019291; -.
HPA; HPA002640; -.
MalaCards; RAF1; -.
MIM; 164760; gene.
MIM; 611553; phenotype.
MIM; 611554; phenotype.
MIM; 615916; phenotype.
neXtProt; NX_P04049; -.
OpenTargets; ENSG00000132155; -.
Orphanet; 154; Familial isolated dilated cardiomyopathy.
Orphanet; 500; LEOPARD syndrome.
Orphanet; 648; Noonan syndrome.
Orphanet; 251612; Pilocytic astrocytoma.
PharmGKB; PA34183; -.
eggNOG; KOG0193; Eukaryota.
eggNOG; ENOG410Y4UP; LUCA.
GeneTree; ENSGT00900000140880; -.
HOGENOM; HOG000252972; -.
HOVERGEN; HBG001886; -.
InParanoid; P04049; -.
KO; K04366; -.
OMA; HQFIRKT; -.
OrthoDB; EOG091G09SB; -.
PhylomeDB; P04049; -.
TreeFam; TF317006; -.
BRENDA; 2.7.10.2; 2681.
Reactome; R-HSA-2672351; Stimuli-sensing channels.
Reactome; R-HSA-392517; Rap1 signalling.
Reactome; R-HSA-430116; GP1b-IX-V activation signalling.
Reactome; R-HSA-442742; CREB phosphorylation through the activation of Ras.
Reactome; R-HSA-5621575; CD209 (DC-SIGN) signaling.
Reactome; R-HSA-5673000; RAF activation.
Reactome; R-HSA-5674135; MAP2K and MAPK activation.
Reactome; R-HSA-5674499; Negative feedback regulation of MAPK pathway.
Reactome; R-HSA-5675221; Negative regulation of MAPK pathway.
Reactome; R-HSA-6802946; Signaling by moderate kinase activity BRAF mutants.
Reactome; R-HSA-6802948; Signaling by high-kinase activity BRAF mutants.
Reactome; R-HSA-6802949; Signaling by RAS mutants.
Reactome; R-HSA-6802952; Signaling by BRAF and RAF fusions.
Reactome; R-HSA-6802955; Paradoxical activation of RAF signaling by kinase inactive BRAF.
SignaLink; P04049; -.
SIGNOR; P04049; -.
ChiTaRS; RAF1; human.
EvolutionaryTrace; P04049; -.
GeneWiki; C-Raf; -.
GenomeRNAi; 5894; -.
PMAP-CutDB; P04049; -.
PRO; PR:P04049; -.
Proteomes; UP000005640; Chromosome 3.
Bgee; ENSG00000132155; -.
CleanEx; HS_RAF1; -.
ExpressionAtlas; P04049; baseline and differential.
Genevisible; P04049; HS.
GO; GO:0005737; C:cytoplasm; IDA:MGI.
GO; GO:0005829; C:cytosol; IDA:UniProtKB.
GO; GO:0005794; C:Golgi apparatus; IPI:MGI.
GO; GO:0005741; C:mitochondrial outer membrane; TAS:ProtInc.
GO; GO:0016607; C:nuclear speck; IDA:HPA.
GO; GO:0005886; C:plasma membrane; IDA:MGI.
GO; GO:0031143; C:pseudopodium; IEA:Ensembl.
GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
GO; GO:0019899; F:enzyme binding; IPI:UniProtKB.
GO; GO:0042802; F:identical protein binding; IPI:IntAct.
GO; GO:0016301; F:kinase activity; TAS:Reactome.
GO; GO:0004709; F:MAP kinase kinase kinase activity; IBA:GO_Central.
GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
GO; GO:0031434; F:mitogen-activated protein kinase kinase binding; IBA:GO_Central.
GO; GO:0046982; F:protein heterodimerization activity; IEA:Ensembl.
GO; GO:0004672; F:protein kinase activity; TAS:ProtInc.
GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
GO; GO:0007190; P:activation of adenylate cyclase activity; NAS:BHF-UCL.
GO; GO:0000186; P:activation of MAPKK activity; IDA:AgBase.
GO; GO:0006915; P:apoptotic process; TAS:ProtInc.
GO; GO:0030154; P:cell differentiation; IEA:Ensembl.
GO; GO:0008283; P:cell proliferation; TAS:ProtInc.
GO; GO:0071550; P:death-inducing signaling complex assembly; IEA:Ensembl.
GO; GO:0060324; P:face development; IEA:Ensembl.
GO; GO:0007507; P:heart development; IEA:Ensembl.
GO; GO:0035773; P:insulin secretion involved in cellular response to glucose stimulus; IEA:Ensembl.
GO; GO:0045104; P:intermediate filament cytoskeleton organization; IEA:Ensembl.
GO; GO:0034220; P:ion transmembrane transport; TAS:Reactome.
GO; GO:0000165; P:MAPK cascade; TAS:Reactome.
GO; GO:0007275; P:multicellular organism development; IBA:GO_Central.
GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB.
GO; GO:0008285; P:negative regulation of cell proliferation; IDA:BHF-UCL.
GO; GO:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; TAS:UniProtKB.
GO; GO:1902042; P:negative regulation of extrinsic apoptotic signaling pathway via death domain receptors; IEA:Ensembl.
GO; GO:0031333; P:negative regulation of protein complex assembly; IDA:UniProtKB.
GO; GO:0009968; P:negative regulation of signal transduction; IBA:GO_Central.
GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; IEA:Ensembl.
GO; GO:0030168; P:platelet activation; TAS:Reactome.
GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IBA:GO_Central.
GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; IDA:UniProtKB.
GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IEA:Ensembl.
GO; GO:0006468; P:protein phosphorylation; TAS:ProtInc.
GO; GO:0042981; P:regulation of apoptotic process; TAS:UniProtKB.
GO; GO:0045595; P:regulation of cell differentiation; TAS:UniProtKB.
GO; GO:2000145; P:regulation of cell motility; TAS:UniProtKB.
GO; GO:0035023; P:regulation of Rho protein signal transduction; TAS:UniProtKB.
GO; GO:0001666; P:response to hypoxia; IEA:Ensembl.
GO; GO:0035994; P:response to muscle stretch; IEA:Ensembl.
GO; GO:0007165; P:signal transduction; TAS:ProtInc.
GO; GO:0035019; P:somatic stem cell population maintenance; IEA:Ensembl.
GO; GO:0002223; P:stimulatory C-type lectin receptor signaling pathway; TAS:Reactome.
GO; GO:0048538; P:thymus development; IEA:Ensembl.
GO; GO:0030878; P:thyroid gland development; IEA:Ensembl.
GO; GO:0042060; P:wound healing; TAS:UniProtKB.
CDD; cd00029; C1; 1.
InterPro; IPR020454; DAG/PE-bd.
InterPro; IPR011009; Kinase-like_dom_sf.
InterPro; IPR002219; PE/DAG-bd.
InterPro; IPR000719; Prot_kinase_dom.
InterPro; IPR017441; Protein_kinase_ATP_BS.
InterPro; IPR003116; RBD_dom.
InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
InterPro; IPR008271; Ser/Thr_kinase_AS.
InterPro; IPR029071; Ubiquitin-like_domsf.
Pfam; PF00130; C1_1; 1.
Pfam; PF07714; Pkinase_Tyr; 1.
Pfam; PF02196; RBD; 1.
PRINTS; PR00008; DAGPEDOMAIN.
SMART; SM00109; C1; 1.
SMART; SM00455; RBD; 1.
SMART; SM00220; S_TKc; 1.
SUPFAM; SSF54236; SSF54236; 1.
SUPFAM; SSF56112; SSF56112; 1.
PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PROSITE; PS50898; RBD; 1.
PROSITE; PS00479; ZF_DAG_PE_1; 1.
PROSITE; PS50081; ZF_DAG_PE_2; 1.
1: Evidence at protein level;
3D-structure; Alternative splicing; ATP-binding; Cardiomyopathy;
Cell membrane; Complete proteome; Cytoplasm; Deafness;
Direct protein sequencing; Disease mutation; Kinase; Membrane;
Metal-binding; Methylation; Mitochondrion; Nucleotide-binding;
Nucleus; Phosphoprotein; Polymorphism; Proto-oncogene;
Reference proteome; Serine/threonine-protein kinase; Transferase;
Zinc; Zinc-finger.
CHAIN 1 648 RAF proto-oncogene serine/threonine-
protein kinase.
/FTId=PRO_0000086596.
DOMAIN 56 131 RBD. {ECO:0000255|PROSITE-
ProRule:PRU00262}.
DOMAIN 349 609 Protein kinase. {ECO:0000255|PROSITE-
ProRule:PRU00159}.
ZN_FING 138 184 Phorbol-ester/DAG-type.
{ECO:0000255|PROSITE-ProRule:PRU00226}.
NP_BIND 355 363 ATP. {ECO:0000255|PROSITE-
ProRule:PRU00159}.
REGION 331 349 Interaction with PEBP1/RKIP.
ACT_SITE 468 468 Proton acceptor.
METAL 139 139 Zinc 1.
METAL 152 152 Zinc 2.
METAL 155 155 Zinc 2.
METAL 165 165 Zinc 1.
METAL 168 168 Zinc 1.
METAL 173 173 Zinc 2.
METAL 176 176 Zinc 2.
METAL 184 184 Zinc 1.
BINDING 375 375 ATP. {ECO:0000255|PROSITE-
ProRule:PRU00159}.
MOD_RES 29 29 Phosphoserine; by MAPK1.
{ECO:0000250|UniProtKB:Q99N57}.
MOD_RES 43 43 Phosphoserine; by PKA and MAPK1.
{ECO:0000269|PubMed:8349614}.
MOD_RES 233 233 Phosphoserine; by PKA.
{ECO:0000269|PubMed:9823899}.
MOD_RES 252 252 Phosphoserine.
{ECO:0000244|PubMed:17525332}.
MOD_RES 259 259 Phosphoserine; by PKA, PKC and PKB/AKT1.
{ECO:0000269|PubMed:10576742,
ECO:0000269|PubMed:10801873,
ECO:0000269|PubMed:11756411,
ECO:0000269|PubMed:15047712,
ECO:0000269|PubMed:16630891,
ECO:0000269|PubMed:16892053,
ECO:0000269|PubMed:8349614}.
MOD_RES 268 268 Phosphothreonine; by autocatalysis.
{ECO:0000269|PubMed:8349614}.
MOD_RES 269 269 Phosphothreonine; by PKA.
{ECO:0000269|PubMed:7477354}.
MOD_RES 289 289 Phosphoserine; by MAPK1.
{ECO:0000244|PubMed:19690332,
ECO:0000269|PubMed:21917714}.
MOD_RES 296 296 Phosphoserine.
{ECO:0000244|PubMed:23186163}.
MOD_RES 301 301 Phosphoserine; by MAPK1.
{ECO:0000244|PubMed:19690332,
ECO:0000244|PubMed:23186163,
ECO:0000269|PubMed:21917714}.
MOD_RES 338 338 Phosphoserine; by PAK1, PAK2, PAK3 and
PAK5. {ECO:0000269|PubMed:11733498,
ECO:0000269|PubMed:15849194,
ECO:0000269|PubMed:16892053,
ECO:0000269|PubMed:18465753,
ECO:0000269|PubMed:21917714}.
MOD_RES 339 339 Phosphoserine; by PAK1, PAK2 and PAK3.
{ECO:0000269|PubMed:15849194}.
MOD_RES 340 340 Phosphotyrosine; by SRC.
{ECO:0000269|PubMed:16892053}.
MOD_RES 341 341 Phosphotyrosine; by SRC.
{ECO:0000269|PubMed:16892053}.
MOD_RES 471 471 Phosphoserine.
{ECO:0000269|PubMed:16093354}.
MOD_RES 491 491 Phosphothreonine.
{ECO:0000269|PubMed:11447113}.
MOD_RES 494 494 Phosphoserine.
{ECO:0000269|PubMed:11447113}.
MOD_RES 497 497 Phosphoserine; by PKC.
{ECO:0000269|PubMed:9823899}.
MOD_RES 499 499 Phosphoserine; by PKC.
{ECO:0000269|PubMed:8349614}.
MOD_RES 563 563 Symmetric dimethylarginine; by PRMT5.
{ECO:0000269|PubMed:21917714}.
MOD_RES 621 621 Phosphoserine.
{ECO:0000269|PubMed:10801873,
ECO:0000269|PubMed:16892053,
ECO:0000269|PubMed:21917714,
ECO:0000269|PubMed:8349614}.
MOD_RES 642 642 Phosphoserine; by MAPK1.
{ECO:0000244|PubMed:18669648,
ECO:0000244|PubMed:23186163}.
VAR_SEQ 278 278 E -> ENNNLSASPRAWSRRFCLRGR (in isoform
2). {ECO:0000305}.
/FTId=VSP_034649.
VARIANT 237 237 A -> T (in CMD1NN; shows a mild increase
in kinase activity; dbSNP:rs587777588).
{ECO:0000269|PubMed:24777450}.
/FTId=VAR_071844.
VARIANT 256 256 R -> S (in NS5; dbSNP:rs397516826).
{ECO:0000269|PubMed:17603483}.
/FTId=VAR_037807.
VARIANT 257 257 S -> L (in NS5 and LPRD2; shows in vitro
greater kinase activity and enhanced ERK
activation than wild-type;
dbSNP:rs80338796).
{ECO:0000269|PubMed:17603482,
ECO:0000269|PubMed:17603483}.
/FTId=VAR_037808.
VARIANT 259 259 S -> A (in an ovarian serous carcinoma
sample; somatic mutation; increased ERK
activation).
{ECO:0000269|PubMed:16630891,
ECO:0000269|PubMed:17344846}.
/FTId=VAR_041037.
VARIANT 259 259 S -> F (in NS5).
{ECO:0000269|PubMed:17603483}.
/FTId=VAR_037809.
VARIANT 260 260 T -> I (in hypertrophic cardiomyopathy;
dbSNP:rs869025501).
{ECO:0000269|PubMed:17603483}.
/FTId=VAR_037810.
VARIANT 260 260 T -> R (in NS5).
{ECO:0000269|PubMed:17603483}.
/FTId=VAR_037811.
VARIANT 261 261 P -> A (in NS5; shows in vitro greater
kinase activity and enhanced MAPK1
activation than wild-type;
dbSNP:rs121434594).
{ECO:0000269|PubMed:17603482}.
/FTId=VAR_037812.
VARIANT 261 261 P -> L (in NS5; shows greater kinase
activity and enhanced MAPK1 activation
than wild-type; dbSNP:rs397516828).
{ECO:0000269|PubMed:17603483}.
/FTId=VAR_037813.
VARIANT 261 261 P -> S (in NS5; shows in vitro greater
kinase activity and enhanced MAPK1
activation than wild-type;
dbSNP:rs121434594).
{ECO:0000269|PubMed:17603482,
ECO:0000269|PubMed:17603483,
ECO:0000269|PubMed:20683980}.
/FTId=VAR_037814.
VARIANT 263 263 V -> A (in NS5; shows in vitro greater
kinase activity and enhanced MAPK1
activation than wild-type).
{ECO:0000269|PubMed:17603482}.
/FTId=VAR_037815.
VARIANT 308 308 P -> L (in dbSNP:rs5746220).
{ECO:0000269|PubMed:14702039,
ECO:0000269|Ref.3}.
/FTId=VAR_018840.
VARIANT 310 310 T -> A (in CMD1NN; shows a mild increase
in kinase activity; dbSNP:rs778155315).
{ECO:0000269|PubMed:24777450}.
/FTId=VAR_071845.
VARIANT 332 332 P -> A (in CMD1NN; shows a mild increase
in kinase activity).
{ECO:0000269|PubMed:24777450}.
/FTId=VAR_071846.
VARIANT 335 335 Q -> H (in a lung adenocarcinoma sample;
somatic mutation).
{ECO:0000269|PubMed:17344846}.
/FTId=VAR_041038.
VARIANT 486 486 D -> G (in NS5; dbSNP:rs397516815).
{ECO:0000269|PubMed:17603483}.
/FTId=VAR_037816.
VARIANT 486 486 D -> N (in NS5; has reduced or absent
kinase activity; dbSNP:rs80338798).
{ECO:0000269|PubMed:17603483}.
/FTId=VAR_037817.
VARIANT 491 491 T -> I (in NS5; has reduced or absent
kinase activity; dbSNP:rs80338799).
{ECO:0000269|PubMed:17603483}.
/FTId=VAR_037818.
VARIANT 491 491 T -> R (in NS5; dbSNP:rs80338799).
{ECO:0000269|PubMed:17603483}.
/FTId=VAR_037819.
VARIANT 603 603 L -> P (in CMD1NN; shows impaired kinase
activity and reduced MAPK3 activation
with this mutation; dbSNP:rs587777586).
{ECO:0000269|PubMed:24777450}.
/FTId=VAR_071847.
VARIANT 612 612 S -> T (in NS5).
{ECO:0000269|PubMed:17603483}.
/FTId=VAR_037820.
VARIANT 613 613 L -> V (in NS5 and LPRD2; shows in vitro
greater kinase activity and enhanced
MAPK1 activation than wild-type;
dbSNP:rs80338797).
{ECO:0000269|PubMed:17603482,
ECO:0000269|PubMed:17603483}.
/FTId=VAR_037821.
VARIANT 626 626 H -> R (in CMD1NN; shows a mild increase
in kinase activity).
{ECO:0000269|PubMed:24777450}.
/FTId=VAR_071848.
VARIANT 641 641 T -> M (in CMD1NN; shows a mild increase
in kinase activity; dbSNP:rs587777587).
{ECO:0000269|PubMed:24777450}.
/FTId=VAR_071849.
MUTAGEN 338 339 SS->AA: Reduced kinase activity; when
associated with 340-D-D-341.
{ECO:0000269|PubMed:16892053}.
MUTAGEN 338 339 SS->DE: Non-inhibited by PPP5C.
Constitutively active and non-inhibited
by PPP5C; when associated with 340-D-D-
341. {ECO:0000269|PubMed:16892053}.
MUTAGEN 340 341 YY->DD: Constitutively active and highly
phosphorylated on S-338, inhibited by
PPP5C. Reduced kinase activity; when
associated with 338-A-A-339.
Constitutively active and non-inhibited
by PPP5C; when associated with 338-D-E-
339. {ECO:0000269|PubMed:16892053}.
MUTAGEN 491 491 T->D: Increased kinase activity but can
still be inhibited by PPP5C; when
associated with D-494.
{ECO:0000269|PubMed:16892053}.
MUTAGEN 494 494 S->D: Increased kinase activity but can
still be inhibited by PPP5C; when
associated with D-491.
{ECO:0000269|PubMed:16892053}.
MUTAGEN 563 563 R->K: Loss of methylation. Increased
stability and catalytic activity in
response to EGF treatment.
{ECO:0000269|PubMed:21917714}.
CONFLICT 240 240 F -> L (in Ref. 6; AAA60247).
{ECO:0000305}.
CONFLICT 542 542 M -> I (in Ref. 6; AAA60247).
{ECO:0000305}.
STRAND 57 62 {ECO:0000244|PDB:1C1Y}.
TURN 63 65 {ECO:0000244|PDB:1C1Y}.
STRAND 66 71 {ECO:0000244|PDB:1C1Y}.
HELIX 78 87 {ECO:0000244|PDB:1C1Y}.
TURN 88 90 {ECO:0000244|PDB:1C1Y}.
HELIX 93 95 {ECO:0000244|PDB:1C1Y}.
STRAND 96 102 {ECO:0000244|PDB:1C1Y}.
HELIX 103 105 {ECO:0000244|PDB:1C1Y}.
STRAND 106 112 {ECO:0000244|PDB:1C1Y}.
HELIX 118 121 {ECO:0000244|PDB:1C1Y}.
STRAND 125 130 {ECO:0000244|PDB:1C1Y}.
STRAND 142 144 {ECO:0000244|PDB:1FAQ}.
STRAND 155 159 {ECO:0000244|PDB:1FAQ}.
STRAND 161 164 {ECO:0000244|PDB:1FAQ}.
TURN 166 169 {ECO:0000244|PDB:1FAQ}.
HELIX 174 176 {ECO:0000244|PDB:1FAR}.
STRAND 177 182 {ECO:0000244|PDB:1FAQ}.
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


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EIAAB33700 Bos taurus,Bovine,cRaf,Proto-oncogene c-RAF,RAF proto-oncogene serine_threonine-protein kinase,RAF1,Raf-1
EIAAB33699 cRaf,Proto-oncogene c-RAF,Raf,RAF proto-oncogene serine_threonine-protein kinase,Raf1,Raf-1,Rat,Rattus norvegicus
EIAAB14724 Feline sarcoma_Fujinami avian sarcoma oncogene homolog,FES,FPS,Homo sapiens,Human,p93c-fes,Proto-oncogene c-Fes,Proto-oncogene c-Fps,Tyrosine-protein kinase Fes_Fps
DL-CRAF-Hu Human C-Raf Proto Oncogene Serine_Threonine Protein Kinase (CRAF) ELISA Kit 96T
G4694 Proto-oncogene serine threonine-protein kinase mos (MOS), Rat, ELISA Kit 96T
G4693 Proto-oncogene serine threonine-protein kinase mos (MOS), Pig, ELISA Kit 96T
G4692 Proto-oncogene serine threonine-protein kinase mos (MOS), Mouse, ELISA Kit 96T
E0726r Bovine ELISA Kit FOR RAF proto-oncogene serine per threonine-protein kinase 96T
G6186 RAF proto-oncogene serine threonine-protein kinase (RAF1), Rat, ELISA Kit 96T
G4696 Proto-oncogene serine threonine-protein kinase pim-1 (PIM1), Cat, ELISA Kit 96T
E0812r Mouse ELISA Kit FOR Proto-oncogene serine per threonine-protein kinase mos 96T
G4691 Proto-oncogene serine threonine-protein kinase mos (MOS), Human, ELISA Kit 96T
SVOP_BOVIN Bovine ELISA Kit FOR RAF proto-oncogene serine per threonine-protein kinase 96T
G4690 Proto-oncogene serine threonine-protein kinase mos (MOS), Chicken, ELISA Kit 96T


 

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