UniProtKB - P04049 (RAF1_HUMAN)
RAF proto-oncogene serine/threonine-protein kinase
RAF1
Functioni
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.
8 PublicationsCatalytic activityi
- EC:2.7.11.11 PublicationThis reaction proceeds in the forward1 Publication direction.
- EC:2.7.11.11 PublicationThis reaction proceeds in the forward1 Publication direction.
Cofactori
Activity regulationi
Sites
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Metal bindingi | 139 | Zinc 1 | 1 | |
Metal bindingi | 152 | Zinc 2 | 1 | |
Metal bindingi | 155 | Zinc 2 | 1 | |
Metal bindingi | 165 | Zinc 1 | 1 | |
Metal bindingi | 168 | Zinc 1 | 1 | |
Metal bindingi | 173 | Zinc 2 | 1 | |
Metal bindingi | 176 | Zinc 2 | 1 | |
Metal bindingi | 184 | Zinc 1 | 1 | |
Binding sitei | 375 | ATPPROSITE-ProRule annotation | 1 | |
Active sitei | 468 | Proton acceptor | 1 |
Regions
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Zinc fingeri | 138 – 184 | Phorbol-ester/DAG-typePROSITE-ProRule annotationAdd BLAST | 47 | |
Nucleotide bindingi | 355 – 363 | ATPPROSITE-ProRule annotation | 9 |
GO - Molecular functioni
- ATP binding Source: UniProtKB-KW
- enzyme binding Source: UniProtKB
- identical protein binding Source: IntAct
- MAP kinase kinase kinase activity Source: GO_Central
- metal ion binding Source: UniProtKB-KW
- protein kinase activity Source: GO_Central
- protein serine/threonine/tyrosine kinase activity Source: RHEA
- protein serine/threonine kinase activity Source: UniProtKB
- protein serine kinase activity Source: RHEA
GO - Biological processi
- activation of adenylate cyclase activity Source: BHF-UCL
- apoptotic process Source: GO_Central
- cell differentiation Source: Ensembl
- death-inducing signaling complex assembly Source: Ensembl
- face development Source: Ensembl
- insulin secretion involved in cellular response to glucose stimulus Source: Ensembl
- intermediate filament cytoskeleton organization Source: Ensembl
- MAPK cascade Source: GO_Central
- negative regulation of apoptotic process Source: UniProtKB
- negative regulation of cell population proliferation Source: BHF-UCL
- negative regulation of cysteine-type endopeptidase activity involved in apoptotic process Source: UniProtKB
- negative regulation of extrinsic apoptotic signaling pathway via death domain receptors Source: Ensembl
- negative regulation of protein-containing complex assembly Source: UniProtKB
- neurotrophin TRK receptor signaling pathway Source: Ensembl
- positive regulation of MAPK cascade Source: GO_Central
- positive regulation of peptidyl-serine phosphorylation Source: UniProtKB
- positive regulation of transcription by RNA polymerase II Source: Ensembl
- protein phosphorylation Source: ProtInc
- regulation of apoptotic process Source: UniProtKB
- regulation of cell differentiation Source: UniProtKB
- regulation of cell motility Source: UniProtKB
- regulation of Rho protein signal transduction Source: UniProtKB
- response to muscle stretch Source: Ensembl
- signal transduction Source: ProtInc
- somatic stem cell population maintenance Source: Ensembl
- thymus development Source: Ensembl
- thyroid gland development Source: Ensembl
- wound healing Source: UniProtKB
Keywordsi
Molecular function | Kinase, Serine/threonine-protein kinase, Transferase |
Ligand | ATP-binding, Metal-binding, Nucleotide-binding, Zinc |
Enzyme and pathway databases
BRENDAi | 2.7.10.2, 2681 |
PathwayCommonsi | P04049 |
Reactomei | R-HSA-2672351, Stimuli-sensing channels R-HSA-392517, Rap1 signalling R-HSA-430116, GP1b-IX-V activation signalling R-HSA-5621575, CD209 (DC-SIGN) signaling R-HSA-5673000, RAF activation R-HSA-5674135, MAP2K and MAPK activation R-HSA-5674499, Negative feedback regulation of MAPK pathway R-HSA-5675221, Negative regulation of MAPK pathway R-HSA-6802946, Signaling by moderate kinase activity BRAF mutants R-HSA-6802948, Signaling by high-kinase activity BRAF mutants R-HSA-6802952, Signaling by BRAF and RAF1 fusions R-HSA-6802955, Paradoxical activation of RAF signaling by kinase inactive BRAF R-HSA-9649948, Signaling downstream of RAS mutants R-HSA-9656223, Signaling by RAF1 mutants R-HSA-9726840, SHOC2 M1731 mutant abolishes MRAS complex function R-HSA-9726842, Gain-of-function MRAS complexes activate RAF signaling |
SignaLinki | P04049 |
SIGNORi | P04049 |
Protein family/group databases
MoonDBi | P04049, Predicted |
Names & Taxonomyi
Protein namesi | Recommended name: RAF proto-oncogene serine/threonine-protein kinaseCurated (EC:2.7.11.11 Publication)Alternative name(s): Proto-oncogene c-RAF Short name: cRaf Raf-1 |
Gene namesi | |
Organismi | Homo sapiens (Human) |
Taxonomic identifieri | 9606 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Proteomesi |
|
Organism-specific databases
HGNCi | HGNC:9829, RAF1 |
MIMi | 164760, gene |
neXtProti | NX_P04049 |
VEuPathDBi | HostDB:ENSG00000132155 |
Subcellular locationi
Mitochondrion
Nucleus
Plasma membrane
Cytoplasm and Cytosol
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.
Cytosol
- cytosol Source: UniProtKB
Golgi apparatus
- Golgi apparatus Source: MGI
Mitochondrion
- mitochondrial outer membrane Source: ProtInc
- mitochondrion Source: GO_Central
Nucleus
- nucleus Source: UniProtKB-SubCell
Plasma Membrane
- plasma membrane Source: HPA
Other locations
- cytoplasm Source: MGI
- pseudopodium Source: Ensembl
Keywords - Cellular componenti
Cell membrane, Cytoplasm, Membrane, Mitochondrion, NucleusPathology & Biotechi
Involvement in diseasei
Noonan syndrome 5 (NS5)3 Publications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Natural variantiVAR_037807 | 256 | R → S in NS5. 1 PublicationCorresponds to variant dbSNP:rs397516826EnsemblClinVar. | 1 | |
Natural variantiVAR_037808 | 257 | S → L in NS5 and LPRD2; shows in vitro greater kinase activity and enhanced ERK activation than wild-type. 2 PublicationsCorresponds to variant dbSNP:rs80338796EnsemblClinVar. | 1 | |
Natural variantiVAR_037809 | 259 | S → F in NS5. 1 PublicationCorresponds to variant dbSNP:rs397516827EnsemblClinVar. | 1 | |
Natural variantiVAR_037811 | 260 | T → R in NS5. 1 Publication | 1 | |
Natural variantiVAR_037812 | 261 | P → A in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 1 PublicationCorresponds to variant dbSNP:rs121434594EnsemblClinVar. | 1 | |
Natural variantiVAR_037813 | 261 | P → L in NS5; shows greater kinase activity and enhanced MAPK1 activation than wild-type. 1 PublicationCorresponds to variant dbSNP:rs397516828EnsemblClinVar. | 1 | |
Natural variantiVAR_037814 | 261 | P → S in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 3 PublicationsCorresponds to variant dbSNP:rs121434594EnsemblClinVar. | 1 | |
Natural variantiVAR_037815 | 263 | V → A in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 1 PublicationCorresponds to variant dbSNP:rs397516830EnsemblClinVar. | 1 | |
Natural variantiVAR_037816 | 486 | D → G in NS5. 1 PublicationCorresponds to variant dbSNP:rs397516815EnsemblClinVar. | 1 | |
Natural variantiVAR_037817 | 486 | D → N in NS5; has reduced or absent kinase activity. 1 PublicationCorresponds to variant dbSNP:rs80338798EnsemblClinVar. | 1 | |
Natural variantiVAR_037818 | 491 | T → I in NS5; has reduced or absent kinase activity. 1 PublicationCorresponds to variant dbSNP:rs80338799EnsemblClinVar. | 1 | |
Natural variantiVAR_037819 | 491 | T → R in NS5. 1 PublicationCorresponds to variant dbSNP:rs80338799EnsemblClinVar. | 1 | |
Natural variantiVAR_037820 | 612 | S → T in NS5. 1 PublicationCorresponds to variant dbSNP:rs1448392469Ensembl. | 1 | |
Natural variantiVAR_037821 | 613 | L → V in NS5 and LPRD2; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 2 PublicationsCorresponds to variant dbSNP:rs80338797EnsemblClinVar. | 1 |
LEOPARD syndrome 2 (LPRD2)1 Publication
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Natural variantiVAR_037808 | 257 | S → L in NS5 and LPRD2; shows in vitro greater kinase activity and enhanced ERK activation than wild-type. 2 PublicationsCorresponds to variant dbSNP:rs80338796EnsemblClinVar. | 1 | |
Natural variantiVAR_037821 | 613 | L → V in NS5 and LPRD2; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 2 PublicationsCorresponds to variant dbSNP:rs80338797EnsemblClinVar. | 1 |
Cardiomyopathy, dilated 1NN (CMD1NN)1 Publication
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Natural variantiVAR_071844 | 237 | A → T in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant dbSNP:rs587777588EnsemblClinVar. | 1 | |
Natural variantiVAR_071845 | 310 | T → A in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant dbSNP:rs778155315Ensembl. | 1 | |
Natural variantiVAR_071846 | 332 | P → A in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant dbSNP:rs1057403865EnsemblClinVar. | 1 | |
Natural variantiVAR_071847 | 603 | L → P in CMD1NN; shows impaired kinase activity and reduced MAPK3 activation with this mutation. 1 PublicationCorresponds to variant dbSNP:rs587777586EnsemblClinVar. | 1 | |
Natural variantiVAR_071848 | 626 | H → R in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant dbSNP:rs1553609795EnsemblClinVar. | 1 | |
Natural variantiVAR_071849 | 641 | T → M in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant dbSNP:rs587777587EnsemblClinVar. | 1 |
Mutagenesis
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Mutagenesisi | 338 – 339 | SS → AA: Reduced kinase activity; when associated with 340-D-D-341. 1 Publication | 2 | |
Mutagenesisi | 338 – 339 | SS → DE: Non-inhibited by PPP5C. Constitutively active and non-inhibited by PPP5C; when associated with 340-D-D-341. 1 Publication | 2 | |
Mutagenesisi | 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. 1 Publication | 2 | |
Mutagenesisi | 375 | K → W: Catalytically inactive. 1 Publication | 1 | |
Mutagenesisi | 491 | T → D: Increased kinase activity but can still be inhibited by PPP5C; when associated with D-494. 1 Publication | 1 | |
Mutagenesisi | 494 | S → D: Increased kinase activity but can still be inhibited by PPP5C; when associated with D-491. 1 Publication | 1 | |
Mutagenesisi | 563 | R → K: Loss of methylation. Increased stability and catalytic activity in response to EGF treatment. 1 Publication | 1 |
Keywords - Diseasei
Cardiomyopathy, Deafness, Disease variant, Proto-oncogeneOrganism-specific databases
DisGeNETi | 5894 |
GeneReviewsi | RAF1 |
MalaCardsi | RAF1 |
MIMi | 611553, phenotype 611554, phenotype 615916, phenotype |
OpenTargetsi | ENSG00000132155 |
Orphaneti | 154, Familial isolated dilated cardiomyopathy 648, Noonan syndrome 500, Noonan syndrome with multiple lentigines 251615, Pilomyxoid astrocytoma |
PharmGKBi | PA34183 |
Miscellaneous databases
Pharosi | P04049, Tclin |
Chemistry databases
ChEMBLi | CHEMBL1906 |
DrugBanki | DB08862, Cholecystokinin DB08912, Dabrafenib DB12010, Fostamatinib DB05268, iCo-007 DB04973, LErafAON DB08896, Regorafenib DB00398, Sorafenib DB05190, XL281 |
DrugCentrali | P04049 |
GuidetoPHARMACOLOGYi | 2184 |
Genetic variation databases
BioMutai | RAF1 |
DMDMi | 125651 |
PTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
ChainiPRO_0000086596 | 1 – 648 | RAF proto-oncogene serine/threonine-protein kinaseAdd BLAST | 648 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Modified residuei | 29 | Phosphoserine; by MAPK1By similarity | 1 | |
Modified residuei | 43 | Phosphoserine; by PKA and MAPK11 Publication | 1 | |
Modified residuei | 252 | PhosphoserineCombined sources | 1 | |
Modified residuei | 259 | Phosphoserine; by PKA, PKC and PKB/AKT17 Publications | 1 | |
Modified residuei | 268 | Phosphothreonine; by autocatalysis1 Publication | 1 | |
Modified residuei | 269 | Phosphothreonine; by PKA1 Publication | 1 | |
Modified residuei | 289 | Phosphoserine; by MAPK1Combined sources1 Publication | 1 | |
Modified residuei | 296 | PhosphoserineCombined sources | 1 | |
Modified residuei | 301 | Phosphoserine; by MAPK1Combined sources1 Publication | 1 | |
Modified residuei | 338 | Phosphoserine; by PAK1, PAK2, PAK3 and PAK55 Publications | 1 | |
Modified residuei | 339 | Phosphoserine; by PAK1, PAK2 and PAK31 Publication | 1 | |
Modified residuei | 340 | Phosphotyrosine; by SRC1 Publication | 1 | |
Modified residuei | 341 | Phosphotyrosine; by SRC1 Publication | 1 | |
Modified residuei | 471 | Phosphoserine1 Publication | 1 | |
Modified residuei | 491 | Phosphothreonine1 Publication | 1 | |
Modified residuei | 494 | Phosphoserine1 Publication | 1 | |
Modified residuei | 499 | Phosphoserine; by PKC1 Publication | 1 | |
Modified residuei | 563 | Symmetric dimethylarginine; by PRMT51 Publication | 1 | |
Modified residuei | 621 | Phosphoserine4 Publications | 1 | |
Modified residuei | 642 | Phosphoserine; by MAPK1Combined sources | 1 |
Post-translational modificationi
Keywords - PTMi
Methylation, PhosphoproteinProteomic databases
CPTACi | CPTAC-1335 CPTAC-1336 CPTAC-1546 CPTAC-1762 |
EPDi | P04049 |
jPOSTi | P04049 |
MassIVEi | P04049 |
MaxQBi | P04049 |
PaxDbi | P04049 |
PeptideAtlasi | P04049 |
PRIDEi | P04049 |
ProteomicsDBi | 51637 [P04049-1] 51638 [P04049-2] |
PTM databases
GlyGeni | P04049, 1 site, 1 O-linked glycan (1 site) |
iPTMneti | P04049 |
PhosphoSitePlusi | P04049 |
Expressioni
Tissue specificityi
Gene expression databases
Bgeei | ENSG00000132155, Expressed in cerebellar hemisphere and 245 other tissues |
ExpressionAtlasi | P04049, baseline and differential |
Genevisiblei | P04049, HS |
Organism-specific databases
HPAi | ENSG00000132155, Low tissue specificity |
Interactioni
Subunit structurei
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 LZTR1 (PubMed:30368668).
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). Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not contain co-chaperones STIP1/HOP and PTGES3/p23 (PubMed:29127155).
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, PubMed:31024343).
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).
Interacts with MFHAS1 (PubMed:23327923).
Interacts with GLS (PubMed:22538822).
Interacts with NEK10 and MAP2K1; the interaction is direct with NEK10 and required for ERK1/2-signaling pathway activation in response to UV irradiation (PubMed:20956560).
By similarity24 PublicationsBinary interactionsi
P04049
GO - Molecular functioni
- enzyme binding Source: UniProtKB
- identical protein binding Source: IntAct
Protein-protein interaction databases
BioGRIDi | 111831, 310 interactors |
CORUMi | P04049 |
DIPi | DIP-1048N |
IntActi | P04049, 208 interactors |
MINTi | P04049 |
STRINGi | 9606.ENSP00000251849 |
Chemistry databases
BindingDBi | P04049 |
Miscellaneous databases
RNActi | P04049, protein |
Structurei
Secondary structure
3D structure databases
AlphaFoldDBi | P04049 |
BMRBi | P04049 |
SMRi | P04049 |
ModBasei | Search... |
PDBe-KBi | Search... |
Miscellaneous databases
EvolutionaryTracei | P04049 |
Family & Domainsi
Domains and Repeats
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Domaini | 56 – 131 | RBDPROSITE-ProRule annotationAdd BLAST | 76 | |
Domaini | 349 – 609 | Protein kinasePROSITE-ProRule annotationAdd BLAST | 261 |
Region
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Regioni | 220 – 334 | DisorderedSequence analysisAdd BLAST | 115 | |
Regioni | 331 – 349 | Interaction with PEBP1/RKIPAdd BLAST | 19 |
Compositional bias
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Compositional biasi | 222 – 269 | Polar residuesSequence analysisAdd BLAST | 48 | |
Compositional biasi | 284 – 310 | Polar residuesSequence analysisAdd BLAST | 27 |
Sequence similaritiesi
Zinc finger
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Zinc fingeri | 138 – 184 | Phorbol-ester/DAG-typePROSITE-ProRule annotationAdd BLAST | 47 |
Keywords - Domaini
Zinc-fingerPhylogenomic databases
eggNOGi | KOG0193, Eukaryota |
GeneTreei | ENSGT00940000156084 |
InParanoidi | P04049 |
OMAi | SWCHRFW |
OrthoDBi | 243095at2759 |
PhylomeDBi | P04049 |
TreeFami | TF317006 |
Family and domain databases
CDDi | cd00029, C1, 1 hit |
IDEALi | IID00292 |
InterProi | View protein in InterPro IPR046349, C1-like_sf IPR020454, DAG/PE-bd IPR011009, Kinase-like_dom_sf IPR002219, PE/DAG-bd IPR000719, Prot_kinase_dom IPR017441, Protein_kinase_ATP_BS IPR003116, RBD_dom IPR001245, Ser-Thr/Tyr_kinase_cat_dom IPR008271, Ser/Thr_kinase_AS IPR029071, Ubiquitin-like_domsf |
Pfami | View protein in Pfam PF00130, C1_1, 1 hit PF07714, PK_Tyr_Ser-Thr, 1 hit PF02196, RBD, 1 hit |
PRINTSi | PR00008, DAGPEDOMAIN |
SMARTi | View protein in SMART SM00109, C1, 1 hit SM00455, RBD, 1 hit SM00220, S_TKc, 1 hit |
SUPFAMi | SSF54236, SSF54236, 1 hit SSF56112, SSF56112, 1 hit SSF57889, SSF57889, 1 hit |
PROSITEi | View protein in PROSITE PS00107, PROTEIN_KINASE_ATP, 1 hit PS50011, PROTEIN_KINASE_DOM, 1 hit PS00108, PROTEIN_KINASE_ST, 1 hit PS50898, RBD, 1 hit PS00479, ZF_DAG_PE_1, 1 hit PS50081, ZF_DAG_PE_2, 1 hit |
s (2+)i Sequence
Sequence statusi: Complete.
This entry describes 2 produced by isoformsialternative splicing. AlignAdd to basketThis entry has 2 described isoforms and 26 potential isoforms that are computationally mapped.Show allAlign All
This isoform has been chosen as the sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry. canonicali
10 20 30 40 50
MEHIQGAWKT ISNGFGFKDA VFDGSSCISP TIVQQFGYQR RASDDGKLTD
60 70 80 90 100
PSKTSNTIRV FLPNKQRTVV NVRNGMSLHD CLMKALKVRG LQPECCAVFR
110 120 130 140 150
LLHEHKGKKA RLDWNTDAAS LIGEELQVDF LDHVPLTTHN FARKTFLKLA
160 170 180 190 200
FCDICQKFLL NGFRCQTCGY KFHEHCSTKV PTMCVDWSNI RQLLLFPNST
210 220 230 240 250
IGDSGVPALP SLTMRRMRES VSRMPVSSQH RYSTPHAFTF NTSSPSSEGS
260 270 280 290 300
LSQRQRSTST PNVHMVSTTL PVDSRMIEDA IRSHSESASP SALSSSPNNL
310 320 330 340 350
SPTGWSQPKT PVPAQRERAP VSGTQEKNKI RPRGQRDSSY YWEIEASEVM
360 370 380 390 400
LSTRIGSGSF GTVYKGKWHG DVAVKILKVV DPTPEQFQAF RNEVAVLRKT
410 420 430 440 450
RHVNILLFMG YMTKDNLAIV TQWCEGSSLY KHLHVQETKF QMFQLIDIAR
460 470 480 490 500
QTAQGMDYLH AKNIIHRDMK SNNIFLHEGL TVKIGDFGLA TVKSRWSGSQ
510 520 530 540 550
QVEQPTGSVL WMAPEVIRMQ DNNPFSFQSD VYSYGIVLYE LMTGELPYSH
560 570 580 590 600
INNRDQIIFM VGRGYASPDL SKLYKNCPKA MKRLVADCVK KVKEERPLFP
610 620 630 640
QILSSIELLQ HSLPKINRSA SEPSLHRAAH TEDINACTLT TSPRLPVF
Computationally mapped potential isoform sequencesi
There are 26 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basketA0A0S2Z4L5 | A0A0S2Z4L5_HUMAN | Non-specific serine/threonine prote... | RAF1 | 615 | Annotation score: | ||
H7C155 | H7C155_HUMAN | Non-specific serine/threonine prote... | RAF1 | 421 | Annotation score: | ||
A0A0B4J1W9 | A0A0B4J1W9_HUMAN | RAF proto-oncogene serine/threonine... | RAF1 | 87 | Annotation score: | ||
A0A8I5KX50 | A0A8I5KX50_HUMAN | RAF proto-oncogene serine/threonine... | RAF1 | 69 | Annotation score: | ||
A0A8I5KQ33 | A0A8I5KQ33_HUMAN | RAF proto-oncogene serine/threonine... | RAF1 | 346 | Annotation score: | ||
A0A8I5KQV4 | A0A8I5KQV4_HUMAN | RAF proto-oncogene serine/threonine... | RAF1 | 611 | Annotation score: | ||
A0A8I5KR46 | A0A8I5KR46_HUMAN | RAF proto-oncogene serine/threonine... | RAF1 | 193 | Annotation score: | ||
A0A8I5KRD1 | A0A8I5KRD1_HUMAN | RAF proto-oncogene serine/threonine... | RAF1 | 109 | Annotation score: | ||
A0A8I5KS16 | A0A8I5KS16_HUMAN | RAF proto-oncogene serine/threonine... | RAF1 | 494 | Annotation score: | ||
A0A8I5KSB0 | A0A8I5KSB0_HUMAN | RAF proto-oncogene serine/threonine... | RAF1 | 573 | Annotation score: | ||
There are more potential isoformsShow all |
Experimental Info
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Sequence conflicti | 240 | F → L in AAA60247 (PubMed:2993863).Curated | 1 | |
Sequence conflicti | 542 | M → I in AAA60247 (PubMed:2993863).Curated | 1 |
Natural variant
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Natural variantiVAR_071844 | 237 | A → T in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant dbSNP:rs587777588EnsemblClinVar. | 1 | |
Natural variantiVAR_037807 | 256 | R → S in NS5. 1 PublicationCorresponds to variant dbSNP:rs397516826EnsemblClinVar. | 1 | |
Natural variantiVAR_037808 | 257 | S → L in NS5 and LPRD2; shows in vitro greater kinase activity and enhanced ERK activation than wild-type. 2 PublicationsCorresponds to variant dbSNP:rs80338796EnsemblClinVar. | 1 | |
Natural variantiVAR_041037 | 259 | S → A in an ovarian serous carcinoma sample; somatic mutation; increased ERK activation. 2 PublicationsCorresponds to variant dbSNP:rs3730271EnsemblClinVar. | 1 | |
Natural variantiVAR_037809 | 259 | S → F in NS5. 1 PublicationCorresponds to variant dbSNP:rs397516827EnsemblClinVar. | 1 | |
Natural variantiVAR_037810 | 260 | T → I in hypertrophic cardiomyopathy; unknown pathological significance. 1 PublicationCorresponds to variant dbSNP:rs869025501EnsemblClinVar. | 1 | |
Natural variantiVAR_037811 | 260 | T → R in NS5. 1 Publication | 1 | |
Natural variantiVAR_037812 | 261 | P → A in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 1 PublicationCorresponds to variant dbSNP:rs121434594EnsemblClinVar. | 1 | |
Natural variantiVAR_037813 | 261 | P → L in NS5; shows greater kinase activity and enhanced MAPK1 activation than wild-type. 1 PublicationCorresponds to variant dbSNP:rs397516828EnsemblClinVar. | 1 | |
Natural variantiVAR_037814 | 261 | P → S in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 3 PublicationsCorresponds to variant dbSNP:rs121434594EnsemblClinVar. | 1 | |
Natural variantiVAR_037815 | 263 | V → A in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 1 PublicationCorresponds to variant dbSNP:rs397516830EnsemblClinVar. | 1 | |
Natural variantiVAR_018840 | 308 | P → L2 PublicationsCorresponds to variant dbSNP:rs5746220EnsemblClinVar. | 1 | |
Natural variantiVAR_071845 | 310 | T → A in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant dbSNP:rs778155315Ensembl. | 1 | |
Natural variantiVAR_071846 | 332 | P → A in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant dbSNP:rs1057403865EnsemblClinVar. | 1 | |
Natural variantiVAR_041038 | 335 | Q → H in a lung adenocarcinoma sample; somatic mutation. 1 Publication | 1 | |
Natural variantiVAR_037816 | 486 | D → G in NS5. 1 PublicationCorresponds to variant dbSNP:rs397516815EnsemblClinVar. | 1 | |
Natural variantiVAR_037817 | 486 | D → N in NS5; has reduced or absent kinase activity. 1 PublicationCorresponds to variant dbSNP:rs80338798EnsemblClinVar. | 1 | |
Natural variantiVAR_037818 | 491 | T → I in NS5; has reduced or absent kinase activity. 1 PublicationCorresponds to variant dbSNP:rs80338799EnsemblClinVar. | 1 | |
Natural variantiVAR_037819 | 491 | T → R in NS5. 1 PublicationCorresponds to variant dbSNP:rs80338799EnsemblClinVar. | 1 | |
Natural variantiVAR_071847 | 603 | L → P in CMD1NN; shows impaired kinase activity and reduced MAPK3 activation with this mutation. 1 PublicationCorresponds to variant dbSNP:rs587777586EnsemblClinVar. | 1 | |
Natural variantiVAR_037820 | 612 | S → T in NS5. 1 PublicationCorresponds to variant dbSNP:rs1448392469Ensembl. | 1 | |
Natural variantiVAR_037821 | 613 | L → V in NS5 and LPRD2; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 2 PublicationsCorresponds to variant dbSNP:rs80338797EnsemblClinVar. | 1 | |
Natural variantiVAR_071848 | 626 | H → R in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant dbSNP:rs1553609795EnsemblClinVar. | 1 | |
Natural variantiVAR_071849 | 641 | T → M in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant dbSNP:rs587777587EnsemblClinVar. | 1 |
Alternative sequence
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Alternative sequenceiVSP_034649 | 278 | E → ENNNLSASPRAWSRRFCLRG R in isoform 2. Curated | 1 |
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | X03484 mRNA Translation: CAA27204.1 AY271661 Genomic DNA Translation: AAP03432.1 AK312248 mRNA Translation: BAG35180.1 EU332868 Genomic DNA Translation: ABY87557.1 CH471055 Genomic DNA Translation: EAW64134.1 BC018119 mRNA Translation: AAH18119.1 L00212 , L00206, L00207, L00208, L00209, L00210, L00211, L00213, M11376 Genomic DNA Translation: AAA60247.1 X54851 Genomic DNA No translation available. |
CCDSi | CCDS2612.1 [P04049-1] CCDS87047.1 [P04049-2] |
PIRi | A00637, TVHUF6 S60341 |
RefSeqi | NP_002871.1, NM_002880.3 [P04049-1] XP_005265412.1, XM_005265355.2 XP_011532276.1, XM_011533974.2 [P04049-1] |
Genome annotation databases
Ensembli | ENST00000251849.9; ENSP00000251849.4; ENSG00000132155.14 ENST00000442415.7; ENSP00000401888.2; ENSG00000132155.14 [P04049-2] ENST00000685653.1; ENSP00000509968.1; ENSG00000132155.14 ENST00000691899.1; ENSP00000508763.1; ENSG00000132155.14 |
GeneIDi | 5894 |
KEGGi | hsa:5894 |
MANE-Selecti | ENST00000442415.7; ENSP00000401888.2; NM_001354689.3; NP_001341618.1 [P04049-2] |
UCSCi | uc003bxf.5, human [P04049-1] |
Keywords - Coding sequence diversityi
Alternative splicingSimilar proteinsi
Cross-referencesi
Web resourcesi
NIEHS-SNPs |
Atlas of Genetics and Cytogenetics in Oncology and Haematology |
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | X03484 mRNA Translation: CAA27204.1 AY271661 Genomic DNA Translation: AAP03432.1 AK312248 mRNA Translation: BAG35180.1 EU332868 Genomic DNA Translation: ABY87557.1 CH471055 Genomic DNA Translation: EAW64134.1 BC018119 mRNA Translation: AAH18119.1 L00212 , L00206, L00207, L00208, L00209, L00210, L00211, L00213, M11376 Genomic DNA Translation: AAA60247.1 X54851 Genomic DNA No translation available. |
CCDSi | CCDS2612.1 [P04049-1] CCDS87047.1 [P04049-2] |
PIRi | A00637, TVHUF6 S60341 |
RefSeqi | NP_002871.1, NM_002880.3 [P04049-1] XP_005265412.1, XM_005265355.2 XP_011532276.1, XM_011533974.2 [P04049-1] |
3D structure databases
Select the link destinations: PDBei RCSB PDBi PDBji Links Updated | PDB entry | Method | Resolution (Å) | Chain | Positions | PDBsum |
1C1Y | X-ray | 1.90 | B | 55-131 | [»] | |
1FAQ | NMR | - | A | 136-187 | [»] | |
1FAR | NMR | - | A | 136-187 | [»] | |
1GUA | X-ray | 2.00 | B | 51-131 | [»] | |
1RFA | NMR | - | A | 55-132 | [»] | |
3CU8 | X-ray | 2.40 | P/Q | 256-264 | [»] | |
3IQJ | X-ray | 1.15 | P | 255-264 | [»] | |
3IQU | X-ray | 1.05 | P | 255-260 | [»] | |
3IQV | X-ray | 1.20 | P | 255-260 | [»] | |
3KUC | X-ray | 1.92 | B | 51-131 | [»] | |
3KUD | X-ray | 2.15 | B | 51-131 | [»] | |
3NKX | X-ray | 2.40 | P/Q | 255-264 | [»] | |
3O8I | X-ray | 2.00 | B | 255-264 | [»] | |
3OMV | X-ray | 4.00 | A/B | 323-618 | [»] | |
4FJ3 | X-ray | 1.95 | P | 229-264 | [»] | |
4G0N | X-ray | 2.45 | B | 54-131 | [»] | |
4G3X | X-ray | 3.25 | B | 55-131 | [»] | |
4IEA | X-ray | 1.70 | P | 618-625 | [»] | |
4IHL | X-ray | 2.20 | P | 229-264 | [»] | |
6NTC | X-ray | 2.90 | B | 55-131 | [»] | |
6NTD | X-ray | 3.15 | B | 55-131 | [»] | |
6PTS | NMR | - | D | 56-187 | [»] | |
6PTW | NMR | - | D | 56-187 | [»] | |
6VJJ | X-ray | 1.40 | B | 52-131 | [»] | |
6XGU | X-ray | 2.70 | B | 52-188 | [»] | |
6XGV | X-ray | 2.11 | B | 52-188 | [»] | |
6XHA | X-ray | 2.87 | B | 52-188 | [»] | |
6XHB | X-ray | 2.50 | B | 52-188 | [»] | |
6XI7 | X-ray | 1.95 | B | 52-188 | [»] | |
7JHP | X-ray | 2.77 | C | 55-187 | [»] | |
AlphaFoldDBi | P04049 | |||||
BMRBi | P04049 | |||||
SMRi | P04049 | |||||
ModBasei | Search... | |||||
PDBe-KBi | Search... |
Protein-protein interaction databases
BioGRIDi | 111831, 310 interactors |
CORUMi | P04049 |
DIPi | DIP-1048N |
IntActi | P04049, 208 interactors |
MINTi | P04049 |
STRINGi | 9606.ENSP00000251849 |
Chemistry databases
BindingDBi | P04049 |
ChEMBLi | CHEMBL1906 |
DrugBanki | DB08862, Cholecystokinin DB08912, Dabrafenib DB12010, Fostamatinib DB05268, iCo-007 DB04973, LErafAON DB08896, Regorafenib DB00398, Sorafenib DB05190, XL281 |
DrugCentrali | P04049 |
GuidetoPHARMACOLOGYi | 2184 |
Protein family/group databases
MoonDBi | P04049, Predicted |
PTM databases
GlyGeni | P04049, 1 site, 1 O-linked glycan (1 site) |
iPTMneti | P04049 |
PhosphoSitePlusi | P04049 |
Genetic variation databases
BioMutai | RAF1 |
DMDMi | 125651 |
Proteomic databases
CPTACi | CPTAC-1335 CPTAC-1336 CPTAC-1546 CPTAC-1762 |
EPDi | P04049 |
jPOSTi | P04049 |
MassIVEi | P04049 |
MaxQBi | P04049 |
PaxDbi | P04049 |
PeptideAtlasi | P04049 |
PRIDEi | P04049 |
ProteomicsDBi | 51637 [P04049-1] 51638 [P04049-2] |
Protocols and materials databases
Antibodypediai | 1131, 3158 antibodies from 49 providers |
CPTCi | P04049, 8 antibodies |
DNASUi | 5894 |
Genome annotation databases
Ensembli | ENST00000251849.9; ENSP00000251849.4; ENSG00000132155.14 ENST00000442415.7; ENSP00000401888.2; ENSG00000132155.14 [P04049-2] ENST00000685653.1; ENSP00000509968.1; ENSG00000132155.14 ENST00000691899.1; ENSP00000508763.1; ENSG00000132155.14 |
GeneIDi | 5894 |
KEGGi | hsa:5894 |
MANE-Selecti | ENST00000442415.7; ENSP00000401888.2; NM_001354689.3; NP_001341618.1 [P04049-2] |
UCSCi | uc003bxf.5, human [P04049-1] |
Organism-specific databases
CTDi | 5894 |
DisGeNETi | 5894 |
GeneCardsi | RAF1 |
GeneReviewsi | RAF1 |
HGNCi | HGNC:9829, RAF1 |
HPAi | ENSG00000132155, Low tissue specificity |
MalaCardsi | RAF1 |
MIMi | 164760, gene 611553, phenotype 611554, phenotype 615916, phenotype |
neXtProti | NX_P04049 |
OpenTargetsi | ENSG00000132155 |
Orphaneti | 154, Familial isolated dilated cardiomyopathy 648, Noonan syndrome 500, Noonan syndrome with multiple lentigines 251615, Pilomyxoid astrocytoma |
PharmGKBi | PA34183 |
VEuPathDBi | HostDB:ENSG00000132155 |
GenAtlasi | Search... |
Phylogenomic databases
eggNOGi | KOG0193, Eukaryota |
GeneTreei | ENSGT00940000156084 |
InParanoidi | P04049 |
OMAi | SWCHRFW |
OrthoDBi | 243095at2759 |
PhylomeDBi | P04049 |
TreeFami | TF317006 |
Enzyme and pathway databases
BRENDAi | 2.7.10.2, 2681 |
PathwayCommonsi | P04049 |
Reactomei | R-HSA-2672351, Stimuli-sensing channels R-HSA-392517, Rap1 signalling R-HSA-430116, GP1b-IX-V activation signalling R-HSA-5621575, CD209 (DC-SIGN) signaling R-HSA-5673000, RAF activation R-HSA-5674135, MAP2K and MAPK activation R-HSA-5674499, Negative feedback regulation of MAPK pathway R-HSA-5675221, Negative regulation of MAPK pathway R-HSA-6802946, Signaling by moderate kinase activity BRAF mutants R-HSA-6802948, Signaling by high-kinase activity BRAF mutants R-HSA-6802952, Signaling by BRAF and RAF1 fusions R-HSA-6802955, Paradoxical activation of RAF signaling by kinase inactive BRAF R-HSA-9649948, Signaling downstream of RAS mutants R-HSA-9656223, Signaling by RAF1 mutants R-HSA-9726840, SHOC2 M1731 mutant abolishes MRAS complex function R-HSA-9726842, Gain-of-function MRAS complexes activate RAF signaling |
SignaLinki | P04049 |
SIGNORi | P04049 |
Miscellaneous databases
BioGRID-ORCSi | 5894, 93 hits in 1120 CRISPR screens |
ChiTaRSi | RAF1, human |
EvolutionaryTracei | P04049 |
GeneWikii | C-Raf |
GenomeRNAii | 5894 |
Pharosi | P04049, Tclin |
PROi | PR:P04049 |
RNActi | P04049, protein |
SOURCEi | Search... |
Gene expression databases
Bgeei | ENSG00000132155, Expressed in cerebellar hemisphere and 245 other tissues |
ExpressionAtlasi | P04049, baseline and differential |
Genevisiblei | P04049, HS |
Family and domain databases
CDDi | cd00029, C1, 1 hit |
IDEALi | IID00292 |
InterProi | View protein in InterPro IPR046349, C1-like_sf IPR020454, DAG/PE-bd IPR011009, Kinase-like_dom_sf IPR002219, PE/DAG-bd IPR000719, Prot_kinase_dom IPR017441, Protein_kinase_ATP_BS IPR003116, RBD_dom IPR001245, Ser-Thr/Tyr_kinase_cat_dom IPR008271, Ser/Thr_kinase_AS IPR029071, Ubiquitin-like_domsf |
Pfami | View protein in Pfam PF00130, C1_1, 1 hit PF07714, PK_Tyr_Ser-Thr, 1 hit PF02196, RBD, 1 hit |
PRINTSi | PR00008, DAGPEDOMAIN |
SMARTi | View protein in SMART SM00109, C1, 1 hit SM00455, RBD, 1 hit SM00220, S_TKc, 1 hit |
SUPFAMi | SSF54236, SSF54236, 1 hit SSF56112, SSF56112, 1 hit SSF57889, SSF57889, 1 hit |
PROSITEi | View protein in PROSITE PS00107, PROTEIN_KINASE_ATP, 1 hit PS50011, PROTEIN_KINASE_DOM, 1 hit PS00108, PROTEIN_KINASE_ST, 1 hit PS50898, RBD, 1 hit PS00479, ZF_DAG_PE_1, 1 hit PS50081, ZF_DAG_PE_2, 1 hit |
MobiDBi | Search... |
Entry informationi
Entry namei | RAF1_HUMAN | |
Accessioni | P04049Primary (citable) accession number: P04049 Secondary accession number(s): B0LPH8 Q9UC20 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | November 1, 1986 |
Last sequence update: | November 1, 1986 | |
Last modified: | May 25, 2022 | |
This is version 251 of the entry and version 1 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Chordata Protein Annotation Program | |
Disclaimer | Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care. |
Miscellaneousi
Keywords - Technical termi
3D-structure, Direct protein sequencing, Reference proteomeDocuments
- Human and mouse protein kinases
Human and mouse protein kinases: classification and index - Human chromosome 3
Human chromosome 3: entries, gene names and cross-references to MIM - Human entries with genetic variants
List of human entries with genetic variants - Human variants curated from literature reports
Index of human variants curated from literature reports - MIM cross-references
Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot - PDB cross-references
Index of Protein Data Bank (PDB) cross-references - SIMILARITY comments
Index of protein domains and families