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Protein

RAF proto-oncogene serine/threonine-protein kinase

Gene

RAF1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

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 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Cofactori

Zn2+Note: Binds 2 Zn2+ ions per subunit.

Enzyme regulationi

Regulation is a highly complex process involving membrane recruitment, protein-protein interactions, dimerization, and phosphorylation/dephosphorylation events. Ras-GTP recruits RAF1 to the membrane, thereby promoting its activation. The inactive conformation of RAF1 is maintained by autoinhibitory interactions occurring between the N-terminal regulatory and the C-terminal catalytic domains and by the binding of a 14-3-3 protein that contacts two phosphorylation sites, Ser-259 and Ser-621. Upon mitogenic stimulation, Ras and PPP2R1A cooperate to release autoinhibition and the subsequent phosphorylation of activating sites: Ser-338, Tyr-341, Thr-491, and Ser-494, yields a fully active kinase. Through a negative feedback mechanism involving MAPK1/ERK2, RAF1 is phosphorylated on Ser-29, Ser-43, Ser-289, Ser-296, Ser-301 and Ser-642 by MAPK1/ERK2, which yields an inactive, desensitized kinase. The signaling-competent conformation of RAF1 is finally re-established by the coordinated action of PIN1, a prolyl isomerase that converts pSer and pThr residues from the cis to the trans conformation, which is preferentially recognized and dephosphorylated by PPP2R1A. Activated by homodimerization and heterodimerization (with BRAF). Also regulated through association with other proteins such as KSR2, CNKSR1/CNK1, PEBP1/RKIP, PHB/prohibitin and SPRY4. PEBP1/RKIP acts by dissociating RAF1 from its substrates MAP2K1/MEK1 and MAP2K2/MEK2. PHB/prohibitin facilitates the displacement of 14-3-3 from RAF1 by activated Ras, thereby promoting cell membrane localization and phosphorylation of RAF1 at the activating Ser-338. SPRY4 inhibits Ras-independent, but not Ras-dependent, activation of RAF1. CNKSR1/CNK1 regulates Src-mediated RAF1 activation.8 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi139Zinc 11
Metal bindingi152Zinc 21
Metal bindingi155Zinc 21
Metal bindingi165Zinc 11
Metal bindingi168Zinc 11
Metal bindingi173Zinc 21
Metal bindingi176Zinc 21
Metal bindingi184Zinc 11
Binding sitei375ATPPROSITE-ProRule annotation1
Active sitei468Proton acceptor1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri138 – 184Phorbol-ester/DAG-typePROSITE-ProRule annotationAdd BLAST47
Nucleotide bindingi355 – 363ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • kinase activity Source: Reactome
  • MAP kinase kinase kinase activity Source: Ensembl
  • metal ion binding Source: UniProtKB-KW
  • protein kinase activity Source: ProtInc
  • protein serine/threonine kinase activity Source: UniProtKB

GO - Biological processi

  • activation of adenylate cyclase activity Source: BHF-UCL
  • activation of MAPKK activity Source: AgBase
  • apoptotic process Source: ProtInc
  • cell differentiation Source: Ensembl
  • cell proliferation Source: ProtInc
  • death-inducing signaling complex assembly Source: Ensembl
  • face development Source: Ensembl
  • heart development Source: Ensembl
  • insulin secretion involved in cellular response to glucose stimulus Source: Ensembl
  • intermediate filament cytoskeleton organization Source: Ensembl
  • ion transmembrane transport Source: Reactome
  • MAPK cascade Source: Reactome
  • negative regulation of apoptotic process Source: UniProtKB
  • negative regulation of cell 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 complex assembly Source: UniProtKB
  • neurotrophin TRK receptor signaling pathway Source: Ensembl
  • platelet activation Source: Reactome
  • positive regulation of peptidyl-serine phosphorylation Source: UniProtKB
  • positive regulation of transcription from RNA polymerase II promoter 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 hypoxia Source: Ensembl
  • response to muscle stretch Source: Ensembl
  • signal transduction Source: ProtInc
  • somatic stem cell population maintenance Source: Ensembl
  • stimulatory C-type lectin receptor signaling pathway Source: Reactome
  • thymus development Source: Ensembl
  • thyroid gland development Source: Ensembl
  • wound healing Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Ligandi

ATP-binding, Metal-binding, Nucleotide-binding, Zinc

Enzyme and pathway databases

BioCyciZFISH:HS05600-MONOMER.
BRENDAi2.7.10.2. 2681.
ReactomeiR-HSA-2672351. Stimuli-sensing channels.
R-HSA-392517. Rap1 signalling.
R-HSA-430116. GP1b-IX-V activation signalling.
R-HSA-442742. CREB phosphorylation through the activation of Ras.
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-6802949. Signaling by RAS mutants.
R-HSA-6802952. Signaling by BRAF and RAF fusions.
R-HSA-6802955. Paradoxical activation of RAF signaling by kinase inactive BRAF.
SignaLinkiP04049.
SIGNORiP04049.

Names & Taxonomyi

Protein namesi
Recommended name:
RAF proto-oncogene serine/threonine-protein kinase (EC:2.7.11.1)
Alternative name(s):
Proto-oncogene c-RAF
Short name:
cRaf
Raf-1
Gene namesi
Name:RAF1
Synonyms:RAF
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 3

Organism-specific databases

HGNCiHGNC:9829. RAF1.

Subcellular locationi

  • Cytoplasm
  • Cell membrane
  • Mitochondrion
  • Nucleus

  • Note: Colocalizes with RGS14 and BRAF in both the cytoplasm and membranes. Phosphorylation at Ser-259 impairs its membrane accumulation. Recruited to the cell membrane by the active Ras protein. Phosphorylation at Ser-338 and Ser-339 by PAK1 is required for its mitochondrial localization. Retinoic acid-induced Ser-621 phosphorylated form of RAF1 is predominantly localized at the nucleus.

GO - Cellular componenti

  • cytoplasm Source: UniProtKB
  • cytosol Source: UniProtKB
  • Golgi apparatus Source: MGI
  • mitochondrial outer membrane Source: ProtInc
  • nucleus Source: UniProtKB-SubCell
  • plasma membrane Source: MGI
  • pseudopodium Source: Ensembl
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane, Mitochondrion, Nucleus

Pathology & Biotechi

Involvement in diseasei

Noonan syndrome 5 (NS5)3 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA 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.
See also OMIM:611553
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_037807256R → S in NS5. 1 PublicationCorresponds to variant rs397516826dbSNPEnsembl.1
Natural variantiVAR_037808257S → L in NS5 and LPRD2; shows in vitro greater kinase activity and enhanced ERK activation than wild-type. 2 PublicationsCorresponds to variant rs80338796dbSNPEnsembl.1
Natural variantiVAR_037809259S → F in NS5. 1 Publication1
Natural variantiVAR_037811260T → R in NS5. 1 Publication1
Natural variantiVAR_037812261P → A in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 1 PublicationCorresponds to variant rs121434594dbSNPEnsembl.1
Natural variantiVAR_037813261P → L in NS5; shows greater kinase activity and enhanced MAPK1 activation than wild-type. 1 PublicationCorresponds to variant rs397516828dbSNPEnsembl.1
Natural variantiVAR_037814261P → S in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 3 PublicationsCorresponds to variant rs121434594dbSNPEnsembl.1
Natural variantiVAR_037815263V → A in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 1 Publication1
Natural variantiVAR_037816486D → G in NS5. 1 PublicationCorresponds to variant rs397516815dbSNPEnsembl.1
Natural variantiVAR_037817486D → N in NS5; has reduced or absent kinase activity. 1 PublicationCorresponds to variant rs80338798dbSNPEnsembl.1
Natural variantiVAR_037818491T → I in NS5; has reduced or absent kinase activity. 1 PublicationCorresponds to variant rs80338799dbSNPEnsembl.1
Natural variantiVAR_037819491T → R in NS5. 1 PublicationCorresponds to variant rs80338799dbSNPEnsembl.1
Natural variantiVAR_037820612S → T in NS5. 1 Publication1
Natural variantiVAR_037821613L → V in NS5 and LPRD2; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 2 PublicationsCorresponds to variant rs80338797dbSNPEnsembl.1
LEOPARD syndrome 2 (LPRD2)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness.
See also OMIM:611554
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_037808257S → L in NS5 and LPRD2; shows in vitro greater kinase activity and enhanced ERK activation than wild-type. 2 PublicationsCorresponds to variant rs80338796dbSNPEnsembl.1
Natural variantiVAR_037821613L → V in NS5 and LPRD2; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 2 PublicationsCorresponds to variant rs80338797dbSNPEnsembl.1
Cardiomyopathy, dilated 1NN (CMD1NN)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.
See also OMIM:615916
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_071844237A → T in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant rs587777588dbSNPEnsembl.1
Natural variantiVAR_071845310T → A in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant rs778155315dbSNPEnsembl.1
Natural variantiVAR_071846332P → A in CMD1NN; shows a mild increase in kinase activity. 1 Publication1
Natural variantiVAR_071847603L → P in CMD1NN; shows impaired kinase activity and reduced MAPK3 activation with this mutation. 1 PublicationCorresponds to variant rs587777586dbSNPEnsembl.1
Natural variantiVAR_071848626H → R in CMD1NN; shows a mild increase in kinase activity. 1 Publication1
Natural variantiVAR_071849641T → M in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant rs587777587dbSNPEnsembl.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi338 – 339SS → AA: Reduced kinase activity; when associated with 340-D-D-341. 1 Publication2
Mutagenesisi338 – 339SS → DE: Non-inhibited by PPP5C. Constituvely active and non-inhibited by PPP5C; when associated with 340-D-D-341. 1 Publication2
Mutagenesisi340 – 341YY → DD: Constituvely active and highly phosphorylated on S-338, inhibited by PPP5C. Reduced kinase activity; when associated with 338-A-A-339. Constituvely active and non-inhibited by PPP5C; when associated with 338-D-E-33. 1 Publication2
Mutagenesisi491T → D: Increased kinase activity but can still be inhibited by PPP5C; when associated with D-494. 1 Publication1
Mutagenesisi494S → D: Increased kinase activity but can still be inhibited by PPP5C; when associated with D-491. 1 Publication1
Mutagenesisi563R → K: Loss of methylation. Increased stability and catalytic activity in response to EGF treatment. 1 Publication1

Keywords - Diseasei

Cardiomyopathy, Deafness, Disease mutation, Proto-oncogene

Organism-specific databases

DisGeNETi5894.
MalaCardsiRAF1.
MIMi611553. phenotype.
611554. phenotype.
615916. phenotype.
OpenTargetsiENSG00000132155.
Orphaneti154. Familial isolated dilated cardiomyopathy.
500. LEOPARD syndrome.
648. Noonan syndrome.
251612. Pilocytic astrocytoma.
PharmGKBiPA34183.

Chemistry databases

ChEMBLiCHEMBL1906.
DrugBankiDB08912. Dabrafenib.
DB08896. Regorafenib.
DB00398. Sorafenib.
GuidetoPHARMACOLOGYi2184.

Polymorphism and mutation databases

BioMutaiRAF1.
DMDMi125651.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000865961 – 648RAF proto-oncogene serine/threonine-protein kinaseAdd BLAST648

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei29Phosphoserine; by MAPK1By similarity1
Modified residuei43Phosphoserine; by PKA and MAPK11 Publication1
Modified residuei233Phosphoserine; by PKA1 Publication1
Modified residuei252PhosphoserineCombined sources1
Modified residuei259Phosphoserine; by PKA, PKC and PKB/AKT17 Publications1
Modified residuei268Phosphothreonine; by autocatalysis1 Publication1
Modified residuei269Phosphothreonine; by PKA1 Publication1
Modified residuei289Phosphoserine; by MAPK1Combined sources1 Publication1
Modified residuei296PhosphoserineCombined sources1
Modified residuei301Phosphoserine; by MAPK1Combined sources1 Publication1
Modified residuei338Phosphoserine; by PAK1, PAK2, PAK3 and PAK55 Publications1
Modified residuei339Phosphoserine; by PAK1, PAK2 and PAK31 Publication1
Modified residuei340Phosphotyrosine; by SRC1 Publication1
Modified residuei341Phosphotyrosine; by SRC1 Publication1
Modified residuei471Phosphoserine1 Publication1
Modified residuei491Phosphothreonine1 Publication1
Modified residuei494Phosphoserine1 Publication1
Modified residuei497Phosphoserine; by PKC1 Publication1
Modified residuei499Phosphoserine; by PKC1 Publication1
Modified residuei563Symmetric dimethylarginine; by PRMT51 Publication1
Modified residuei621Phosphoserine4 Publications1
Modified residuei642Phosphoserine; by MAPK1Combined sources1

Post-translational modificationi

Phosphorylation at Thr-269, Ser-338, Tyr-341, Thr-491 and Ser-494 results in its activation. Phosphorylation at Ser-29, Ser-43, Ser-289, Ser-296, Ser-301 and Ser-642 by MAPK1/ERK2 results in its inactivation. Phosphorylation at Ser-259 induces the interaction with YWHAZ and inactivates kinase activity. Dephosphorylation of Ser-259 by the complex containing protein phosphatase 1, SHOC2 and M-Ras/MRAS relieves inactivation, leading to stimulate RAF1 activity. Phosphorylation at Ser-338 by PAK1 and PAK5 and Ser-339 by PAK1 is required for its mitochondrial localization. Phosphorylation at Ser-621 in response to growth factor treatment stabilizes the protein, possibly by preventing proteasomal degradation. Phosphorylation at Ser-289, Ser-296, Ser-301, Ser-338 and Ser-621 are somehow linked to the methylation potential of cells. Treatment of cells with HGF in the presence of the methylation inhibitor 5'-methylthioadenosine (MTA) results in increased phosphorylation at Ser-338 and Ser-621 and decreased phosphorylation at Ser-296, Ser-301 and Ser-338. Dephosphorylation at Ser-338 by PPP5C results in a activity decrease.15 Publications
Methylated at Arg-563 in response to EGF treatment. This modification leads to destabilization of the protein, possibly through proteasomal degradation.1 Publication

Keywords - PTMi

Methylation, Phosphoprotein

Proteomic databases

EPDiP04049.
MaxQBiP04049.
PaxDbiP04049.
PeptideAtlasiP04049.
PRIDEiP04049.

PTM databases

iPTMnetiP04049.
PhosphoSitePlusiP04049.

Miscellaneous databases

PMAP-CutDBP04049.

Expressioni

Tissue specificityi

In skeletal muscle, isoform 1 is more abundant than isoform 2.1 Publication

Gene expression databases

BgeeiENSG00000132155.
CleanExiHS_RAF1.
ExpressionAtlasiP04049. baseline and differential.
GenevisibleiP04049. HS.

Organism-specific databases

HPAiCAB019291.
HPA002640.

Interactioni

Subunit structurei

Monomer. 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. Interacts with FAM83B; displaces 14-3-3 proteins from RAF1 and activates RAF1 (PubMed:22886302).By similarity17 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
itself4EBI-365996,EBI-365996
AKT1P317492EBI-365996,EBI-296087
BADQ929342EBI-365996,EBI-700771
BRAFP1505646EBI-365996,EBI-365980
CCT3P493683EBI-365996,EBI-356673
CDC25AP303044EBI-365996,EBI-747671
CDC37Q165434EBI-365996,EBI-295634
CPS1P313274EBI-365996,EBI-536811
HRASP0111214EBI-365996,EBI-350145
HSP90AB1P082383EBI-365996,EBI-352572
HSPA5P110214EBI-365996,EBI-354921
KRASP01116-22EBI-365996,EBI-367427
LoxP283012EBI-365996,EBI-642911From a different organism.
MAP2K1Q0275031EBI-365996,EBI-492564
MAP2K2P365073EBI-365996,EBI-1056930
Mapk8ip3Q9ESN9-22EBI-365996,EBI-9549291From a different organism.
NFATC3Q129682EBI-365996,EBI-5278441
NSP034952EBI-365996,EBI-2548993From a different organism.
NS5AO394744EBI-365996,EBI-7016711From a different organism.
OIP5O434824EBI-365996,EBI-536879
PAK2Q131772EBI-365996,EBI-1045887
PDGFRBP096192EBI-365996,EBI-641237
PEBP1P300867EBI-365996,EBI-716384
PEBP4Q96S964EBI-365996,EBI-8563667
PKMP146183EBI-365996,EBI-353408
RAP1AP628342EBI-365996,EBI-491414
RAS2P011202EBI-365996,EBI-14838From a different organism.
RB1P064003EBI-365996,EBI-491274
RCAN1P53805-24EBI-365996,EBI-1541912
SFNP319473EBI-365996,EBI-476295
TIMM50Q3ZCQ84EBI-365996,EBI-355175
YWHABP3194618EBI-365996,EBI-359815
YWHAEP622583EBI-365996,EBI-356498
YWHAHQ049176EBI-365996,EBI-306940
YWHAQP273483EBI-365996,EBI-359854
YWHAZP6310413EBI-365996,EBI-347088

Protein-protein interaction databases

BioGridi111831. 159 interactors.
DIPiDIP-1048N.
IntActiP04049. 110 interactors.
MINTiMINT-86694.
STRINGi9606.ENSP00000251849.

Chemistry databases

BindingDBiP04049.

Structurei

Secondary structure

1648
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi57 – 62Combined sources6
Turni63 – 65Combined sources3
Beta strandi66 – 71Combined sources6
Helixi78 – 87Combined sources10
Turni88 – 90Combined sources3
Helixi93 – 95Combined sources3
Beta strandi96 – 102Combined sources7
Helixi103 – 105Combined sources3
Beta strandi106 – 112Combined sources7
Helixi118 – 121Combined sources4
Beta strandi125 – 130Combined sources6
Beta strandi142 – 144Combined sources3
Beta strandi155 – 159Combined sources5
Beta strandi161 – 164Combined sources4
Turni166 – 169Combined sources4
Helixi174 – 176Combined sources3
Beta strandi177 – 182Combined sources6

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1C1YX-ray1.90B55-131[»]
1FAQNMR-A136-187[»]
1FARNMR-A136-187[»]
1GUAX-ray2.00B51-131[»]
1RFANMR-A55-132[»]
3CU8X-ray2.40P/Q256-264[»]
3IQJX-ray1.15P255-264[»]
3IQUX-ray1.05P255-260[»]
3IQVX-ray1.20P255-260[»]
3KUCX-ray1.92B51-131[»]
3KUDX-ray2.15B51-131[»]
3NKXX-ray2.40P/Q255-264[»]
3O8IX-ray2.00B255-264[»]
3OMVX-ray4.00A/B323-618[»]
4FJ3X-ray1.95P229-264[»]
4G0NX-ray2.45B54-131[»]
4G3XX-ray3.25B55-131[»]
4IEAX-ray1.70P618-625[»]
4IHLX-ray2.20P229-264[»]
DisProtiDP00171.
ProteinModelPortaliP04049.
SMRiP04049.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP04049.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini56 – 131RBDPROSITE-ProRule annotationAdd BLAST76
Domaini349 – 609Protein kinasePROSITE-ProRule annotationAdd BLAST261

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni331 – 349Interaction with PEBP1/RKIPAdd BLAST19

Sequence similaritiesi

Contains 1 phorbol-ester/DAG-type zinc finger.PROSITE-ProRule annotation
Contains 1 protein kinase domain.PROSITE-ProRule annotation
Contains 1 RBD (Ras-binding) domain.PROSITE-ProRule annotation

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri138 – 184Phorbol-ester/DAG-typePROSITE-ProRule annotationAdd BLAST47

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiKOG0193. Eukaryota.
ENOG410Y4UP. LUCA.
GeneTreeiENSGT00760000118807.
HOGENOMiHOG000252972.
HOVERGENiHBG001886.
InParanoidiP04049.
KOiK04366.
OMAiDGPSCIS.
OrthoDBiEOG091G09SB.
PhylomeDBiP04049.
TreeFamiTF317006.

Family and domain databases

CDDicd00029. C1. 1 hit.
InterProiIPR020454. DAG/PE-bd.
IPR011009. Kinase-like_dom.
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-rel_dom.
[Graphical view]
PfamiPF00130. C1_1. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
PF02196. RBD. 1 hit.
[Graphical view]
PRINTSiPR00008. DAGPEDOMAIN.
SMARTiSM00109. C1. 1 hit.
SM00455. RBD. 1 hit.
SM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF54236. SSF54236. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiPS00107. 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.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P04049-1) [UniParc]FASTAAdd to basket
Also known as: 6C

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        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
Length:648
Mass (Da):73,052
Last modified:November 1, 1986 - v1
Checksum:iEF821B5349711BC3
GO
Isoform 2 (identifier: P04049-2) [UniParc]FASTAAdd to basket
Also known as: 1A

The sequence of this isoform differs from the canonical sequence as follows:
     278-278: E → ENNNLSASPRAWSRRFCLRGR

Show »
Length:668
Mass (Da):75,395
Checksum:iBD64D7A649342F5D
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti240F → L in AAA60247 (PubMed:2993863).Curated1
Sequence conflicti542M → I in AAA60247 (PubMed:2993863).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_071844237A → T in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant rs587777588dbSNPEnsembl.1
Natural variantiVAR_037807256R → S in NS5. 1 PublicationCorresponds to variant rs397516826dbSNPEnsembl.1
Natural variantiVAR_037808257S → L in NS5 and LPRD2; shows in vitro greater kinase activity and enhanced ERK activation than wild-type. 2 PublicationsCorresponds to variant rs80338796dbSNPEnsembl.1
Natural variantiVAR_041037259S → A in an ovarian serous carcinoma sample; somatic mutation; increased ERK activation. 2 Publications1
Natural variantiVAR_037809259S → F in NS5. 1 Publication1
Natural variantiVAR_037810260T → I in hypertrophic cardiomyopathy. 1 Publication1
Natural variantiVAR_037811260T → R in NS5. 1 Publication1
Natural variantiVAR_037812261P → A in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 1 PublicationCorresponds to variant rs121434594dbSNPEnsembl.1
Natural variantiVAR_037813261P → L in NS5; shows greater kinase activity and enhanced MAPK1 activation than wild-type. 1 PublicationCorresponds to variant rs397516828dbSNPEnsembl.1
Natural variantiVAR_037814261P → S in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 3 PublicationsCorresponds to variant rs121434594dbSNPEnsembl.1
Natural variantiVAR_037815263V → A in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 1 Publication1
Natural variantiVAR_018840308P → L.2 PublicationsCorresponds to variant rs5746220dbSNPEnsembl.1
Natural variantiVAR_071845310T → A in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant rs778155315dbSNPEnsembl.1
Natural variantiVAR_071846332P → A in CMD1NN; shows a mild increase in kinase activity. 1 Publication1
Natural variantiVAR_041038335Q → H in a lung adenocarcinoma sample; somatic mutation. 1 Publication1
Natural variantiVAR_037816486D → G in NS5. 1 PublicationCorresponds to variant rs397516815dbSNPEnsembl.1
Natural variantiVAR_037817486D → N in NS5; has reduced or absent kinase activity. 1 PublicationCorresponds to variant rs80338798dbSNPEnsembl.1
Natural variantiVAR_037818491T → I in NS5; has reduced or absent kinase activity. 1 PublicationCorresponds to variant rs80338799dbSNPEnsembl.1
Natural variantiVAR_037819491T → R in NS5. 1 PublicationCorresponds to variant rs80338799dbSNPEnsembl.1
Natural variantiVAR_071847603L → P in CMD1NN; shows impaired kinase activity and reduced MAPK3 activation with this mutation. 1 PublicationCorresponds to variant rs587777586dbSNPEnsembl.1
Natural variantiVAR_037820612S → T in NS5. 1 Publication1
Natural variantiVAR_037821613L → V in NS5 and LPRD2; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 2 PublicationsCorresponds to variant rs80338797dbSNPEnsembl.1
Natural variantiVAR_071848626H → R in CMD1NN; shows a mild increase in kinase activity. 1 Publication1
Natural variantiVAR_071849641T → M in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant rs587777587dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_034649278E → ENNNLSASPRAWSRRFCLRG R in isoform 2. Curated1

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.
CCDSiCCDS2612.1. [P04049-1]
PIRiA00637. TVHUF6.
S60341.
RefSeqiNP_002871.1. NM_002880.3. [P04049-1]
XP_005265412.1. XM_005265355.2. [P04049-1]
XP_011532276.1. XM_011533974.2. [P04049-1]
UniGeneiHs.159130.

Genome annotation databases

EnsembliENST00000251849; ENSP00000251849; ENSG00000132155. [P04049-1]
ENST00000442415; ENSP00000401888; ENSG00000132155. [P04049-2]
GeneIDi5894.
KEGGihsa:5894.
UCSCiuc003bxf.5. human. [P04049-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

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.
CCDSiCCDS2612.1. [P04049-1]
PIRiA00637. TVHUF6.
S60341.
RefSeqiNP_002871.1. NM_002880.3. [P04049-1]
XP_005265412.1. XM_005265355.2. [P04049-1]
XP_011532276.1. XM_011533974.2. [P04049-1]
UniGeneiHs.159130.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1C1YX-ray1.90B55-131[»]
1FAQNMR-A136-187[»]
1FARNMR-A136-187[»]
1GUAX-ray2.00B51-131[»]
1RFANMR-A55-132[»]
3CU8X-ray2.40P/Q256-264[»]
3IQJX-ray1.15P255-264[»]
3IQUX-ray1.05P255-260[»]
3IQVX-ray1.20P255-260[»]
3KUCX-ray1.92B51-131[»]
3KUDX-ray2.15B51-131[»]
3NKXX-ray2.40P/Q255-264[»]
3O8IX-ray2.00B255-264[»]
3OMVX-ray4.00A/B323-618[»]
4FJ3X-ray1.95P229-264[»]
4G0NX-ray2.45B54-131[»]
4G3XX-ray3.25B55-131[»]
4IEAX-ray1.70P618-625[»]
4IHLX-ray2.20P229-264[»]
DisProtiDP00171.
ProteinModelPortaliP04049.
SMRiP04049.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi111831. 159 interactors.
DIPiDIP-1048N.
IntActiP04049. 110 interactors.
MINTiMINT-86694.
STRINGi9606.ENSP00000251849.

Chemistry databases

BindingDBiP04049.
ChEMBLiCHEMBL1906.
DrugBankiDB08912. Dabrafenib.
DB08896. Regorafenib.
DB00398. Sorafenib.
GuidetoPHARMACOLOGYi2184.

PTM databases

iPTMnetiP04049.
PhosphoSitePlusiP04049.

Polymorphism and mutation databases

BioMutaiRAF1.
DMDMi125651.

Proteomic databases

EPDiP04049.
MaxQBiP04049.
PaxDbiP04049.
PeptideAtlasiP04049.
PRIDEiP04049.

Protocols and materials databases

DNASUi5894.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000251849; ENSP00000251849; ENSG00000132155. [P04049-1]
ENST00000442415; ENSP00000401888; ENSG00000132155. [P04049-2]
GeneIDi5894.
KEGGihsa:5894.
UCSCiuc003bxf.5. human. [P04049-1]

Organism-specific databases

CTDi5894.
DisGeNETi5894.
GeneCardsiRAF1.
GeneReviewsiRAF1.
HGNCiHGNC:9829. RAF1.
HPAiCAB019291.
HPA002640.
MalaCardsiRAF1.
MIMi164760. gene.
611553. phenotype.
611554. phenotype.
615916. phenotype.
neXtProtiNX_P04049.
OpenTargetsiENSG00000132155.
Orphaneti154. Familial isolated dilated cardiomyopathy.
500. LEOPARD syndrome.
648. Noonan syndrome.
251612. Pilocytic astrocytoma.
PharmGKBiPA34183.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0193. Eukaryota.
ENOG410Y4UP. LUCA.
GeneTreeiENSGT00760000118807.
HOGENOMiHOG000252972.
HOVERGENiHBG001886.
InParanoidiP04049.
KOiK04366.
OMAiDGPSCIS.
OrthoDBiEOG091G09SB.
PhylomeDBiP04049.
TreeFamiTF317006.

Enzyme and pathway databases

BioCyciZFISH:HS05600-MONOMER.
BRENDAi2.7.10.2. 2681.
ReactomeiR-HSA-2672351. Stimuli-sensing channels.
R-HSA-392517. Rap1 signalling.
R-HSA-430116. GP1b-IX-V activation signalling.
R-HSA-442742. CREB phosphorylation through the activation of Ras.
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-6802949. Signaling by RAS mutants.
R-HSA-6802952. Signaling by BRAF and RAF fusions.
R-HSA-6802955. Paradoxical activation of RAF signaling by kinase inactive BRAF.
SignaLinkiP04049.
SIGNORiP04049.

Miscellaneous databases

ChiTaRSiRAF1. human.
EvolutionaryTraceiP04049.
GeneWikiiC-Raf.
GenomeRNAii5894.
PMAP-CutDBP04049.
PROiP04049.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000132155.
CleanExiHS_RAF1.
ExpressionAtlasiP04049. baseline and differential.
GenevisibleiP04049. HS.

Family and domain databases

CDDicd00029. C1. 1 hit.
InterProiIPR020454. DAG/PE-bd.
IPR011009. Kinase-like_dom.
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-rel_dom.
[Graphical view]
PfamiPF00130. C1_1. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
PF02196. RBD. 1 hit.
[Graphical view]
PRINTSiPR00008. DAGPEDOMAIN.
SMARTiSM00109. C1. 1 hit.
SM00455. RBD. 1 hit.
SM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF54236. SSF54236. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiPS00107. 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.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiRAF1_HUMAN
AccessioniPrimary (citable) accession number: P04049
Secondary accession number(s): B0LPH8
, B2R5N3, Q15278, Q9UC20
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 1, 1986
Last sequence update: November 1, 1986
Last modified: November 30, 2016
This is version 208 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 3
    Human chromosome 3: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  7. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.