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MGP002571

UniProt Annotations

Entry Information
Gene NameRaf-1 proto-oncogene, serine/threonine kinase
Protein EntryRAF1_HUMAN
UniProt IDP04049
SpeciesHuman
Comments
Comment typeDescription
Alternative ProductsEvent=Alternative splicing; Named isoforms=2; Name=1; Synonyms=6C; IsoId=P04049-1; Sequence=Displayed; Name=2; Synonyms=1A; IsoId=P04049-2; Sequence=VSP_034649;
Catalytic ActivityATP + a protein = ADP + a phosphoprotein.
CofactorName=Zn(2+); Xref=ChEBI:CHEBI:29105; Note=Binds 2 Zn(2+) ions per subunit.;
DiseaseCardiomyopathy, 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.
DiseaseLEOPARD 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.
DiseaseNoonan 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.
Enzyme RegulationRegulation 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}.
FunctionSerine/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}.
InteractionSelf; NbExp=4; 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=39; 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=14; 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=2; IntAct=EBI-365996, EBI-367427; P28301:Lox (xeno); NbExp=2; IntAct=EBI-365996, EBI-642911; Q02750:MAP2K1; NbExp=5; IntAct=EBI-365996, EBI-492564; Q9ESN9-2:Mapk8ip3 (xeno); NbExp=2; IntAct=EBI-365996, EBI-9549291; Q12968:NFATC3; NbExp=2; IntAct=EBI-365996, EBI-5278441; 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; P09619:PDGFRB; NbExp=2; IntAct=EBI-365996, EBI-641237; P30086:PEBP1; NbExp=7; 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=2; IntAct=EBI-365996, EBI-476295; Q3ZCQ8:TIMM50; NbExp=3; IntAct=EBI-365996, EBI-355175; P31946:YWHAB; NbExp=17; IntAct=EBI-365996, EBI-359815; Q04917:YWHAH; NbExp=3; IntAct=EBI-365996, EBI-306940; P63104:YWHAZ; NbExp=12; IntAct=EBI-365996, EBI-347088;
PtmMethylated at Arg-563 in response to EGF treatment. This modification leads to destabilization of the protein, possibly through proteasomal degradation. {ECO:0000269|PubMed:21917714}.
PtmPhosphorylation 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 PAK7/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:17525332, ECO:0000269|PubMed:18465753, ECO:0000269|PubMed:18669648, ECO:0000269|PubMed:19690332, ECO:0000269|PubMed:21917714, ECO:0000269|PubMed:7477354, ECO:0000269|PubMed:8349614, ECO:0000269|PubMed:9823899}.
SimilarityBelongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. RAF subfamily. {ECO:0000305}.
SimilarityContains 1 phorbol-ester/DAG-type zinc finger. {ECO:0000255|PROSITE-ProRule:PRU00226}.
SimilarityContains 1 protein kinase domain. {ECO:0000255|PROSITE-ProRule:PRU00159}.
SimilarityContains 1 RBD (Ras-binding) domain. {ECO:0000255|PROSITE-ProRule:PRU00262}.
Subcellular LocationCytoplasm. 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.
SubunitMonomer. Homodimer. Heterodimerizes with BRAF and this heterodimer possesses a highly increased kinase activity compared to the respective homodimers or monomers. Heterodimerization is mitogen-regulated and enhanced by 14-3-3 proteins. MAPK1/ERK2 activation can induce a negative feedback that promotes the dissociation of the heterodimer. Forms a multiprotein complex with Ras (M-Ras/MRAS), SHOC2 and protein phosphatase 1 (PPP1CA, PPP1CB and PPP1CC). Interacts with Ras proteins; the interaction is antagonized by RIN1. 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. Interacts (when phosphorylated at Ser-259) with YWHAZ (unphosphorylated at 'Thr- 232'). 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. Interacts with PAK1 (via kinase domain). The phosphorylated form interacts with PIN1. The Ser-338 and Ser-339 phosphorylated form (by PAK1) interacts with BCL2. Interacts with PEBP1/RKIP and this interaction is enhanced if RAF1 is phosphorylated on residues Ser- 338, Ser-339, Tyr-340 and Tyr-341. Interacts with ADCY2, ADCY5, ADCY6, DGKH, RCAN1/DSCR1, ROCK2, PPP1R12A, PKB/AKT1, PPP2CA, PPP2R1B, SPRY2, SPRY4, CNKSR1/CNK1, KSR2 and PHB/prohibitin. In its active form, interacts with PRMT5. {ECO:0000250, ECO:0000269|PubMed:10576742, ECO:0000269|PubMed:10801873, ECO:0000269|PubMed:11427728, ECO:0000269|PubMed:11719507, ECO:0000269|PubMed:11733498, 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:9360956}.
Tissue SpecificityIn skeletal muscle, isoform 1 is more abundant than isoform 2. {ECO:0000269|PubMed:1886707}.
Web ResourceName=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/RAF1ID42032ch3p25.html";
Web ResourceName=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/raf1/";
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