ID   ARAF_HUMAN              Reviewed;         606 AA.
AC   P10398; P07557; Q5H9B2; Q5H9B3;
DT   01-APR-1988, integrated into UniProtKB/Swiss-Prot.
DT   01-OCT-1996, sequence version 2.
DT   27-MAR-2024, entry version 243.
DE   RecName: Full=Serine/threonine-protein kinase A-Raf;
DE            EC=2.7.11.1;
DE   AltName: Full=Proto-oncogene A-Raf;
DE   AltName: Full=Proto-oncogene A-Raf-1;
DE   AltName: Full=Proto-oncogene Pks;
GN   Name=ARAF; Synonyms=ARAF1, PKS, PKS2;
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=3029685; DOI=10.1093/nar/15.2.595;
RA   Beck T.W., Huleihel M., Gunnell M., Bonner T.I., Rapp U.R.;
RT   "The complete coding sequence of the human A-raf-1 oncogene and
RT   transforming activity of a human A-raf carrying retrovirus.";
RL   Nucleic Acids Res. 15:595-609(1987).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC   TISSUE=Placenta;
RX   PubMed=8020955; DOI=10.1006/geno.1994.1125;
RA   Lee J.-E., Beck T.W., Brennscheidt U., DeGennaro L.J., Rapp U.R.;
RT   "The complete sequence and promoter activity of the human A-raf-1 gene
RT   (ARAF1).";
RL   Genomics 20:43-55(1994).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION (ISOFORM 2), AND
RP   ALTERNATIVE SPLICING.
RX   PubMed=17535970; DOI=10.1083/jcb.200703195;
RA   Yokoyama T., Takano K., Yoshida A., Katada F., Sun P., Takenawa T.,
RA   Andoh T., Endo T.;
RT   "DA-Raf1, a competent intrinsic dominant-negative antagonist of the Ras-ERK
RT   pathway, is required for myogenic differentiation.";
RL   J. Cell Biol. 177:781-793(2007).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA   Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA   Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA   Phelan M., Farmer A.;
RT   "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL   Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC   TISSUE=Placenta;
RA   Li W.B., Gruber C., Jessee J., Polayes D.;
RT   "Full-length cDNA libraries and normalization.";
RL   Submitted (APR-2003) to the EMBL/GenBank/DDBJ databases.
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15772651; DOI=10.1038/nature03440;
RA   Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA   Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L.,
RA   Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C.,
RA   Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A.,
RA   Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P.,
RA   Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D.,
RA   Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D.,
RA   Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L.,
RA   Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P.,
RA   Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G.,
RA   Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J.,
RA   Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D.,
RA   Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L.,
RA   Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z.,
RA   Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA   Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA   Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O.,
RA   Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H.,
RA   Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T.,
RA   Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L.,
RA   Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R.,
RA   Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y.,
RA   Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K.,
RA   Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J.,
RA   Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L.,
RA   Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S.,
RA   Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A.,
RA   Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L.,
RA   Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA   Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA   McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S.,
RA   Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C.,
RA   Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S.,
RA   Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V.,
RA   Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K.,
RA   Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA   Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA   Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA   Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B.,
RA   Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C.,
RA   d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q.,
RA   Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N.,
RA   Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A.,
RA   Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J.,
RA   Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A.,
RA   Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA   Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L.,
RA   Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S.,
RA   Rogers J., Bentley D.R.;
RT   "The DNA sequence of the human X chromosome.";
RL   Nature 434:325-337(2005).
RN   [7]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Kidney;
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   [8]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 292-589 (ISOFORM 1).
RX   PubMed=3529082; DOI=10.1073/pnas.83.17.6312;
RA   Mark G.E., Seeley T.W., Shows T.B., Mountz J.D.;
RT   "Pks, a raf-related sequence in humans.";
RL   Proc. Natl. Acad. Sci. U.S.A. 83:6312-6316(1986).
RN   [9]
RP   INTERACTION WITH NELFD.
RX   PubMed=11952167; DOI=10.1023/a:1014437024129;
RA   Yin X.L., Chen S., Gu J.X.;
RT   "Identification of TH1 as an interaction partner of A-Raf kinase.";
RL   Mol. Cell. Biochem. 231:69-74(2002).
RN   [10]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA   Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT   "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT   networks.";
RL   Cell 127:635-648(2006).
RN   [11]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-257, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=16964243; DOI=10.1038/nbt1240;
RA   Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT   "A probability-based approach for high-throughput protein phosphorylation
RT   analysis and site localization.";
RL   Nat. Biotechnol. 24:1285-1292(2006).
RN   [12]
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   [13]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-186, AND IDENTIFICATION BY
RP   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   [14]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA   Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA   Elledge S.J., Gygi S.P.;
RT   "A quantitative atlas of mitotic phosphorylation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN   [15]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-318, AND IDENTIFICATION BY
RP   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   [16]
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   [17]
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   [18]
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   [19]
RP   FUNCTION IN TOR SIGNALING.
RX   PubMed=22609986; DOI=10.1038/ncb2507;
RA   Gan X., Wang J., Wang C., Sommer E., Kozasa T., Srinivasula S., Alessi D.,
RA   Offermanns S., Simon M.I., Wu D.;
RT   "PRR5L degradation promotes mTORC2-mediated PKC-delta phosphorylation and
RT   cell migration downstream of Galpha12.";
RL   Nat. Cell Biol. 14:686-696(2012).
RN   [20]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-157; SER-162; THR-253;
RP   SER-257 AND SER-269, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP   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   [21]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-181; SER-186 AND SER-257, AND
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   [22]
RP   FUNCTION.
RX   PubMed=36402789; DOI=10.1038/s41467-022-34907-0;
RA   McGrail K., Granado-Martinez P., Esteve-Puig R., Garcia-Ortega S., Ding Y.,
RA   Sanchez-Redondo S., Ferrer B., Hernandez-Losa J., Canals F., Manzano A.,
RA   Navarro-Sabate A., Bartrons R., Yanes O., Perez-Alea M., Munoz-Couselo E.,
RA   Garcia-Patos V., Recio J.A.;
RT   "BRAF activation by metabolic stress promotes glycolysis sensitizing
RT   NRASQ61-mutated melanomas to targeted therapy.";
RL   Nat. Commun. 13:7113-7113(2022).
RN   [23]
RP   STRUCTURE BY NMR OF 19-91.
RG   RIKEN structural genomics initiative (RSGI);
RT   "Solution structure of the N-terminal RAS-binding domain (RBD) in human A-
RT   RAF kinase.";
RL   Submitted (JUL-2005) to the PDB data bank.
RN   [24]
RP   VARIANTS [LARGE SCALE ANALYSIS] THR-98; CYS-331 AND ASP-578.
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).
CC   -!- FUNCTION: Involved in the transduction of mitogenic signals from the
CC       cell membrane to the nucleus. May also regulate the TOR signaling
CC       cascade. Phosphorylates PFKFB2 (PubMed:36402789).
CC       {ECO:0000269|PubMed:22609986, ECO:0000269|PubMed:36402789}.
CC   -!- FUNCTION: [Isoform 2]: Serves as a positive regulator of myogenic
CC       differentiation by inducing cell cycle arrest, the expression of
CC       myogenin and other muscle-specific proteins, and myotube formation.
CC       {ECO:0000269|PubMed:22609986}.
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   -!- 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;
CC   -!- COFACTOR:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000250};
CC       Note=Binds 2 Zn(2+) ions per subunit. {ECO:0000250};
CC   -!- SUBUNIT: Interacts with TH1L/NELFD. {ECO:0000269|PubMed:11952167}.
CC   -!- INTERACTION:
CC       P10398; P00966: ASS1; NbExp=4; IntAct=EBI-365961, EBI-536842;
CC       P10398; Q9UNS2: COPS3; NbExp=3; IntAct=EBI-365961, EBI-350590;
CC       P10398; P31327: CPS1; NbExp=3; IntAct=EBI-365961, EBI-536811;
CC       P10398; Q12805: EFEMP1; NbExp=3; IntAct=EBI-365961, EBI-536772;
CC       P10398; P01112: HRAS; NbExp=7; IntAct=EBI-365961, EBI-350145;
CC       P10398; P08238: HSP90AB1; NbExp=9; IntAct=EBI-365961, EBI-352572;
CC       P10398; O43187: IRAK2; NbExp=2; IntAct=EBI-365961, EBI-447733;
CC       P10398; Q92985: IRF7; NbExp=2; IntAct=EBI-365961, EBI-968267;
CC       P10398; P36507: MAP2K2; NbExp=9; IntAct=EBI-365961, EBI-1056930;
CC       P10398; Q8IXH7: NELFCD; NbExp=5; IntAct=EBI-365961, EBI-536725;
CC       P10398; O95848: NUDT14; NbExp=3; IntAct=EBI-365961, EBI-536866;
CC       P10398; Q96KB5: PBK; NbExp=3; IntAct=EBI-365961, EBI-536853;
CC       P10398; O94906: PRPF6; NbExp=4; IntAct=EBI-365961, EBI-536755;
CC       P10398; P53611: RABGGTB; NbExp=3; IntAct=EBI-365961, EBI-536715;
CC       P10398; P62070: RRAS2; NbExp=3; IntAct=EBI-365961, EBI-491037;
CC       P10398; P31947: SFN; NbExp=4; IntAct=EBI-365961, EBI-476295;
CC       P10398; O43615: TIMM44; NbExp=3; IntAct=EBI-365961, EBI-861737;
CC       P10398; Q3ZCQ8: TIMM50; NbExp=4; IntAct=EBI-365961, EBI-355175;
CC       P10398; P58753: TIRAP; NbExp=2; IntAct=EBI-365961, EBI-528644;
CC       P10398; P62258: YWHAE; NbExp=7; IntAct=EBI-365961, EBI-356498;
CC       P10398; P63104: YWHAZ; NbExp=8; IntAct=EBI-365961, EBI-347088;
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=P10398-1; Sequence=Displayed;
CC       Name=2; Synonyms=DA-Raf1;
CC         IsoId=P10398-2; Sequence=VSP_045609, VSP_045610;
CC   -!- TISSUE SPECIFICITY: Predominantly in urogenital tissues.
CC   -!- MISCELLANEOUS: [Isoform 2]: Has a wider tissue distribution than
CC       isoform 1, and acts as a dominant-negative antagonist. {ECO:0000305}.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr
CC       protein kinase family. RAF subfamily. {ECO:0000305}.
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; X04790; CAA28476.1; -; mRNA.
DR   EMBL; L24038; AAA65219.1; -; Genomic_DNA.
DR   EMBL; U01337; AAB03517.1; -; Genomic_DNA.
DR   EMBL; AB158254; BAE66645.1; -; mRNA.
DR   EMBL; BT019864; AAV38667.1; -; mRNA.
DR   EMBL; AL542736; -; NOT_ANNOTATED_CDS; mRNA.
DR   EMBL; Z84466; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC002466; AAH02466.1; -; mRNA.
DR   EMBL; M13829; AAB08754.1; -; mRNA.
DR   CCDS; CCDS35232.1; -. [P10398-1]
DR   CCDS; CCDS59164.1; -. [P10398-2]
DR   PIR; A53026; TVHUAF.
DR   RefSeq; NP_001243125.1; NM_001256196.1.
DR   RefSeq; NP_001243126.1; NM_001256197.1. [P10398-2]
DR   RefSeq; NP_001645.1; NM_001654.4. [P10398-1]
DR   RefSeq; XP_011542210.1; XM_011543908.2.
DR   PDB; 1WXM; NMR; -; A=19-91.
DR   PDB; 2MSE; NMR; -; D=19-91.
DR   PDBsum; 1WXM; -.
DR   PDBsum; 2MSE; -.
DR   AlphaFoldDB; P10398; -.
DR   BMRB; P10398; -.
DR   SMR; P10398; -.
DR   BioGRID; 106864; 408.
DR   CORUM; P10398; -.
DR   DIP; DIP-31374N; -.
DR   IntAct; P10398; 128.
DR   MINT; P10398; -.
DR   STRING; 9606.ENSP00000290277; -.
DR   BindingDB; P10398; -.
DR   ChEMBL; CHEMBL1169596; -.
DR   DrugBank; DB00171; ATP.
DR   DrugCentral; P10398; -.
DR   GuidetoPHARMACOLOGY; 1933; -.
DR   GlyGen; P10398; 1 site, 1 O-linked glycan (1 site).
DR   iPTMnet; P10398; -.
DR   PhosphoSitePlus; P10398; -.
DR   BioMuta; ARAF; -.
DR   DMDM; 1730068; -.
DR   CPTAC; CPTAC-1339; -.
DR   CPTAC; CPTAC-1343; -.
DR   CPTAC; CPTAC-1344; -.
DR   CPTAC; CPTAC-1345; -.
DR   CPTAC; CPTAC-1547; -.
DR   CPTAC; CPTAC-3065; -.
DR   CPTAC; CPTAC-5774; -.
DR   CPTAC; CPTAC-5775; -.
DR   CPTAC; CPTAC-5776; -.
DR   CPTAC; CPTAC-5823; -.
DR   CPTAC; CPTAC-5824; -.
DR   CPTAC; CPTAC-5825; -.
DR   CPTAC; CPTAC-5826; -.
DR   CPTAC; non-CPTAC-5346; -.
DR   CPTAC; non-CPTAC-5347; -.
DR   CPTAC; non-CPTAC-5348; -.
DR   CPTAC; non-CPTAC-5350; -.
DR   CPTAC; non-CPTAC-5351; -.
DR   CPTAC; non-CPTAC-5533; -.
DR   CPTAC; non-CPTAC-5730; -.
DR   CPTAC; non-CPTAC-5731; -.
DR   EPD; P10398; -.
DR   jPOST; P10398; -.
DR   MassIVE; P10398; -.
DR   MaxQB; P10398; -.
DR   PaxDb; 9606-ENSP00000290277; -.
DR   PeptideAtlas; P10398; -.
DR   ProteomicsDB; 52601; -. [P10398-1]
DR   ProteomicsDB; 62876; -.
DR   Pumba; P10398; -.
DR   TopDownProteomics; P10398-1; -. [P10398-1]
DR   Antibodypedia; 11388; 793 antibodies from 39 providers.
DR   CPTC; P10398; 5 antibodies.
DR   DNASU; 369; -.
DR   Ensembl; ENST00000377039.2; ENSP00000366238.1; ENSG00000078061.14. [P10398-2]
DR   Ensembl; ENST00000377045.9; ENSP00000366244.4; ENSG00000078061.14. [P10398-1]
DR   GeneID; 369; -.
DR   KEGG; hsa:369; -.
DR   MANE-Select; ENST00000377045.9; ENSP00000366244.4; NM_001654.5; NP_001645.1.
DR   UCSC; uc031tjj.2; human. [P10398-1]
DR   AGR; HGNC:646; -.
DR   CTD; 369; -.
DR   DisGeNET; 369; -.
DR   GeneCards; ARAF; -.
DR   HGNC; HGNC:646; ARAF.
DR   HPA; ENSG00000078061; Low tissue specificity.
DR   MalaCards; ARAF; -.
DR   MIM; 311010; gene.
DR   neXtProt; NX_P10398; -.
DR   OpenTargets; ENSG00000078061; -.
DR   PharmGKB; PA24928; -.
DR   VEuPathDB; HostDB:ENSG00000078061; -.
DR   eggNOG; KOG0193; Eukaryota.
DR   GeneTree; ENSGT00940000159633; -.
DR   HOGENOM; CLU_023684_1_1_1; -.
DR   InParanoid; P10398; -.
DR   OrthoDB; 4560496at2759; -.
DR   PhylomeDB; P10398; -.
DR   TreeFam; TF317006; -.
DR   BRENDA; 2.7.10.2; 2681.
DR   PathwayCommons; P10398; -.
DR   Reactome; R-HSA-5673000; RAF activation.
DR   Reactome; R-HSA-5674135; MAP2K and MAPK activation.
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; P10398; -.
DR   SIGNOR; P10398; -.
DR   BioGRID-ORCS; 369; 13 hits in 824 CRISPR screens.
DR   ChiTaRS; ARAF; human.
DR   EvolutionaryTrace; P10398; -.
DR   GeneWiki; ARAF; -.
DR   GenomeRNAi; 369; -.
DR   Pharos; P10398; Tchem.
DR   PRO; PR:P10398; -.
DR   Proteomes; UP000005640; Chromosome X.
DR   RNAct; P10398; Protein.
DR   Bgee; ENSG00000078061; Expressed in hindlimb stylopod muscle and 185 other cell types or tissues.
DR   ExpressionAtlas; P10398; baseline and differential.
DR   GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR   GO; GO:0005739; C:mitochondrion; IBA:GO_Central.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
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:0000165; P:MAPK cascade; IBA:GO_Central.
DR   GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB.
DR   GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW.
DR   GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; IDA:UniProtKB.
DR   GO; GO:0036211; P:protein modification process; TAS:ProtInc.
DR   GO; GO:0032434; P:regulation of proteasomal ubiquitin-dependent protein catabolic process; IMP:UniProtKB.
DR   GO; GO:0032006; P:regulation of TOR signaling; IMP:UniProtKB.
DR   CDD; cd20870; C1_A_C-Raf; 1.
DR   CDD; cd17133; RBD_ARAF; 1.
DR   CDD; cd14150; STKc_A-Raf; 1.
DR   Gene3D; 3.30.60.20; -; 1.
DR   Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1.
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   PANTHER; PTHR23257:SF727; NON-SPECIFIC SERINE_THREONINE PROTEIN KINASE; 1.
DR   PANTHER; PTHR23257; SERINE-THREONINE PROTEIN KINASE; 1.
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; SSF57889; Cysteine-rich domain; 1.
DR   SUPFAM; SSF56112; Protein kinase-like (PK-like); 1.
DR   SUPFAM; SSF54236; Ubiquitin-like; 1.
DR   PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR   PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR   PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
DR   PROSITE; PS50898; RBD; 1.
DR   PROSITE; PS00479; ZF_DAG_PE_1; 1.
DR   PROSITE; PS50081; ZF_DAG_PE_2; 1.
DR   Genevisible; P10398; HS.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; ATP-binding; Kinase; Metal-binding;
KW   Nucleotide-binding; Phosphoprotein; Proto-oncogene; Reference proteome;
KW   Serine/threonine-protein kinase; Transferase; Zinc; Zinc-finger.
FT   CHAIN           1..606
FT                   /note="Serine/threonine-protein kinase A-Raf"
FT                   /id="PRO_0000085622"
FT   DOMAIN          19..91
FT                   /note="RBD"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00262"
FT   DOMAIN          310..570
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   ZN_FING         98..144
FT                   /note="Phorbol-ester/DAG-type"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00226"
FT   REGION          160..207
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          240..290
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        160..188
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        240..271
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        272..290
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        429
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT                   ECO:0000255|PROSITE-ProRule:PRU10027"
FT   BINDING         99
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250"
FT   BINDING         112
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250"
FT   BINDING         115
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250"
FT   BINDING         125
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250"
FT   BINDING         128
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250"
FT   BINDING         133
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250"
FT   BINDING         136
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250"
FT   BINDING         144
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250"
FT   BINDING         316..324
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         336
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   MOD_RES         157
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   MOD_RES         162
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   MOD_RES         181
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0007744|PubMed:24275569"
FT   MOD_RES         186
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18691976,
FT                   ECO:0007744|PubMed:24275569"
FT   MOD_RES         253
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   MOD_RES         257
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:16964243,
FT                   ECO:0007744|PubMed:23186163, ECO:0007744|PubMed:24275569"
FT   MOD_RES         269
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   MOD_RES         318
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0007744|PubMed:19690332"
FT   VAR_SEQ         186
FT                   /note="S -> R (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:17535970, ECO:0000303|Ref.5"
FT                   /id="VSP_045609"
FT   VAR_SEQ         187..606
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:17535970, ECO:0000303|Ref.5"
FT                   /id="VSP_045610"
FT   VARIANT         98
FT                   /note="M -> T (in dbSNP:rs56197559)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040375"
FT   VARIANT         331
FT                   /note="G -> C (in a colorectal adenocarcinoma sample;
FT                   somatic mutation)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040376"
FT   VARIANT         578
FT                   /note="E -> D (in dbSNP:rs55852926)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040377"
FT   CONFLICT        368
FT                   /note="L -> P (in Ref. 8; AAB08754)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        378
FT                   /note="F -> V (in Ref. 8; AAB08754)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        469
FT                   /note="S -> P (in Ref. 8; AAB08754)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        478
FT                   /note="I -> T (in Ref. 8; AAB08754)"
FT                   /evidence="ECO:0000305"
FT   STRAND          19..24
FT                   /evidence="ECO:0007829|PDB:1WXM"
FT   STRAND          26..28
FT                   /evidence="ECO:0007829|PDB:1WXM"
FT   STRAND          30..34
FT                   /evidence="ECO:0007829|PDB:1WXM"
FT   HELIX           42..50
FT                   /evidence="ECO:0007829|PDB:1WXM"
FT   TURN            51..53
FT                   /evidence="ECO:0007829|PDB:2MSE"
FT   STRAND          56..67
FT                   /evidence="ECO:0007829|PDB:1WXM"
FT   STRAND          69..72
FT                   /evidence="ECO:0007829|PDB:1WXM"
FT   STRAND          74..78
FT                   /evidence="ECO:0007829|PDB:1WXM"
FT   HELIX           79..81
FT                   /evidence="ECO:0007829|PDB:2MSE"
FT   STRAND          82..84
FT                   /evidence="ECO:0007829|PDB:2MSE"
FT   STRAND          85..90
FT                   /evidence="ECO:0007829|PDB:1WXM"
SQ   SEQUENCE   606 AA;  67585 MW;  D23E5711304AA468 CRC64;
     MEPPRGPPAN GAEPSRAVGT VKVYLPNKQR TVVTVRDGMS VYDSLDKALK VRGLNQDCCV
     VYRLIKGRKT VTAWDTAIAP LDGEELIVEV LEDVPLTMHN FVRKTFFSLA FCDFCLKFLF
     HGFRCQTCGY KFHQHCSSKV PTVCVDMSTN RQQFYHSVQD LSGGSRQHEA PSNRPLNELL
     TPQGPSPRTQ HCDPEHFPFP APANAPLQRI RSTSTPNVHM VSTTAPMDSN LIQLTGQSFS
     TDAAGSRGGS DGTPRGSPSP ASVSSGRKSP HSKSPAEQRE RKSLADDKKK VKNLGYRDSG
     YYWEVPPSEV QLLKRIGTGS FGTVFRGRWH GDVAVKVLKV SQPTAEQAQA FKNEMQVLRK
     TRHVNILLFM GFMTRPGFAI ITQWCEGSSL YHHLHVADTR FDMVQLIDVA RQTAQGMDYL
     HAKNIIHRDL KSNNIFLHEG LTVKIGDFGL ATVKTRWSGA QPLEQPSGSV LWMAAEVIRM
     QDPNPYSFQS DVYAYGVVLY ELMTGSLPYS HIGCRDQIIF MVGRGYLSPD LSKISSNCPK
     AMRRLLSDCL KFQREERPLF PQILATIELL QRSLPKIERS ASEPSLHRTQ ADELPACLLS
     AARLVP
//