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P04049

- RAF1_HUMAN

UniProt

P04049 - RAF1_HUMAN

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Protein

RAF proto-oncogene serine/threonine-protein kinase

Gene

RAF1

Organism
Homo sapiens (Human)
Status
Reviewed - 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

Binds 2 zinc 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)LengthDescriptionGraphical viewFeature identifierActions
Metal bindingi139 – 1391Zinc 1
Metal bindingi152 – 1521Zinc 2
Metal bindingi155 – 1551Zinc 2
Metal bindingi165 – 1651Zinc 1
Metal bindingi168 – 1681Zinc 1
Metal bindingi173 – 1731Zinc 2
Metal bindingi176 – 1761Zinc 2
Metal bindingi184 – 1841Zinc 1
Binding sitei375 – 3751ATPPROSITE-ProRule annotation
Active sitei468 – 4681Proton acceptor

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Zinc fingeri138 – 18447Phorbol-ester/DAG-typePROSITE-ProRule annotationAdd
BLAST
Nucleotide bindingi355 – 3639ATPPROSITE-ProRule annotation

GO - Molecular functioni

  1. ATP binding Source: UniProtKB-KW
  2. identical protein binding Source: IntAct
  3. MAP kinase kinase kinase activity Source: Ensembl
  4. metal ion binding Source: UniProtKB-KW
  5. protein kinase activity Source: ProtInc
  6. protein serine/threonine kinase activity Source: UniProtKB

GO - Biological processi

  1. activation of adenylate cyclase activity Source: BHF-UCL
  2. activation of MAPKK activity Source: Reactome
  3. apoptotic process Source: ProtInc
  4. axon guidance Source: Reactome
  5. blood coagulation Source: Reactome
  6. cell proliferation Source: ProtInc
  7. death-inducing signaling complex assembly Source: Ensembl
  8. epidermal growth factor receptor signaling pathway Source: Reactome
  9. Fc-epsilon receptor signaling pathway Source: Reactome
  10. fibroblast growth factor receptor signaling pathway Source: Reactome
  11. heart development Source: Ensembl
  12. innate immune response Source: Reactome
  13. insulin receptor signaling pathway Source: Reactome
  14. intermediate filament cytoskeleton organization Source: Ensembl
  15. ion transmembrane transport Source: Reactome
  16. MAPK cascade Source: Reactome
  17. negative regulation of apoptotic process Source: UniProtKB
  18. negative regulation of cell proliferation Source: BHF-UCL
  19. negative regulation of cysteine-type endopeptidase activity involved in apoptotic process Source: UniProtKB
  20. negative regulation of extrinsic apoptotic signaling pathway via death domain receptors Source: Ensembl
  21. negative regulation of protein complex assembly Source: UniProtKB
  22. neurotrophin TRK receptor signaling pathway Source: Reactome
  23. platelet activation Source: Reactome
  24. positive regulation of peptidyl-serine phosphorylation Source: UniProtKB
  25. protein phosphorylation Source: ProtInc
  26. Ras protein signal transduction Source: Reactome
  27. regulation of apoptotic process Source: UniProtKB
  28. regulation of cell differentiation Source: UniProtKB
  29. regulation of cell motility Source: UniProtKB
  30. regulation of Rho protein signal transduction Source: UniProtKB
  31. response to hypoxia Source: Ensembl
  32. signal transduction Source: ProtInc
  33. small GTPase mediated signal transduction Source: Reactome
  34. somatic stem cell maintenance Source: Ensembl
  35. synaptic transmission Source: Reactome
  36. transmembrane transport Source: Reactome
  37. 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

BRENDAi2.7.10.2. 2681.
ReactomeiREACT_160189. Stimuli-sensing channels.
REACT_20568. CREB phosphorylation through the activation of Ras.
REACT_2077. RAF activation.
REACT_23847. GP1b-IX-V activation signalling.
REACT_23898. Rap1 signalling.
REACT_614. RAF phosphorylates MEK.
REACT_962. MEK activation.
SignaLinkiP04049.

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
ProteomesiUP000005640: 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

  1. cytoplasm Source: UniProtKB
  2. cytosol Source: UniProtKB
  3. Golgi apparatus Source: MGI
  4. mitochondrial outer membrane Source: ProtInc
  5. nucleus Source: UniProtKB-KW
  6. plasma membrane Source: MGI
  7. pseudopodium Source: Ensembl
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane, Mitochondrion, Nucleus

Pathology & Biotechi

Involvement in diseasei

Noonan 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.3 Publications
Note: The disease is caused by mutations affecting the gene represented in this entry.
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti256 – 2561R → S in NS5. 1 Publication
VAR_037807
Natural varianti257 – 2571S → L in NS5 and LEOPARD2; shows in vitro greater kinase activity and enhanced ERK activation than wild-type. 2 Publications
VAR_037808
Natural varianti259 – 2591S → F in NS5. 1 Publication
VAR_037809
Natural varianti260 – 2601T → R in NS5. 1 Publication
VAR_037811
Natural varianti261 – 2611P → A in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 1 Publication
VAR_037812
Natural varianti261 – 2611P → L in NS5; shows greater kinase activity and enhanced MAPK1 activation than wild-type. 1 Publication
VAR_037813
Natural varianti261 – 2611P → S in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 3 Publications
VAR_037814
Natural varianti263 – 2631V → A in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 1 Publication
VAR_037815
Natural varianti486 – 4861D → G in NS5. 1 Publication
VAR_037816
Natural varianti486 – 4861D → N in NS5; has reduced or absent kinase activity. 1 Publication
VAR_037817
Natural varianti491 – 4911T → I in NS5; has reduced or absent kinase activity. 1 Publication
VAR_037818
Natural varianti491 – 4911T → R in NS5. 1 Publication
VAR_037819
Natural varianti612 – 6121S → T in NS5. 1 Publication
VAR_037820
Natural varianti613 – 6131L → V in NS5 and LEOPARD2; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 2 Publications
VAR_037821
LEOPARD syndrome 2 (LEOPARD2) [MIM:611554]: A disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness.1 Publication
Note: The disease is caused by mutations affecting the gene represented in this entry.
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti257 – 2571S → L in NS5 and LEOPARD2; shows in vitro greater kinase activity and enhanced ERK activation than wild-type. 2 Publications
VAR_037808
Natural varianti613 – 6131L → V in NS5 and LEOPARD2; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 2 Publications
VAR_037821

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi338 – 3392SS → AA: Reduced kinase activity; when associated with 340-D-D-341. 1 Publication
Mutagenesisi338 – 3392SS → DE: Non-inhibited by PPP5C. Constituvely active and non-inhibited by PPP5C; when associated with 340-D-D-341. 1 Publication
Mutagenesisi340 – 3412YY → 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 Publication
Mutagenesisi491 – 4911T → D: Increased kinase activity but can still be inhibited by PPP5C; when associated with D-494. 1 Publication
Mutagenesisi494 – 4941S → D: Increased kinase activity but can still be inhibited by PPP5C; when associated with D-491. 1 Publication
Mutagenesisi563 – 5631R → K: Loss of methylation. Increased stability and catalytic activity in response to EGF treatment. 1 Publication

Keywords - Diseasei

Deafness, Disease mutation, Proto-oncogene

Organism-specific databases

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

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 648648RAF proto-oncogene serine/threonine-protein kinasePRO_0000086596Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei29 – 291Phosphoserine; by MAPK1By similarity
Modified residuei43 – 431Phosphoserine; by PKA and MAPK11 Publication
Modified residuei233 – 2331Phosphoserine; by PKA1 Publication
Modified residuei252 – 2521Phosphoserine1 Publication
Modified residuei259 – 2591Phosphoserine; by PKA, PKC and PKB/AKT17 Publications
Modified residuei268 – 2681Phosphothreonine; by autocatalysis1 Publication
Modified residuei269 – 2691Phosphothreonine; by PKA1 Publication
Modified residuei289 – 2891Phosphoserine; by MAPK12 Publications
Modified residuei296 – 2961Phosphoserine; by MAPK1By similarity
Modified residuei301 – 3011Phosphoserine; by MAPK12 Publications
Modified residuei338 – 3381Phosphoserine; by PAK1, PAK2, PAK3 and PAK7/PAK55 Publications
Modified residuei339 – 3391Phosphoserine; by PAK1, PAK2 and PAK31 Publication
Modified residuei340 – 3401Phosphotyrosine; by SRC1 Publication
Modified residuei341 – 3411Phosphotyrosine; by SRC1 Publication
Modified residuei471 – 4711Phosphoserine1 Publication
Modified residuei491 – 4911Phosphothreonine1 Publication
Modified residuei494 – 4941Phosphoserine1 Publication
Modified residuei497 – 4971Phosphoserine; by PKC1 Publication
Modified residuei499 – 4991Phosphoserine; by PKC1 Publication
Modified residuei563 – 5631Symmetric dimethylarginine; by PRMT51 Publication
Modified residuei621 – 6211Phosphoserine4 Publications
Modified residuei642 – 6421Phosphoserine; by MAPK11 Publication

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 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.18 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

MaxQBiP04049.
PaxDbiP04049.
PRIDEiP04049.

PTM databases

PhosphoSiteiP04049.

Miscellaneous databases

PMAP-CutDBP04049.

Expressioni

Tissue specificityi

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

Gene expression databases

BgeeiP04049.
CleanExiHS_RAF1.
ExpressionAtlasiP04049. baseline and differential.
GenevestigatoriP04049.

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.By similarity16 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
itself4EBI-365996,EBI-365996
AKT1P317492EBI-365996,EBI-296087
BADQ929342EBI-365996,EBI-700771
BRAFP1505639EBI-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.
MAP2K1Q027505EBI-365996,EBI-492564
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
SFNP319472EBI-365996,EBI-476295
TIMM50Q3ZCQ83EBI-365996,EBI-355175
YWHABP3194617EBI-365996,EBI-359815
YWHAHQ049173EBI-365996,EBI-306940
YWHAZP6310412EBI-365996,EBI-347088

Protein-protein interaction databases

BioGridi111831. 123 interactions.
DIPiDIP-1048N.
IntActiP04049. 87 interactions.
MINTiMINT-86694.
STRINGi9606.ENSP00000251849.

Structurei

Secondary structure

1
648
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Beta strandi57 – 626
Turni63 – 653
Beta strandi66 – 716
Helixi78 – 8710
Turni88 – 903
Helixi93 – 953
Beta strandi96 – 1027
Helixi103 – 1053
Beta strandi106 – 1127
Helixi118 – 1214
Beta strandi125 – 1306
Beta strandi142 – 1443
Beta strandi155 – 1595
Beta strandi161 – 1644
Turni166 – 1694
Helixi174 – 1763
Beta strandi177 – 1826

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
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. Positions 55-131, 136-187, 325-633.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP04049.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini56 – 13176RBDPROSITE-ProRule annotationAdd
BLAST
Domaini349 – 609261Protein kinasePROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni331 – 34919Interaction with PEBP1/RKIPAdd
BLAST

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)LengthDescriptionGraphical viewFeature identifierActions
Zinc fingeri138 – 18447Phorbol-ester/DAG-typePROSITE-ProRule annotationAdd
BLAST

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00760000118807.
HOGENOMiHOG000252972.
HOVERGENiHBG001886.
InParanoidiP04049.
KOiK04366.
OMAiDGPSCIS.
OrthoDBiEOG7F5128.
PhylomeDBiP04049.
TreeFamiTF317006.

Family and domain databases

InterProiIPR020454. DAG/PE-bd.
IPR011009. Kinase-like_dom.
IPR002219. PE/DAG-bd.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR003116. Raf-like_ras-bd.
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.
[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. Align

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)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti240 – 2401F → L in AAA60247. (PubMed:2993863)Curated
Sequence conflicti542 – 5421M → I in AAA60247. (PubMed:2993863)Curated

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti256 – 2561R → S in NS5. 1 Publication
VAR_037807
Natural varianti257 – 2571S → L in NS5 and LEOPARD2; shows in vitro greater kinase activity and enhanced ERK activation than wild-type. 2 Publications
VAR_037808
Natural varianti259 – 2591S → A in an ovarian serous carcinoma sample; somatic mutation; increased ERK activation. 1 Publication
VAR_041037
Natural varianti259 – 2591S → F in NS5. 1 Publication
VAR_037809
Natural varianti260 – 2601T → I in hypertrophic cardiomyopathy. 1 Publication
VAR_037810
Natural varianti260 – 2601T → R in NS5. 1 Publication
VAR_037811
Natural varianti261 – 2611P → A in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 1 Publication
VAR_037812
Natural varianti261 – 2611P → L in NS5; shows greater kinase activity and enhanced MAPK1 activation than wild-type. 1 Publication
VAR_037813
Natural varianti261 – 2611P → S in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 3 Publications
VAR_037814
Natural varianti263 – 2631V → A in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 1 Publication
VAR_037815
Natural varianti308 – 3081P → L.2 Publications
Corresponds to variant rs5746220 [ dbSNP | Ensembl ].
VAR_018840
Natural varianti335 – 3351Q → H in a lung adenocarcinoma sample; somatic mutation. 1 Publication
VAR_041038
Natural varianti486 – 4861D → G in NS5. 1 Publication
VAR_037816
Natural varianti486 – 4861D → N in NS5; has reduced or absent kinase activity. 1 Publication
VAR_037817
Natural varianti491 – 4911T → I in NS5; has reduced or absent kinase activity. 1 Publication
VAR_037818
Natural varianti491 – 4911T → R in NS5. 1 Publication
VAR_037819
Natural varianti612 – 6121S → T in NS5. 1 Publication
VAR_037820
Natural varianti613 – 6131L → V in NS5 and LEOPARD2; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 2 Publications
VAR_037821

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei278 – 2781E → ENNNLSASPRAWSRRFCLRG R in isoform 2. CuratedVSP_034649

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
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_005265355.1. [P04049-1]
UniGeneiHs.159130.

Genome annotation databases

EnsembliENST00000251849; ENSP00000251849; ENSG00000132155. [P04049-1]
ENST00000442415; ENSP00000401888; ENSG00000132155. [P04049-2]
GeneIDi5894.
KEGGihsa:5894.
UCSCiuc003bxf.4. human. [P04049-1]

Polymorphism databases

DMDMi125651.

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:
EMBL
GenBank
DDBJ
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 ]
PIRi A00637. TVHUF6.
S60341.
RefSeqi NP_002871.1. NM_002880.3. [P04049-1 ]
XP_005265412.1. XM_005265355.1. [P04049-1 ]
UniGenei Hs.159130.

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
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 [» ]
DisProti DP00171.
ProteinModelPortali P04049.
SMRi P04049. Positions 55-131, 136-187, 325-633.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 111831. 123 interactions.
DIPi DIP-1048N.
IntActi P04049. 87 interactions.
MINTi MINT-86694.
STRINGi 9606.ENSP00000251849.

Chemistry

BindingDBi P04049.
ChEMBLi CHEMBL1906.
DrugBanki DB08912. Dabrafenib.
DB08896. Regorafenib.
DB00398. Sorafenib.
GuidetoPHARMACOLOGYi 2184.

PTM databases

PhosphoSitei P04049.

Polymorphism databases

DMDMi 125651.

Proteomic databases

MaxQBi P04049.
PaxDbi P04049.
PRIDEi P04049.

Protocols and materials databases

DNASUi 5894.
Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENST00000251849 ; ENSP00000251849 ; ENSG00000132155 . [P04049-1 ]
ENST00000442415 ; ENSP00000401888 ; ENSG00000132155 . [P04049-2 ]
GeneIDi 5894.
KEGGi hsa:5894.
UCSCi uc003bxf.4. human. [P04049-1 ]

Organism-specific databases

CTDi 5894.
GeneCardsi GC03M012625.
GeneReviewsi RAF1.
HGNCi HGNC:9829. RAF1.
HPAi CAB019291.
HPA002640.
MIMi 164760. gene.
611553. phenotype.
611554. phenotype.
neXtProti NX_P04049.
Orphaneti 154. Familial isolated dilated cardiomyopathy.
500. LEOPARD syndrome.
648. Noonan syndrome.
251612. Pilocytic astrocytoma.
PharmGKBi PA34183.
GenAtlasi Search...

Phylogenomic databases

eggNOGi COG0515.
GeneTreei ENSGT00760000118807.
HOGENOMi HOG000252972.
HOVERGENi HBG001886.
InParanoidi P04049.
KOi K04366.
OMAi DGPSCIS.
OrthoDBi EOG7F5128.
PhylomeDBi P04049.
TreeFami TF317006.

Enzyme and pathway databases

BRENDAi 2.7.10.2. 2681.
Reactomei REACT_160189. Stimuli-sensing channels.
REACT_20568. CREB phosphorylation through the activation of Ras.
REACT_2077. RAF activation.
REACT_23847. GP1b-IX-V activation signalling.
REACT_23898. Rap1 signalling.
REACT_614. RAF phosphorylates MEK.
REACT_962. MEK activation.
SignaLinki P04049.

Miscellaneous databases

ChiTaRSi RAF1. human.
EvolutionaryTracei P04049.
GeneWikii C-Raf.
GenomeRNAii 5894.
NextBioi 22930.
PMAP-CutDB P04049.
PROi P04049.
SOURCEi Search...

Gene expression databases

Bgeei P04049.
CleanExi HS_RAF1.
ExpressionAtlasi P04049. baseline and differential.
Genevestigatori P04049.

Family and domain databases

InterProi IPR020454. DAG/PE-bd.
IPR011009. Kinase-like_dom.
IPR002219. PE/DAG-bd.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR003116. Raf-like_ras-bd.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008271. Ser/Thr_kinase_AS.
IPR029071. Ubiquitin-rel_dom.
[Graphical view ]
Pfami PF00130. C1_1. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
PF02196. RBD. 1 hit.
[Graphical view ]
PRINTSi PR00008. DAGPEDOMAIN.
SMARTi SM00109. C1. 1 hit.
SM00455. RBD. 1 hit.
[Graphical view ]
SUPFAMi SSF54236. SSF54236. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEi 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.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  1. "The complete coding sequence of the human raf oncogene and the corresponding structure of the c-raf-1 gene."
    Bonner T.I., Oppermann H., Seeburg P., Kerby S.B., Gunnell M.A., Young A.C., Rapp U.R.
    Nucleic Acids Res. 14:1009-1015(1986) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
  2. "Complete sequencing and characterization of 21,243 full-length human cDNAs."
    Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.
    , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
    Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), VARIANT LEU-308.
  3. NIEHS SNPs program
    Submitted (DEC-2007) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT LEU-308.
  4. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  5. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
    Tissue: Pancreas.
  6. "Structure and biological activity of human homologs of the raf/mil oncogene."
    Bonner T.I., Kerby S.B., Sutrave P., Gunnell M.A., Mark G., Rapp U.R.
    Mol. Cell. Biol. 5:1400-1407(1985) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 228-648.
  7. "Protein arginine methyltransferase 5 regulates ERK1/2 signal transduction amplitude and cell fate through CRAF."
    Andreu-Perez P., Esteve-Puig R., de Torre-Minguela C., Lopez-Fauqued M., Bech-Serra J.J., Tenbaum S., Garcia-Trevijano E.R., Canals F., Merlino G., Avila M.A., Recio J.A.
    Sci. Signal. 4:RA58-RA58(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: PROTEIN SEQUENCE OF 42-53; 60-65; 310-316 AND 564-572, INTERACTION WITH PRMT5, METHYLATION AT ARG-563, PHOSPHORYLATION AT SER-289; SER-296; SER-301; SER-338 AND SER-621, MUTAGENESIS OF ARG-563.
  8. "Phosphorylation of Raf by ceramide-activated protein kinase."
    Yao B., Zhang Y., Delikat S., Mathias S., Basu S., Kolesnick R.
    Nature 378:307-310(1995) [PubMed] [Europe PMC] [Abstract]
    Cited for: PROTEIN SEQUENCE OF 254-278, PHOSPHORYLATION AT THR-269.
  9. "An alternatively spliced c-mil/raf mRNA is predominantly expressed in chicken muscular tissues and conserved among vertebrate species."
    Dozier C., Ansieau S., Ferreira E., Coll J., Stehelin D.
    Oncogene 6:1307-1311(1991) [PubMed] [Europe PMC] [Abstract]
    Cited for: PARTIAL NUCLEOTIDE SEQUENCE [GENOMIC DNA], ALTERNATIVE SPLICING, TISSUE SPECIFICITY.
    Tissue: Placenta.
  10. "Identification of the major phosphorylation sites of the Raf-1 kinase."
    Morrison D.K., Heidecker G., Rapp U.R., Copeland T.D.
    J. Biol. Chem. 268:17309-17316(1993) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION AT SER-43; SER-259; THR-268; SER-499 AND SER-621.
  11. "14-3-3 is phosphorylated by casein kinase I on residue 233. Phosphorylation at this site in vivo regulates Raf/14-3-3 interaction."
    Dubois T., Rommel C., Howell S., Steinhussen U., Soneji Y., Morrice N., Moelling K., Aitken A.
    J. Biol. Chem. 272:28882-28888(1997) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH YWHAZ, FUNCTION.
  12. "The protein kinase Pak3 positively regulates Raf-1 activity through phosphorylation of serine 338."
    King A.J., Sun H., Diaz B., Barnard D., Miao W., Bagrodia S., Marshall M.S.
    Nature 396:180-183(1998) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION.
  13. Erratum
    King A.J., Sun H., Diaz B., Barnard D., Miao W., Bagrodia S., Marshall M.S.
    Nature 406:439-439(2000)
  14. "Phosphorylation and regulation of Raf by Akt (protein kinase B)."
    Zimmermann S., Moelling K.
    Science 286:1741-1744(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION AT SER-259 BY PKB/AKT1, ENZYME REGULATION, INTERACTION WITH PKB/AKT1.
  15. "Raf-1-associated protein phosphatase 2A as a positive regulator of kinase activation."
    Abraham D., Podar K., Pacher M., Kubicek M., Welzel N., Hemmings B.A., Dilworth S.M., Mischak H., Kolch W., Baccarini M.
    J. Biol. Chem. 275:22300-22304(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION AT SER-259 AND SER-621, DEPHOSPHORYLATION AT SER-43; SER-259 AND SER-621, ENZYME REGULATION, INTERACTION WITH PPP2CA AND PPP2R1B.
  16. "Positive and negative regulation of Raf kinase activity and function by phosphorylation."
    Chong H., Lee J., Guan K.L.
    EMBO J. 20:3716-3727(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: ENZYME REGULATION, PHOSPHORYLATION AT THR-491 AND SER-494.
  17. "Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism."
    Chen J., Fujii K., Zhang L., Roberts T., Fu H.
    Proc. Natl. Acad. Sci. U.S.A. 98:7783-7788(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INTERACTION WITH MAP3K5/ASK1.
  18. "Phosphorylation of the myosin-binding subunit of myosin phosphatase by Raf-1 and inhibition of phosphatase activity."
    Broustas C.G., Grammatikakis N., Eto M., Dent P., Brautigan D.L., Kasid U.
    J. Biol. Chem. 277:3053-3059(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN PHOSPHORYLATION OF PPP1R12A, INTERACTION WITH PPP1R12A.
  19. "Interaction between active Pak1 and Raf-1 is necessary for phosphorylation and activation of Raf-1."
    Zang M., Hayne C., Luo Z.
    J. Biol. Chem. 277:4395-4405(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION AT SER-338 BY PAK1, ENZYME REGULATION, INTERACTION WITH PAK1.
  20. "Dephosphorylation of Ser-259 regulates Raf-1 membrane association."
    Kubicek M., Pacher M., Abraham D., Podar K., Eulitz M., Baccarini M.
    J. Biol. Chem. 277:7913-7919(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION AT SER-259, DEPHOSPHORYLATION AT SER-259, SUBCELLULAR LOCATION.
  21. "The RAS effector RIN1 directly competes with RAF and is regulated by 14-3-3 proteins."
    Wang Y., Waldron R.T., Dhaka A., Patel A., Riley M.M., Rozengurt E., Colicelli J.
    Mol. Cell. Biol. 22:916-926(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: COMPETITION WITH RIN1.
  22. "Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1."
    Sasaki A., Taketomi T., Kato R., Saeki K., Nonami A., Sasaki M., Kuriyama M., Saito N., Shibuya M., Yoshimura A.
    Nat. Cell Biol. 5:427-432(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: ENZYME REGULATION, INTERACTION WITH SPRY2 AND SPRY4.
  23. "LGI1, a putative tumor metastasis suppressor gene, controls in vitro invasiveness and expression of matrix metalloproteinases in glioma cells through the ERK1/2 pathway."
    Kunapuli P., Kasyapa C.S., Hawthorn L., Cowell J.K.
    J. Biol. Chem. 279:23151-23157(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION AT SER-259.
  24. Erratum
    Kunapuli P., Kasyapa C.S., Hawthorn L., Cowell J.K.
    J. Biol. Chem. 282:2752-2752(2007)
  25. "Raf kinase activation of adenylyl cyclases: isoform-selective regulation."
    Ding Q., Gros R., Gray I.D., Taussig R., Ferguson S.S., Feldman R.D.
    Mol. Pharmacol. 66:921-928(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN PHOSPHORYLATION OF ADCY2; ADCY5 AND ADCY6, INTERACTION WITH ADCY2; ADCY5 AND ADCY6.
  26. "Role of the kinase MST2 in suppression of apoptosis by the proto-oncogene product Raf-1."
    O'Neill E., Rushworth L., Baccarini M., Kolch W.
    Science 306:2267-2270(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH STK3/MST2, FUNCTION.
  27. Cited for: INTERACTION WITH RCAN1/DSCR1.
  28. "Second nature: biological functions of the Raf-1 'kinase'."
    Baccarini M.
    FEBS Lett. 579:3271-3277(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: REVIEW ON FUNCTION.
  29. "p21-activated Kinase 1 (Pak1)-dependent phosphorylation of Raf-1 regulates its mitochondrial localization, phosphorylation of BAD, and Bcl-2 association."
    Jin S., Zhuo Y., Guo W., Field J.
    J. Biol. Chem. 280:24698-24705(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN PHOSPHORYLATION OF BAD, PHOSPHORYLATION AT SER-338 AND SER-339 BY PAK1, SUBCELLULAR LOCATION, INTERACTION WITH BCL2.
  30. "Identification of Raf-1 S471 as a novel phosphorylation site critical for Raf-1 and B-Raf kinase activities and for MEK binding."
    Zhu J., Balan V., Bronisz A., Balan K., Sun H., Leicht D.T., Luo Z., Qin J., Avruch J., Tzivion G.
    Mol. Biol. Cell 16:4733-4744(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION AT SER-471.
  31. "A phosphatase holoenzyme comprised of Shoc2/Sur8 and the catalytic subunit of PP1 functions as an M-Ras effector to modulate Raf activity."
    Rodriguez-Viciana P., Oses-Prieto J., Burlingame A., Fried M., McCormick F.
    Mol. Cell 22:217-230(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: IDENTIFICATION IN A COMPLEX WITH PP1CA; PPP1CB; PPP1CC; SHOC2 AND MRAS, PHOSPHORYLATION AT SER-259, CHARACTERIZATION OF VARIANT ALA-259.
  32. "Regulation and role of Raf-1/B-Raf heterodimerization."
    Rushworth L.K., Hindley A.D., O'Neill E., Kolch W.
    Mol. Cell. Biol. 26:2262-2272(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBUNIT.
  33. "Regulation of the Raf-MEK-ERK pathway by protein phosphatase 5."
    von Kriegsheim A., Pitt A., Grindlay G.J., Kolch W., Dhillon A.S.
    Nat. Cell Biol. 8:1011-1016(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION AS KINASE, ENZYME REGULATION, PHOSPHORYLATION AT SER-259; SER-338; TYR-340; TYR-341 AND SER-621, DEPHOSPHORYLATION AT SER-338 BY PPP5C, MUTAGENESIS OF 338-SER-SER-339; 340-TYR-TYR-341; THR-491 AND SER-494.
  34. "Phosphatase and feedback regulation of Raf-1 signaling."
    Dhillon A.S., von Kriegsheim A., Grindlay J., Kolch W.
    Cell Cycle 6:3-7(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: REVIEW ON REGULATION.
  35. "Raf 1 represses expression of the tight junction protein occludin via activation of the zinc-finger transcription factor slug."
    Wang Z., Wade P., Mandell K.J., Akyildiz A., Parkos C.A., Mrsny R.J., Nusrat A.
    Oncogene 26:1222-1230(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  36. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-252, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Embryonic kidney.
  37. "The RKIP (Raf-1 Kinase Inhibitor Protein) conserved pocket binds to the phosphorylated N-region of Raf-1 and inhibits the Raf-1-mediated activated phosphorylation of MEK."
    Rath O., Park S., Tang H.H., Banfield M.J., Brady R.L., Lee Y.C., Dignam J.D., Sedivy J.M., Kolch W., Yeung K.C.
    Cell. Signal. 20:935-941(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: ENZYME REGULATION, INTERACTION WITH PEBP1/RKIP.
  38. "p21 activated kinase 5 activates Raf-1 and targets it to mitochondria."
    Wu X., Carr H.S., Dan I., Ruvolo P.P., Frost J.A.
    J. Cell. Biochem. 105:167-175(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION AT SER-338 BY PAK5.
  39. "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient phosphoproteomic analysis."
    Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III
    J. Proteome Res. 7:1346-1351(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Cervix carcinoma.
  40. "Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle."
    Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M.
    Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Cervix carcinoma.
  41. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-642, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Cervix carcinoma.
  42. "Retinoic acid induces nuclear accumulation of Raf1 during differentiation of HL-60 cells."
    Smith J., Bunaciu R.P., Reiterer G., Coder D., George T., Asaly M., Yen A.
    Exp. Cell Res. 315:2241-2248(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBCELLULAR LOCATION.
  43. "Diacylglycerol kinase eta augments C-Raf activity and B-Raf/C-Raf heterodimerization."
    Yasuda S., Kai M., Imai S., Takeishi K., Taketomi A., Toyota M., Kanoh H., Sakane F.
    J. Biol. Chem. 284:29559-29570(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: ENZYME REGULATION, SUBUNIT, SUBCELLULAR LOCATION, INTERACTION WITH DGKH.
  44. "Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."
    Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K.
    Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-289 AND SER-301, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Leukemic T-cell.
  45. "RAF protein-serine/threonine kinases: structure and regulation."
    Roskoski R. Jr.
    Biochem. Biophys. Res. Commun. 399:313-317(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: REVIEW.
  46. "Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis."
    Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.
    Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Cervix carcinoma.
  47. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
  48. Cited for: REVIEW.
  49. "System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation."
    Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.
    Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
  50. "The 2.2 A crystal structure of the Ras-binding domain of the serine/threonine kinase c-Raf1 in complex with Rap1A and a GTP analogue."
    Nassar N., Horn G., Herrmann C., Scherer A., McCormick F., Wittinghofer A.
    Nature 375:554-560(1995) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 51-131.
  51. "Ras/Rap effector specificity determined by charge reversal."
    Nassar N., Horn G., Herrmann C., Block C., Janknecht R., Wittinghofer A.
    Nat. Struct. Biol. 3:723-729(1996) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 56-131.
  52. "Solution structure of the Ras-binding domain of c-Raf-1 and identification of its Ras interaction surface."
    Emerson S.D., Madison V.S., Palermo R.E., Waugh D.S., Scheffler J.E., Tsao K.L., Kiefer S.E., Liu S.P., Fry D.C.
    Biochemistry 34:6911-6918(1995) [PubMed] [Europe PMC] [Abstract]
    Cited for: STRUCTURE BY NMR OF 55-132.
  53. "The solution structure of the Raf-1 cysteine-rich domain: a novel ras and phospholipid binding site."
    Mott H.R., Carpenter J.W., Zhong S., Ghosh S., Bell R.M., Campbell S.L.
    Proc. Natl. Acad. Sci. U.S.A. 93:8312-8317(1996) [PubMed] [Europe PMC] [Abstract]
    Cited for: STRUCTURE BY NMR OF 136-187.
  54. Cited for: VARIANTS NS5 SER-256; PHE-259; ARG-260; LEU-261; SER-261; ASN-486; GLY-486; ILE-491; ARG-491 AND THR-612, VARIANT HYPERTROPHIC CARDIOMYOPATHY ILE-260, VARIANTS LEOPARD2 LEU-257 AND VAL-613, VARIANT NS5 LEU-257, CHARACTERIZATION OF VARIANTS NS5 SER-261; ASN-486 AND ILE-491, CHARACTERIZATION OF VARIANT LEOPARD SYNDROME-2 VAL-613.
  55. Cited for: VARIANTS NS5 LEU-257; ALA-261; SER-261; ALA-263 AND VAL-613, CHARACTERIZATION OF VARIANTS NS5 LEU-257; ALA-261; SER-261; ALA-263 AND VAL-613.
  56. "Patterns of somatic mutation in human cancer genomes."
    Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.
    , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.
    Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANTS [LARGE SCALE ANALYSIS] ALA-259 AND HIS-335.
  57. "Noonan syndrome associated with both a new Jnk-activating familial SOS1 and a de novo RAF1 mutations."
    Longoni M., Moncini S., Cisternino M., Morella I.M., Ferraiuolo S., Russo S., Mannarino S., Brazzelli V., Coi P., Zippel R., Venturin M., Riva P.
    Am. J. Med. Genet. A 152:2176-2184(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANT NS5 SER-261.

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: October 29, 2014
This is version 185 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

External Data

Dasty 3