CPLM 1.0 - Compendium of Protein Lysine Modification
TagContent
CPLM ID CPLM-002080
UniProt Accession
Genbank Protein ID
Genbank Nucleotide ID
Protein Name
 RAF proto-oncogene serine/threonine-protein kinase 
Protein Synonyms/Alias
 Proto-oncogene c-RAF; cRaf; Raf-1 
Gene Name
 RAF1 
Gene Synonyms/Alias
 RAF 
Created Date
 July 27, 2013 
Organism
 Homo sapiens (Human) 
NCBI Taxa ID
 9606 
Lysine Modification
Position
Peptide
Type
References
490NIIHRDMKSNNIFLHubiquitination[1]
611LVADCVKKVKEERPLubiquitination[1]
Reference
 [1] Refined preparation and use of anti-diglycine remnant (K-ε-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments.
 Udeshi ND, Svinkina T, Mertins P, Kuhn E, Mani DR, Qiao JW, Carr SA.
 Mol Cell Proteomics. 2013 Mar;12(3):825-31. [PMID: 23266961] 
Functional Description
 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. 
Sequence Annotation
 DOMAIN 56 131 RBD.
 DOMAIN 349 609 Protein kinase.
 ZN_FING 138 184 Phorbol-ester/DAG-type.
 NP_BIND 355 363 ATP (By similarity).
 REGION 331 349 Interaction with PEBP1/RKIP.
 ACT_SITE 468 468 Proton acceptor.
 METAL 139 139 Zinc 1.
 METAL 152 152 Zinc 2.
 METAL 155 155 Zinc 2.
 METAL 165 165 Zinc 1.
 METAL 168 168 Zinc 1.
 METAL 173 173 Zinc 2.
 METAL 176 176 Zinc 2.
 METAL 184 184 Zinc 1.
 BINDING 375 375 ATP (By similarity).
 MOD_RES 29 29 Phosphoserine; by MAPK1 (By similarity).
 MOD_RES 43 43 Phosphoserine; by PKA and MAPK1.
 MOD_RES 233 233 Phosphoserine; by PKA.
 MOD_RES 252 252 Phosphoserine.
 MOD_RES 259 259 Phosphoserine; by PKA, PKC and PKB/AKT1.
 MOD_RES 268 268 Phosphothreonine; by autocatalysis.
 MOD_RES 269 269 Phosphothreonine; by PKA.
 MOD_RES 289 289 Phosphoserine; by MAPK1.
 MOD_RES 296 296 Phosphoserine; by MAPK1 (By similarity).
 MOD_RES 301 301 Phosphoserine; by MAPK1.
 MOD_RES 338 338 Phosphoserine; by PAK1, PAK2, PAK3 and
 MOD_RES 339 339 Phosphoserine; by PAK1, PAK2 and PAK3.
 MOD_RES 340 340 Phosphotyrosine; by SRC.
 MOD_RES 341 341 Phosphotyrosine; by SRC.
 MOD_RES 471 471 Phosphoserine.
 MOD_RES 491 491 Phosphothreonine.
 MOD_RES 494 494 Phosphoserine.
 MOD_RES 497 497 Phosphoserine; by PKC.
 MOD_RES 499 499 Phosphoserine; by PKC.
 MOD_RES 563 563 Symmetric dimethylarginine; by PRMT5.
 MOD_RES 621 621 Phosphoserine.
 MOD_RES 642 642 Phosphoserine; by MAPK1.  
Keyword
 3D-structure; Alternative splicing; ATP-binding; Cell membrane; Complete proteome; Cytoplasm; Deafness; Direct protein sequencing; Disease mutation; Kinase; Membrane; Metal-binding; Methylation; Mitochondrion; Nucleotide-binding; Nucleus; Phosphoprotein; Polymorphism; Proto-oncogene; Reference proteome; Serine/threonine-protein kinase; Transferase; Zinc; Zinc-finger. 
Sequence Source
 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 
Protein Length
 648 AA 
Protein Sequence
MEHIQGAWKT ISNGFGFKDA VFDGSSCISP TIVQQFGYQR RASDDGKLTD PSKTSNTIRV 60
FLPNKQRTVV NVRNGMSLHD CLMKALKVRG LQPECCAVFR LLHEHKGKKA RLDWNTDAAS 120
LIGEELQVDF LDHVPLTTHN FARKTFLKLA FCDICQKFLL NGFRCQTCGY KFHEHCSTKV 180
PTMCVDWSNI RQLLLFPNST IGDSGVPALP SLTMRRMRES VSRMPVSSQH RYSTPHAFTF 240
NTSSPSSEGS LSQRQRSTST PNVHMVSTTL PVDSRMIENN NLSASPRAWS RRFCLRGRDA 300
IRSHSESASP SALSSSPNNL SPTGWSQPKT PVPAQRERAP VSGTQEKNKI RPRGQRDSSY 360
YWEIEASEVM LSTRIGSGSF GTVYKGKWHG DVAVKILKVV DPTPEQFQAF RNEVAVLRKT 420
RHVNILLFMG YMTKDNLAIV TQWCEGSSLY KHLHVQETKF QMFQLIDIAR QTAQGMDYLH 480
AKNIIHRDMK SNNIFLHEGL TVKIGDFGLA TVKSRWSGSQ QVEQPTGSVL WMAPEVIRMQ 540
DNNPFSFQSD VYSYGIVLYE LMTGELPYSH INNRDQIIFM VGRGYASPDL SKLYKNCPKA 600
MKRLVADCVK KVKEERPLFP QILSSIELLQ HSLPKINRSA SEPSLHRAAH TEDINACTLT 660
TSPRLPVF 668 
Gene Ontology
 GO:0005829; C:cytosol; TAS:Reactome.
 GO:0005741; C:mitochondrial outer membrane; TAS:ProtInc.
 GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
 GO:0005886; C:plasma membrane; TAS:Reactome.
 GO:0031143; C:pseudopodium; IEA:Compara.
 GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
 GO:0004709; F:MAP kinase kinase kinase activity; IEA:Compara.
 GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
 GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
 GO:0007190; P:activation of adenylate cyclase activity; NAS:BHF-UCL.
 GO:0000186; P:activation of MAPKK activity; TAS:Reactome.
 GO:0007411; P:axon guidance; TAS:Reactome.
 GO:0008283; P:cell proliferation; TAS:ProtInc.
 GO:0007010; P:cytoskeleton organization; IEA:Compara.
 GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
 GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
 GO:0007507; P:heart development; IEA:Compara.
 GO:0045087; P:innate immune response; TAS:Reactome.
 GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
 GO:0034220; P:ion transmembrane transport; TAS:Reactome.
 GO:0000165; P:MAPK cascade; TAS:Reactome.
 GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB.
 GO:0008285; P:negative regulation of cell proliferation; IDA:BHF-UCL.
 GO:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; TAS:UniProtKB.
 GO:0031333; P:negative regulation of protein complex assembly; IDA:UniProtKB.
 GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
 GO:0030168; P:platelet activation; TAS:Reactome.
 GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; IDA:UniProtKB.
 GO:0007265; P:Ras protein signal transduction; TAS:Reactome.
 GO:0045595; P:regulation of cell differentiation; TAS:UniProtKB.
 GO:2000145; P:regulation of cell motility; TAS:UniProtKB.
 GO:0035023; P:regulation of Rho protein signal transduction; TAS:UniProtKB.
 GO:0001666; P:response to hypoxia; IEA:Compara.
 GO:0007268; P:synaptic transmission; TAS:Reactome. 
Interpro
 IPR020454; DAG/PE-bd.
 IPR011009; Kinase-like_dom.
 IPR002219; Prot_Kinase_C-like_PE/DAG-bd.
 IPR000719; Prot_kinase_cat_dom.
 IPR017441; Protein_kinase_ATP_BS.
 IPR003116; Raf-like_ras-bd.
 IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
 IPR008271; Ser/Thr_kinase_AS. 
Pfam
 PF00130; C1_1
 PF07714; Pkinase_Tyr
 PF02196; RBD 
SMART
 SM00109; C1
 SM00455; RBD 
PROSITE
 PS00107; PROTEIN_KINASE_ATP
 PS50011; PROTEIN_KINASE_DOM
 PS00108; PROTEIN_KINASE_ST
 PS50898; RBD
 PS00479; ZF_DAG_PE_1
 PS50081; ZF_DAG_PE_2 
PRINTS
 PR00008; DAGPEDOMAIN.