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P04049

- RAF1_HUMAN

UniProt

P04049 - RAF1_HUMAN

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
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    • History
      Entry version 184 (01 Oct 2014)
      Sequence version 1 (01 Nov 1986)
      Previous versions | rss
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    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 binding Source: UniProtKB
    6. protein kinase activity Source: ProtInc
    7. 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. synaptic transmission Source: Reactome
    35. transmembrane transport Source: Reactome
    36. wound healing Source: UniProtKB

    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: Reactome
    3. Golgi apparatus Source: MGI
    4. mitochondrial outer membrane Source: ProtInc
    5. nucleus Source: UniProtKB-SubCell
    6. plasma membrane Source: MGI
    7. pseudopodium Source: Ensembl

    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.
    Mutagenesisi338 – 3392SS → DE: Non-inhibited by PPP5C. Constituvely active and non-inhibited by PPP5C; when associated with 340-D-D-341.
    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.
    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.
    Orphaneti500. 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 MAPK12 Publications
    Modified residuei233 – 2331Phosphoserine; by PKA1 Publication
    Modified residuei252 – 2521Phosphoserine2 Publications
    Modified residuei259 – 2591Phosphoserine; by PKA, PKC and PKB/AKT18 Publications
    Modified residuei268 – 2681Phosphothreonine; by autocatalysis2 Publications
    Modified residuei269 – 2691Phosphothreonine; by PKA2 Publications
    Modified residuei289 – 2891Phosphoserine; by MAPK13 Publications
    Modified residuei296 – 2961Phosphoserine; by MAPK1By similarity
    Modified residuei301 – 3011Phosphoserine; by MAPK13 Publications
    Modified residuei338 – 3381Phosphoserine; by PAK1, PAK2, PAK3 and PAK7/PAK56 Publications
    Modified residuei339 – 3391Phosphoserine; by PAK1, PAK2 and PAK32 Publications
    Modified residuei340 – 3401Phosphotyrosine; by SRC2 Publications
    Modified residuei341 – 3411Phosphotyrosine; by SRC2 Publications
    Modified residuei471 – 4711Phosphoserine2 Publications
    Modified residuei491 – 4911Phosphothreonine2 Publications
    Modified residuei494 – 4941Phosphoserine2 Publications
    Modified residuei497 – 4971Phosphoserine; by PKC1 Publication
    Modified residuei499 – 4991Phosphoserine; by PKC2 Publications
    Modified residuei563 – 5631Symmetric dimethylarginine; by PRMT51 Publication
    Modified residuei621 – 6211Phosphoserine5 Publications
    Modified residuei642 – 6421Phosphoserine; by MAPK12 Publications

    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

    ArrayExpressiP04049.
    BgeeiP04049.
    CleanExiHS_RAF1.
    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. 119 interactions.
    DIPiDIP-1048N.
    IntActiP04049. 86 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, 325-615.
    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.
    HOGENOMiHOG000252972.
    HOVERGENiHBG001886.
    InParanoidiP04049.
    KOiK04366.
    OMAiDGPSCIS.
    OrthoDBiEOG7F5128.
    PhylomeDBiP04049.
    TreeFamiTF317006.

    Family and domain databases

    InterProiIPR020454. DAG/PE-bd.
    IPR011009. Kinase-like_dom.
    IPR002219. Prot_Kinase_C-like_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.

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    MEHIQGAWKT ISNGFGFKDA VFDGSSCISP TIVQQFGYQR RASDDGKLTD    50
    PSKTSNTIRV FLPNKQRTVV NVRNGMSLHD CLMKALKVRG LQPECCAVFR 100
    LLHEHKGKKA RLDWNTDAAS LIGEELQVDF LDHVPLTTHN FARKTFLKLA 150
    FCDICQKFLL NGFRCQTCGY KFHEHCSTKV PTMCVDWSNI RQLLLFPNST 200
    IGDSGVPALP SLTMRRMRES VSRMPVSSQH RYSTPHAFTF NTSSPSSEGS 250
    LSQRQRSTST PNVHMVSTTL PVDSRMIEDA IRSHSESASP SALSSSPNNL 300
    SPTGWSQPKT PVPAQRERAP VSGTQEKNKI RPRGQRDSSY YWEIEASEVM 350
    LSTRIGSGSF GTVYKGKWHG DVAVKILKVV DPTPEQFQAF RNEVAVLRKT 400
    RHVNILLFMG YMTKDNLAIV TQWCEGSSLY KHLHVQETKF QMFQLIDIAR 450
    QTAQGMDYLH AKNIIHRDMK SNNIFLHEGL TVKIGDFGLA TVKSRWSGSQ 500
    QVEQPTGSVL WMAPEVIRMQ DNNPFSFQSD VYSYGIVLYE LMTGELPYSH 550
    INNRDQIIFM VGRGYASPDL SKLYKNCPKA MKRLVADCVK KVKEERPLFP 600
    QILSSIELLQ HSLPKINRSA SEPSLHRAAH TEDINACTLT TSPRLPVF 648
    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, 325-615.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 111831. 119 interactions.
    DIPi DIP-1048N.
    IntActi P04049. 86 interactions.
    MINTi MINT-86694.
    STRINGi 9606.ENSP00000251849.

    Chemistry

    BindingDBi P04049.
    ChEMBLi CHEMBL1906.
    DrugBanki 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 500. LEOPARD syndrome.
    648. Noonan syndrome.
    251612. Pilocytic astrocytoma.
    PharmGKBi PA34183.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi COG0515.
    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

    ArrayExpressi P04049.
    Bgeei P04049.
    CleanExi HS_RAF1.
    Genevestigatori P04049.

    Family and domain databases

    InterProi IPR020454. DAG/PE-bd.
    IPR011009. Kinase-like_dom.
    IPR002219. Prot_Kinase_C-like_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

    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 1, 2014
    This is version 184 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