ID RAF1_MOUSE Reviewed; 648 AA. AC Q99N57; Q3UR68; Q58E75; Q91WH1; Q99N58; Q9QUU8; DT 15-AUG-2003, integrated into UniProtKB/Swiss-Prot. DT 01-MAR-2002, sequence version 2. DT 27-MAR-2024, entry version 203. DE RecName: Full=RAF proto-oncogene serine/threonine-protein kinase; DE EC=2.7.11.1 {ECO:0000250|UniProtKB:P04049}; DE AltName: Full=Proto-oncogene c-RAF; DE Short=cRaf; DE AltName: Full=Raf-1; GN Name=Raf1; Synonyms=Craf; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY. RC TISSUE=Liver; RX PubMed=11597136; DOI=10.1006/geno.2001.6627; RA Gray T.A., Azama K., Whitmore K., Min A., Abe S., Nicholls R.D.; RT "Phylogenetic conservation of the makorin-2 gene, encoding a multiple zinc- RT finger protein, antisense to the raf1 proto-oncogene."; RL Genomics 77:119-126(2001). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC STRAIN=C57BL/6J; TISSUE=Embryo; RX PubMed=16141072; DOI=10.1126/science.1112014; RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J., RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.; RT "The transcriptional landscape of the mammalian genome."; RL Science 309:1559-1563(2005). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC STRAIN=Czech II, and FVB/N; TISSUE=Kidney, and Mammary tumor; 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 [4] RP PARTIAL NUCLEOTIDE SEQUENCE [GENOMIC DNA], ALTERNATIVE SPLICING, AND TISSUE RP SPECIFICITY. 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 [5] RP FUNCTION, AND INTERACTION WITH ROCK2. RX PubMed=15753127; DOI=10.1083/jcb.200409162; RA Ehrenreiter K., Piazzolla D., Velamoor V., Sobczak I., Small J.V., RA Takeda J., Leung T., Baccarini M.; RT "Raf-1 regulates Rho signaling and cell migration."; RL J. Cell Biol. 168:955-964(2005). RN [6] RP PHOSPHORYLATION AT SER-29; SER-43; SER-259; SER-289; SER-296; SER-301; RP SER-338; SER-621 AND SER-642, ACTIVITY REGULATION, AND INTERACTION WITH RP PIN1; PPP2CA AND PPP2R1B. RX PubMed=15664191; DOI=10.1016/j.molcel.2004.11.055; RA Dougherty M.K., Muller J., Ritt D.A., Zhou M., Zhou X.Z., Copeland T.D., RA Conrads T.P., Veenstra T.D., Lu K.P., Morrison D.K.; RT "Regulation of Raf-1 by direct feedback phosphorylation."; RL Mol. Cell 17:215-224(2005). RN [7] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=17242355; DOI=10.1073/pnas.0609836104; RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.; RT "Large-scale phosphorylation analysis of mouse liver."; RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007). RN [8] 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 [9] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-296; SER-301 AND SER-642, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Pancreas, Spleen, RC and Testis; RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001; RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R., RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.; RT "A tissue-specific atlas of mouse protein phosphorylation and expression."; RL Cell 143:1174-1189(2010). 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. Plays a role in the oncogenic CC transformation of epithelial cells via repression of the TJ protein, CC occludin (OCLN) by inducing the up-regulation of a transcriptional CC repressor SNAI2/SLUG, which induces down-regulation of OCLN. Restricts CC caspase activation in response to selected stimuli, notably Fas CC stimulation, pathogen-mediated macrophage apoptosis, and erythroid CC differentiation (By similarity). Regulates Rho signaling and migration, CC and is required for normal wound healing. CC {ECO:0000250|UniProtKB:P04049, ECO:0000269|PubMed:15753127}. 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:0000250|UniProtKB:P04049}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17990; CC Evidence={ECO:0000250|UniProtKB:P04049}; 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:0000250|UniProtKB:P04049}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46609; CC Evidence={ECO:0000250|UniProtKB:P04049}; 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 -!- 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 (By similarity). {ECO:0000250}. CC -!- SUBUNIT: Monomer (By similarity). Homodimer (By similarity). CC Heterodimerizes with BRAF and this heterodimer possesses a highly CC increased kinase activity compared to the respective homodimers or CC monomers (By similarity). Heterodimerization is mitogen-regulated and CC enhanced by 14-3-3 proteins (By similarity). MAPK1/ERK2 activation can CC induce a negative feedback that promotes the dissociation of the CC heterodimer (By similarity). Forms a multiprotein complex with Ras (M- CC Ras/MRAS), SHOC2 and protein phosphatase 1 (PPP1CA, PPP1CB and PPP1CC) CC (By similarity). Interacts with LZTR1 (By similarity). Interacts with CC Ras proteins; the interaction is antagonized by RIN1 (By similarity). CC Weakly interacts with RIT1 (By similarity). Interacts (via N-terminus) CC with RGS14 (via RBD domains); the interaction mediates the formation of CC a ternary complex with BRAF, a ternary complex inhibited by GNAI1 (By CC similarity). Probably forms a complex composed of chaperones HSP90 and CC HSP70, co-chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, CC AKT, RAF1 and NR3C1; this complex does not contain co-chaperones CC STIP1/HOP and PTGES3/p23 (By similarity). Interacts with STK3/MST2; the CC interaction inhibits its pro-apoptotic activity (By similarity). CC Interacts (when phosphorylated at Ser-259) with YWHAZ (unphosphorylated CC at 'Thr-232') (By similarity). 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 (By similarity). Interacts with PAK1 (via kinase domain) CC (By similarity). The Ser-338 and Ser-339 phosphorylated form (by PAK1) CC interacts with BCL2 (By similarity). Interacts with PEBP1/RKIP and this CC interaction is enhanced if RAF1 is phosphorylated on residues Ser-338, CC Ser-339, Tyr-340 and Tyr-341 (By similarity). Interacts with ADCY2, CC ADCY5, ADCY6, DGKH, RCAN1/DSCR1, PPP1R12A, PKB/AKT1, SPRY2, SPRY4, CC CNKSR1/CNK1, KSR2 and PHB/prohibitin (By similarity). The CC phosphorylated form interacts with PIN1 (PubMed:15664191). Interacts CC with PPP2CA, PPP2R1B and ROCK2 (PubMed:15753127, PubMed:15664191). In CC its active form, interacts with PRMT5 (By similarity). Interacts with CC FAM83B; displaces 14-3-3 proteins from RAF1 and activates RAF1 (By CC similarity). Interacts with PDE8A; the interaction promotes RAF1 CC activity (By similarity). Interacts with MFHAS1 (By similarity). CC Interacts with GLS (By similarity). Interacts with NEK10 and MAP2K1; CC the interaction is direct with NEK10 and required for ERK1/2-signaling CC pathway activation in response to UV irradiation (By similarity). CC {ECO:0000250|UniProtKB:P04049, ECO:0000250|UniProtKB:P11345, CC ECO:0000269|PubMed:15664191, ECO:0000269|PubMed:15753127}. CC -!- INTERACTION: CC Q99N57; P28028: Braf; NbExp=2; IntAct=EBI-397757, EBI-2584830; CC Q99N57; P32883-2: Kras; NbExp=3; IntAct=EBI-397757, EBI-644285; CC Q99N57; Q8CFI0: Nedd4l; NbExp=2; IntAct=EBI-397757, EBI-8046183; CC Q99N57; Q9WVC6: Sgk1; NbExp=2; IntAct=EBI-397757, EBI-15591730; CC Q99N57; Q9Z2S7-3: Tsc22d3; NbExp=2; IntAct=EBI-397757, EBI-15771036; CC Q99N57; P15056: BRAF; Xeno; NbExp=3; IntAct=EBI-397757, EBI-365980; CC Q99N57; P01111: NRAS; Xeno; NbExp=2; IntAct=EBI-397757, EBI-721993; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Cell membrane CC {ECO:0000250}. Mitochondrion {ECO:0000250}. Nucleus CC {ECO:0000269|PubMed:19298812}. Note=Colocalizes with RGS14 and BRAF in CC both the cytoplasm and membranes. Phosphorylation at Ser-259 impairs CC its membrane accumulation. Recruited to the cell membrane by the active CC Ras protein. Phosphorylation at Ser-338 and Ser-339 by PAK1 is required CC for its mitochondrial localization (By similarity). Retinoic acid- CC induced Ser-621 phosphorylated form of RAF1 is predominantly localized CC at the nucleus. {ECO:0000250}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; Synonyms=6C; CC IsoId=Q99N57-1; Sequence=Displayed; CC Name=2; Synonyms=1A; CC IsoId=Q99N57-2; Sequence=VSP_034629; CC -!- TISSUE SPECIFICITY: Present in all tissues tested: testis, ovary, small CC intestine, colon, peripheral blood leukocytes, fetal liver, bone CC marrow, thymus, lymph node and spleen, and the cell lines melanoma G- CC 361, lung carcinoma A-549, colorectal adenocarcinoma SW480, Burkitt's CC lymphoma Raji and lymphoblastic leukemia MOLT-4. In skeletal muscle, CC isoform 1 is more abundant than isoform 2. CC {ECO:0000269|PubMed:11597136, 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 (By similarity). Phosphorylation at Ser-621 CC in response to growth factor treatment stabilizes the protein, possibly CC by preventing proteasomal degradation. Phosphorylation at Ser-289, Ser- CC 296, Ser-301, Ser-338 and Ser-621 are somehow linked to the methylation CC potential of cells. Treatment of cells with HGF in the presence of the CC methylation 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 a decreased of activity (By similarity). CC {ECO:0000250|UniProtKB:P04049}. 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:0000250}. 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; AB057655; BAB39748.1; -; mRNA. DR EMBL; AB057663; BAB39743.2; -; mRNA. DR EMBL; AK141745; BAE24820.1; -; mRNA. DR EMBL; BC015273; AAH15273.1; -; mRNA. DR EMBL; BC092040; AAH92040.1; -; mRNA. DR EMBL; X55432; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR CCDS; CCDS20441.1; -. [Q99N57-1] DR RefSeq; NP_084056.1; NM_029780.3. [Q99N57-1] DR RefSeq; XP_006505426.1; XM_006505363.3. DR RefSeq; XP_006505427.1; XM_006505364.2. [Q99N57-2] DR RefSeq; XP_006505428.1; XM_006505365.2. DR AlphaFoldDB; Q99N57; -. DR BMRB; Q99N57; -. DR SMR; Q99N57; -. DR BioGRID; 225343; 19. DR CORUM; Q99N57; -. DR DIP; DIP-31555N; -. DR IntAct; Q99N57; 15. DR MINT; Q99N57; -. DR STRING; 10090.ENSMUSP00000000451; -. DR BindingDB; Q99N57; -. DR ChEMBL; CHEMBL3804748; -. DR iPTMnet; Q99N57; -. DR PhosphoSitePlus; Q99N57; -. DR SwissPalm; Q99N57; -. DR EPD; Q99N57; -. DR jPOST; Q99N57; -. DR MaxQB; Q99N57; -. DR PaxDb; 10090-ENSMUSP00000000451; -. DR PeptideAtlas; Q99N57; -. DR ProteomicsDB; 254892; -. [Q99N57-1] DR ProteomicsDB; 254893; -. [Q99N57-2] DR Pumba; Q99N57; -. DR Antibodypedia; 1131; 3571 antibodies from 50 providers. DR DNASU; 110157; -. DR Ensembl; ENSMUST00000000451.14; ENSMUSP00000000451.8; ENSMUSG00000000441.18. [Q99N57-1] DR Ensembl; ENSMUST00000112949.8; ENSMUSP00000108571.2; ENSMUSG00000000441.18. [Q99N57-1] DR GeneID; 110157; -. DR KEGG; mmu:110157; -. DR UCSC; uc009dix.1; mouse. [Q99N57-1] DR AGR; MGI:97847; -. DR CTD; 5894; -. DR MGI; MGI:97847; Raf1. DR VEuPathDB; HostDB:ENSMUSG00000000441; -. DR eggNOG; KOG0193; Eukaryota. DR GeneTree; ENSGT00940000156084; -. DR HOGENOM; CLU_023684_1_1_1; -. DR InParanoid; Q99N57; -. DR OMA; SPSSWCH; -. DR OrthoDB; 4560496at2759; -. DR PhylomeDB; Q99N57; -. DR TreeFam; TF317006; -. DR Reactome; R-MMU-2672351; Stimuli-sensing channels. DR Reactome; R-MMU-392517; Rap1 signalling. DR Reactome; R-MMU-430116; GP1b-IX-V activation signalling. DR Reactome; R-MMU-5621575; CD209 (DC-SIGN) signaling. DR Reactome; R-MMU-5673000; RAF activation. DR Reactome; R-MMU-5674135; MAP2K and MAPK activation. DR Reactome; R-MMU-5674499; Negative feedback regulation of MAPK pathway. DR Reactome; R-MMU-5675221; Negative regulation of MAPK pathway. DR Reactome; R-MMU-9732724; IFNG signaling activates MAPKs. DR BioGRID-ORCS; 110157; 10 hits in 80 CRISPR screens. DR ChiTaRS; Raf1; mouse. DR PRO; PR:Q99N57; -. DR Proteomes; UP000000589; Chromosome 6. DR RNAct; Q99N57; Protein. DR Bgee; ENSMUSG00000000441; Expressed in granulocyte and 264 other cell types or tissues. DR ExpressionAtlas; Q99N57; baseline and differential. DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB. DR GO; GO:0005829; C:cytosol; ISO:MGI. DR GO; GO:0005794; C:Golgi apparatus; ISO:MGI. 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; ISS:UniProtKB. DR GO; GO:0031143; C:pseudopodium; IDA:UniProtKB. DR GO; GO:0010856; F:adenylate cyclase activator activity; ISO:MGI. DR GO; GO:0008179; F:adenylate cyclase binding; ISO:MGI. DR GO; GO:0005524; F:ATP binding; ISO:MGI. DR GO; GO:0019899; F:enzyme binding; ISO:MGI. DR GO; GO:0042802; F:identical protein binding; ISO:MGI. DR GO; GO:0004709; F:MAP kinase kinase kinase activity; IDA:MGI. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0031434; F:mitogen-activated protein kinase kinase binding; ISO:MGI. DR GO; GO:0004672; F:protein kinase activity; ISO:MGI. DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IMP:MGI. DR GO; GO:0044877; F:protein-containing complex binding; ISO:MGI. DR GO; GO:0031267; F:small GTPase binding; IPI:MGI. DR GO; GO:0030154; P:cell differentiation; IGI:MGI. DR GO; GO:0071550; P:death-inducing signaling complex assembly; IMP:MGI. DR GO; GO:0038133; P:ERBB2-ERBB3 signaling pathway; IDA:MGI. DR GO; GO:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; IMP:MGI. DR GO; GO:0060324; P:face development; IGI:MGI. DR GO; GO:0008286; P:insulin receptor signaling pathway; IDA:MGI. DR GO; GO:0035773; P:insulin secretion involved in cellular response to glucose stimulus; IMP:MGI. DR GO; GO:0048009; P:insulin-like growth factor receptor signaling pathway; IDA:MGI. DR GO; GO:0045104; P:intermediate filament cytoskeleton organization; IMP:MGI. DR GO; GO:0001678; P:intracellular glucose homeostasis; IMP:MGI. DR GO; GO:0035556; P:intracellular signal transduction; TAS:MGI. DR GO; GO:0000165; P:MAPK cascade; ISO:MGI. DR GO; GO:0042552; P:myelination; IMP:MGI. DR GO; GO:0043066; P:negative regulation of apoptotic process; ISO:MGI. DR GO; GO:0008285; P:negative regulation of cell population proliferation; ISO:MGI. DR GO; GO:1902042; P:negative regulation of extrinsic apoptotic signaling pathway via death domain receptors; IMP:MGI. DR GO; GO:0031333; P:negative regulation of protein-containing complex assembly; ISO:MGI. DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; IMP:MGI. DR GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW. DR GO; GO:0043410; P:positive regulation of MAPK cascade; ISO:MGI. DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; ISO:MGI. DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IMP:MGI. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IMP:MGI. DR GO; GO:0001666; P:response to hypoxia; ISO:MGI. DR GO; GO:0035994; P:response to muscle stretch; IMP:MGI. DR GO; GO:0014044; P:Schwann cell development; IMP:MGI. DR GO; GO:0035019; P:somatic stem cell population maintenance; IGI:MGI. DR GO; GO:0048538; P:thymus development; IGI:MGI. DR GO; GO:0030878; P:thyroid gland development; IGI:MGI. DR GO; GO:0044342; P:type B pancreatic cell proliferation; IMP:MGI. DR CDD; cd20870; C1_A_C-Raf; 1. DR CDD; cd17135; RBD_CRAF; 1. DR CDD; cd14149; STKc_C-Raf; 1. DR Gene3D; 3.30.60.20; -; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR InterPro; IPR046349; C1-like_sf. DR InterPro; IPR020454; DAG/PE-bd. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR002219; PE/DAG-bd. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR003116; RBD_dom. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR InterPro; IPR029071; Ubiquitin-like_domsf. DR PANTHER; PTHR23257:SF763; RAF PROTO-ONCOGENE SERINE_THREONINE-PROTEIN KINASE; 1. DR PANTHER; PTHR23257; SERINE-THREONINE PROTEIN KINASE; 1. DR Pfam; PF00130; C1_1; 1. DR Pfam; PF00069; Pkinase; 1. DR Pfam; PF02196; RBD; 1. DR PRINTS; PR00008; DAGPEDOMAIN. DR SMART; SM00109; C1; 1. DR SMART; SM00455; RBD; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF57889; Cysteine-rich domain; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR SUPFAM; SSF54236; Ubiquitin-like; 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. DR PROSITE; PS50898; RBD; 1. DR PROSITE; PS00479; ZF_DAG_PE_1; 1. DR PROSITE; PS50081; ZF_DAG_PE_2; 1. DR Genevisible; Q99N57; MM. PE 1: Evidence at protein level; KW Alternative splicing; ATP-binding; Cell membrane; Cytoplasm; Kinase; KW Membrane; Metal-binding; Methylation; Mitochondrion; Nucleotide-binding; KW Nucleus; Phosphoprotein; Proto-oncogene; Reference proteome; KW Serine/threonine-protein kinase; Transferase; Zinc; Zinc-finger. FT CHAIN 1..648 FT /note="RAF proto-oncogene serine/threonine-protein kinase" FT /id="PRO_0000086597" 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 205..265 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 281..335 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 331..349 FT /note="Interaction with PEBP1/RKIP" FT /evidence="ECO:0000250" FT COMPBIAS 222..265 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 /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10027" FT BINDING 139 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000250" FT BINDING 152 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000250" FT BINDING 155 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000250" FT BINDING 165 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000250" FT BINDING 168 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000250" FT BINDING 173 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000250" FT BINDING 176 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000250" FT BINDING 184 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000250" 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:0000269|PubMed:15664191" FT MOD_RES 43 FT /note="Phosphoserine; by PKA and MAPK1" FT /evidence="ECO:0000269|PubMed:15664191" FT MOD_RES 233 FT /note="Phosphoserine; by PKA" FT /evidence="ECO:0000250|UniProtKB:P04049" FT MOD_RES 252 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P04049" FT MOD_RES 259 FT /note="Phosphoserine; by PKA, PKC and PKB/AKT1" FT /evidence="ECO:0000250|UniProtKB:P04049" FT MOD_RES 268 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:P04049" FT MOD_RES 269 FT /note="Phosphothreonine; by PKA" FT /evidence="ECO:0000250|UniProtKB:P04049" FT MOD_RES 289 FT /note="Phosphoserine; by MAPK1" FT /evidence="ECO:0000269|PubMed:15664191" FT MOD_RES 296 FT /note="Phosphoserine; by MAPK1" FT /evidence="ECO:0000269|PubMed:15664191, FT ECO:0007744|PubMed:21183079" FT MOD_RES 301 FT /note="Phosphoserine; by MAPK1" FT /evidence="ECO:0000269|PubMed:15664191, FT ECO:0007744|PubMed:21183079" FT MOD_RES 338 FT /note="Phosphoserine; by PAK1, PAK2, PAK3 and PAK5" FT /evidence="ECO:0000250|UniProtKB:P04049" FT MOD_RES 339 FT /note="Phosphoserine; by PAK1, PAK2 and PAK3" FT /evidence="ECO:0000250|UniProtKB:P04049" FT MOD_RES 340 FT /note="Phosphotyrosine; by SRC" FT /evidence="ECO:0000250|UniProtKB:P04049" FT MOD_RES 341 FT /note="Phosphotyrosine; by SRC" FT /evidence="ECO:0000250|UniProtKB:P04049" FT MOD_RES 471 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P04049" FT MOD_RES 491 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:P04049" FT MOD_RES 494 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P04049" FT MOD_RES 497 FT /note="Phosphoserine; by PKC" FT /evidence="ECO:0000250|UniProtKB:P04049" FT MOD_RES 499 FT /note="Phosphoserine; by PKC" FT /evidence="ECO:0000250|UniProtKB:P04049" FT MOD_RES 563 FT /note="Symmetric dimethylarginine; by PRMT5" FT /evidence="ECO:0000250|UniProtKB:P04049" FT MOD_RES 621 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:15664191" FT MOD_RES 642 FT /note="Phosphoserine; by MAPK1" FT /evidence="ECO:0000269|PubMed:15664191, FT ECO:0007744|PubMed:21183079" FT VAR_SEQ 278 FT /note="E -> ESNSLNASPRACSRRFCLRGR (in isoform 2)" FT /evidence="ECO:0000305" FT /id="VSP_034629" FT CONFLICT 522 FT /note="D -> N (in Ref. 3; AAH92040)" FT /evidence="ECO:0000305" FT CONFLICT 543 FT /note="A -> T (in Ref. 3; AAH92040)" FT /evidence="ECO:0000305" SQ SEQUENCE 648 AA; 72917 MW; B70104AEF51C44A5 CRC64; MEHIQGAWKT ISNGFGLKDA VFDGSSCISP TIVQQFGYQR RASDDGKLTD SSKTSNTIRV FLPNKQRTVV NVRNGMSLHD CLMKALKVRG LQPECCAVFR LLQEHKGKKA RLDWNTDAAS LIGEELQVDF LDHVPLTTHN FARKTFLKLA FCDICQKFLL NGFRCQTCGY KFHEHCSTKV PTMCVDWSNI RQLLLFPNST VGDSGVPAPP SFPMRRMRES VSRMPASSQH RYSTPHAFTF NTSSPSSEGS LSQRQRSTST PNVHMVSTTL HVDSRMIEDA IRSHSESASP SALSSSPNNL SPTGWSQPKT PVPAQRERAP GSGTQEKNKI RPRGQRDSSY YWEIEASEVM LSTRIGSGSF GTVYKGKWHG DVAVKILKVV DPTPEQLQAF RNEVAVLRKT RHVNILLFMG YMTKDNLAIV TQWCEGSSLY KHLHVQETKF QMFQLIDIAR QTAQGMDYLH AKNIIHRDMK SNNIFLHEGL TVKIGDFGLA TVKSRWSGSQ QVEQPTGSVL WMAPEVIRMQ DDNPFSFQSD VYSYGIVLYE LMAGELPYAH INNRDQIIFM VGRGYASPDL SRLYKNCPKA MKRLVADCVK KVKEERPLFP QILSSIELLQ HSLPKINRSA SEPSLHRAAH TEDINACTLT TSPRLPVF //