RAF1 - RAF proto-oncogene serine/threonine-protein kinase - human protein (Function)
 
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RAF1 »  RAF proto-oncogene serine/threonine-protein kinase   [ EC 2.7.11.1 ]
 
Protein also known as:  Proto-oncogene c-RAF (cRaf).
Gene name:  RAF1
Entry whose protein(s) existence is based on evidence at protein level
extend overview
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GENE REF ISO

Function

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Overview 
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.  
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  • CuratedUniProtKB
GO molecular function 
ATP bindingdefinition[GO:0005524]  
  • IEAUniProtKB KW
Identical protein bindingdefinition[GO:0042802]  
3
  • IPIIntAct
MAP kinase kinase kinase activitydefinition[GO:0004709] silver  
  • IEAOrtholog Compara
Metal ion bindingdefinition[GO:0046872]  
  • IEAUniProtKB KW
Mitogen-activated protein kinase kinase bindingdefinition[GO:0031434] silver  
  • IEAOrtholog Compara
Protein bindingdefinition[GO:0005515]  
48
  • IPIIntAct
  • IPIUniProtKB
  • IPIBHF-UCL
Protein heterodimerization activitydefinition[GO:0046982] silver  
  • IEAOrtholog Compara
Protein kinase activitydefinition[GO:0004672]  
2
  • TASPINC
Protein serine/threonine kinase activitydefinition[GO:0004674]  
1
  • IDAUniProtKB
Ras GTPase bindingdefinition[GO:0017016] silver  
  • IEAOrtholog Compara
GO biological process 
Activation of adenylate cyclase activitydefinition[GO:0007190]  
1
  • NASBHF-UCL
Apoptotic processdefinition[GO:0006915]  
1
  • TASPINC
Cell proliferationdefinition[GO:0008283]  
1
  • TASPINC
Death-inducing signaling complex assemblydefinition[GO:0071550] silver  
  • IEAOrtholog Compara
Heart developmentdefinition[GO:0007507] silver  
  • IEAOrtholog Compara
Intermediate filament cytoskeleton organizationdefinition[GO:0045104] silver  
  • IEAOrtholog Compara
Negative regulation of apoptotic processdefinition[GO:0043066]  
1
  • IDAUniProtKB
Negative regulation of cell proliferationdefinition[GO:0008285]  
1
  • IDABHF-UCL
Negative regulation of cysteine-type endopeptidase activity involved in apoptotic processdefinition[GO:0043154]  
1
  • TASUniProtKB
Negative regulation of extrinsic apoptotic signaling pathway via death domain receptorsdefinition[GO:1902042] silver  
  • IEAOrtholog Compara
Negative regulation of protein complex assemblydefinition[GO:0031333]  
1
  • IDAUniProtKB
Positive regulation of peptidyl-serine phosphorylationdefinition[GO:0033138]  
1
  • IDAUniProtKB
Protein phosphorylationdefinition[GO:0006468]  
1
  • TASPINC
Regulation of apoptotic processdefinition[GO:0042981]  
1
  • TASUniProtKB
Regulation of cell differentiationdefinition[GO:0045595]  
1
  • TASUniProtKB
Regulation of cell motilitydefinition[GO:2000145]  
1
  • TASUniProtKB
Regulation of Rho protein signal transductiondefinition[GO:0035023]  
1
  • TASUniProtKB
Response to hypoxiadefinition[GO:0001666] silver  
  • IEAOrtholog Compara
Signal transductiondefinition[GO:0007165]  
1
  • TASPINC
Wound healingdefinition[GO:0042060]  
1
  • TASUniProtKB
Enzymatic activity 
This protein acts as an enzyme. It is known to catalyze the following reaction
EC 2.7.11.1: ATP + a protein ADP + a phosphoprotein.  
  • CuratedUniProtKB
It requires the following cofactor
Binds 2 zinc ions per subunit.  
  • CuratedUniProtKB
It is regulated in the following manner
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.  
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  • CuratedUniProtKB
 
More information is available from:
Pathways 
According to KEGG, this protein belongs to the following pathways:
Acute myeloid leukemia  hsa05221+5894  
B cell receptor signaling pathway  hsa04662+5894  
Bladder cancer  hsa05219+5894  
Chemokine signaling pathway  hsa04062+5894  
Chronic myeloid leukemia  hsa05220+5894  
Colorectal cancer  hsa05210+5894  
Endometrial cancer  hsa05213+5894  
ErbB signaling pathway  hsa04012+5894  
Fc epsilon RI signaling pathway  hsa04664+5894  
Fc gamma R-mediated phagocytosis  hsa04666+5894  
Focal adhesion  hsa04510+5894  
Gap junction  hsa04540+5894  
Glioma  hsa05214+5894  
GnRH signaling pathway  hsa04912+5894  
Hepatitis C  hsa05160+5894  
Influenza A  hsa05164+5894  
Insulin signaling pathway  hsa04910+5894  
Long-term depression  hsa04730+5894  
Long-term potentiation  hsa04720+5894  
MAPK signaling pathway  hsa04010+5894  
Melanogenesis  hsa04916+5894  
Melanoma  hsa05218+5894  
Natural killer cell mediated cytotoxicity  hsa04650+5894  
Neurotrophin signaling pathway  hsa04722+5894  
Non-small cell lung cancer  hsa05223+5894  
Pancreatic cancer  hsa05212+5894  
Pathways in cancer  hsa05200+5894  
Progesterone-mediated oocyte maturation  hsa04914+5894  
Prostate cancer  hsa05215+5894  
Regulation of actin cytoskeleton  hsa04810+5894  
Renal cell carcinoma  hsa05211+5894  
T cell receptor signaling pathway  hsa04660+5894  
Tuberculosis  hsa05152+5894  
Vascular smooth muscle contraction  hsa04270+5894  
VEGF signaling pathway  hsa04370+5894  
According to Reactome, this protein belongs to the following pathways:
Developmental Biology  REACT_111045  
Disease  REACT_116125  
Hemostasis  REACT_604  
Immune System  REACT_6900  
Neuronal System  REACT_13685  
Signal Transduction  REACT_111102  
Transmembrane transport of small molecules  REACT_15518  
 

Keywords

Molecular function 
Kinase  definition   [KW-0418]
Serine/threonine-protein kinase  definition   [KW-0723]
Transferase  definition   [KW-0808]
Technical term 
Reference proteome  definition   [KW-1185]
 

Further external links

Other
GeneWiki: C-Raf
GenomeRNAi: 5894
PRO: PR:P04049
Chemistry
GuidetoPHARMACOLOGY: 2184