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UniProtKB - Q99N57 (RAF1_MOUSE)

Protein

RAF proto-oncogene serine/threonine-protein kinase

Gene

Raf1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -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. 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 (By similarity). Regulates Rho signaling and migration, and is required for normal wound healing.By similarity1 Publication

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Cofactori

Zn2+By similarityNote: Binds 2 Zn2+ ions per subunit.By similarity

Activity 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 (By similarity).By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi139Zinc 1By similarity1
Metal bindingi152Zinc 2By similarity1
Metal bindingi155Zinc 2By similarity1
Metal bindingi165Zinc 1By similarity1
Metal bindingi168Zinc 1By similarity1
Metal bindingi173Zinc 2By similarity1
Metal bindingi176Zinc 2By similarity1
Metal bindingi184Zinc 1By similarity1
Binding sitei375ATPPROSITE-ProRule annotation1
Active sitei468Proton acceptorPROSITE-ProRule annotation1

Regions

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

GO - Molecular functioni

View the complete GO annotation on QuickGO ...

GO - Biological processi

View the complete GO annotation on QuickGO ...

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase
LigandATP-binding, Metal-binding, Nucleotide-binding, Zinc

Enzyme and pathway databases

ReactomeiR-MMU-2672351 Stimuli-sensing channels
R-MMU-392517 Rap1 signalling
R-MMU-430116 GP1b-IX-V activation signalling
R-MMU-442742 CREB phosphorylation through the activation of Ras
R-MMU-5621575 CD209 (DC-SIGN) signaling
R-MMU-5673000 RAF activation
R-MMU-5674135 MAP2K and MAPK activation
R-MMU-5674499 Negative feedback regulation of MAPK pathway
R-MMU-5675221 Negative regulation of MAPK pathway

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:Craf
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Myomorpha › Muroidea › Muridae › Murinae › Mus › Mus
Proteomesi
  • UP000000589 Componenti: Chromosome 6

Organism-specific databases

MGIiMGI:97847 Raf1

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane, Mitochondrion, Nucleus

Pathology & Biotechi

Keywords - Diseasei

Proto-oncogene

Chemistry databases

ChEMBLiCHEMBL3804748

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000865971 – 648RAF proto-oncogene serine/threonine-protein kinaseAdd BLAST648

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei29Phosphoserine; by MAPK11 Publication1
Modified residuei43Phosphoserine; by PKA and MAPK11 Publication1
Modified residuei233Phosphoserine; by PKABy similarity1
Modified residuei252PhosphoserineBy similarity1
Modified residuei259Phosphoserine; by PKA, PKC and PKB/AKT1By similarity1
Modified residuei268Phosphothreonine; by autocatalysisBy similarity1
Modified residuei269Phosphothreonine; by PKABy similarity1
Modified residuei289Phosphoserine; by MAPK11 Publication1
Modified residuei296Phosphoserine; by MAPK1Combined sources1 Publication1
Modified residuei301Phosphoserine; by MAPK1Combined sources1 Publication1
Modified residuei338Phosphoserine; by PAK1, PAK2, PAK3 and PAK5By similarity1
Modified residuei339Phosphoserine; by PAK1, PAK2 and PAK3By similarity1
Modified residuei340Phosphotyrosine; by SRCBy similarity1
Modified residuei341Phosphotyrosine; by SRCBy similarity1
Modified residuei471PhosphoserineBy similarity1
Modified residuei491PhosphothreonineBy similarity1
Modified residuei494PhosphoserineBy similarity1
Modified residuei497Phosphoserine; by PKCBy similarity1
Modified residuei499Phosphoserine; by PKCBy similarity1
Modified residuei563Symmetric dimethylarginine; by PRMT5By similarity1
Modified residuei621Phosphoserine1 Publication1
Modified residuei642Phosphoserine; by MAPK1Combined sources1 Publication1

Post-translational modificationi

Phosphorylation at Thr-269, Ser-338, Tyr-341, Thr-491 and Ser-494 results in its activation. Phosphorylation at Ser-29, Ser-43, Ser-289, Ser-296, Ser-301 and Ser-642 by MAPK1/ERK2 results in its inactivation. Phosphorylation at Ser-259 induces the interaction with YWHAZ and inactivates kinase activity. Dephosphorylation of Ser-259 by the complex containing protein phosphatase 1, SHOC2 and M-Ras/MRAS relieves inactivation, leading to stimulate RAF1 activity. Phosphorylation at Ser-338 by PAK1 and PAK5 and Ser-339 by PAK1 is required for its mitochondrial localization (By similarity). 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 decreased of activity (By similarity).By similarity
Methylated at Arg-563 in response to EGF treatment. This modification leads to destabilization of the protein, possibly through proteasomal degradation.By similarity

Keywords - PTMi

Methylation, Phosphoprotein

Proteomic databases

PaxDbiQ99N57
PeptideAtlasiQ99N57
PRIDEiQ99N57

PTM databases

iPTMnetiQ99N57
PhosphoSitePlusiQ99N57

Expressioni

Tissue specificityi

Present in all tissues tested: testis, ovary, small intestine, colon, peripheral blood leukocytes, fetal liver, bone marrow, thymus, lymph node and spleen, and the cell lines melanoma G-361, lung carcinoma A-549, colorectal adenocarcinoma SW480, Burkitt's lymphoma Raji and lymphoblastic leukemia MOLT-4. In skeletal muscle, isoform 1 is more abundant than isoform 2.2 Publications

Gene expression databases

BgeeiENSMUSG00000000441 Expressed in 301 organ(s), highest expression level in primary oocyte
CleanExiMM_RAF1
ExpressionAtlasiQ99N57 baseline and differential
GenevisibleiQ99N57 MM

Interactioni

Subunit structurei

Monomer (By similarity). Homodimer (By similarity). Heterodimerizes with BRAF and this heterodimer possesses a highly increased kinase activity compared to the respective homodimers or monomers (By similarity). Heterodimerization is mitogen-regulated and enhanced by 14-3-3 proteins (By similarity). MAPK1/ERK2 activation can induce a negative feedback that promotes the dissociation of the heterodimer (By similarity). Forms a multiprotein complex with Ras (M-Ras/MRAS), SHOC2 and protein phosphatase 1 (PPP1CA, PPP1CB and PPP1CC) (By similarity). Interacts with Ras proteins; the interaction is antagonized by RIN1 (By similarity). Weakly interacts with RIT1 (By similarity). 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). Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not contain co-chaperones STIP1/HOP and PTGES3/p23 (By similarity). Interacts with STK3/MST2; the interaction inhibits its pro-apoptotic activity (By similarity). Interacts (when phosphorylated at Ser-259) with YWHAZ (unphosphorylated at 'Thr-232') (By similarity). 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 (By similarity). Interacts with PAK1 (via kinase domain) (By similarity). The Ser-338 and Ser-339 phosphorylated form (by PAK1) interacts with BCL2 (By similarity). Interacts with PEBP1/RKIP and this interaction is enhanced if RAF1 is phosphorylated on residues Ser-338, Ser-339, Tyr-340 and Tyr-341 (By similarity). Interacts with ADCY2, ADCY5, ADCY6, DGKH, RCAN1/DSCR1, PPP1R12A, PKB/AKT1, SPRY2, SPRY4, CNKSR1/CNK1, KSR2 and PHB/prohibitin (By similarity). The phosphorylated form interacts with PIN1 (PubMed:15664191). Interacts with PPP2CA, PPP2R1B and ROCK2 (PubMed:15753127, PubMed:15664191). In its active form, interacts with PRMT5 (By similarity). Interacts with FAM83B; displaces 14-3-3 proteins from RAF1 and activates RAF1 (By similarity). Interacts with PDE8A; the interaction promotes RAF1 activity (By similarity). Interacts with MFHAS1 (By similarity).By similarity2 Publications

Binary interactionsi

GO - Molecular functioni

View the complete GO annotation on QuickGO ...

Protein-protein interaction databases

BioGridi225343, 16 interactors
CORUMiQ99N57
DIPiDIP-31555N
IntActiQ99N57, 16 interactors
MINTiQ99N57
STRINGi10090.ENSMUSP00000000451

Chemistry databases

BindingDBiQ99N57

Structurei

3D structure databases

ProteinModelPortaliQ99N57
SMRiQ99N57
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

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

Region

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

Sequence similaritiesi

Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. RAF subfamily.Curated

Zinc finger

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

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiKOG0193 Eukaryota
ENOG410Y4UP LUCA
GeneTreeiENSGT00900000140880
HOGENOMiHOG000252972
HOVERGENiHBG001886
InParanoidiQ99N57
KOiK04366
OMAiHQFIRKT
OrthoDBiEOG091G09SB
PhylomeDBiQ99N57
TreeFamiTF317006

Family and domain databases

CDDicd00029 C1, 1 hit
InterProiView protein in InterPro
IPR020454 DAG/PE-bd
IPR011009 Kinase-like_dom_sf
IPR002219 PE/DAG-bd
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR003116 RBD_dom
IPR001245 Ser-Thr/Tyr_kinase_cat_dom
IPR008271 Ser/Thr_kinase_AS
IPR029071 Ubiquitin-like_domsf
PfamiView protein in Pfam
PF00130 C1_1, 1 hit
PF07714 Pkinase_Tyr, 1 hit
PF02196 RBD, 1 hit
PRINTSiPR00008 DAGPEDOMAIN
SMARTiView protein in SMART
SM00109 C1, 1 hit
SM00455 RBD, 1 hit
SM00220 S_TKc, 1 hit
SUPFAMiSSF54236 SSF54236, 1 hit
SSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
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

Sequences (2+)i

Sequence statusi: Complete.

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

This entry has 2 described isoforms and 3 potential isoforms that are computationally mapped.iShow all

Isoform 1 (identifier: Q99N57-1) [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 ISNGFGLKDA VFDGSSCISP TIVQQFGYQR RASDDGKLTD 
        60         70         80         90        100
SSKTSNTIRV FLPNKQRTVV NVRNGMSLHD CLMKALKVRG LQPECCAVFR 
       110        120        130        140        150
LLQEHKGKKA RLDWNTDAAS LIGEELQVDF LDHVPLTTHN FARKTFLKLA 
       160        170        180        190        200
FCDICQKFLL NGFRCQTCGY KFHEHCSTKV PTMCVDWSNI RQLLLFPNST 
       210        220        230        240        250
VGDSGVPAPP SFPMRRMRES VSRMPASSQH RYSTPHAFTF NTSSPSSEGS 
       260        270        280        290        300
LSQRQRSTST PNVHMVSTTL HVDSRMIEDA IRSHSESASP SALSSSPNNL 
       310        320        330        340        350
SPTGWSQPKT PVPAQRERAP GSGTQEKNKI RPRGQRDSSY YWEIEASEVM 
       360        370        380        390        400
LSTRIGSGSF GTVYKGKWHG DVAVKILKVV DPTPEQLQAF 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 DDNPFSFQSD VYSYGIVLYE LMAGELPYAH 
       560        570        580        590        600
INNRDQIIFM VGRGYASPDL SRLYKNCPKA MKRLVADCVK KVKEERPLFP 
       610        620        630        640 
QILSSIELLQ HSLPKINRSA SEPSLHRAAH TEDINACTLT TSPRLPVF
Length:648
Mass (Da):72,917
Last modified:March 1, 2002 - v2
Checksum:iB70104AEF51C44A5
GO
Isoform 2 (identifier: Q99N57-2) [UniParc]FASTAAdd to basket
Also known as: 1A

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

Show »
Length:668
Mass (Da):75,151
Checksum:iD70FF05B80BCF8ED
GO

Computationally mapped potential isoform sequencesi

There are 3 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
A0A0N4SWH5A0A0N4SWH5_MOUSE
RAF proto-oncogene serine/threonine...
Raf1
96Annotation score:
F6TUC4F6TUC4_MOUSE
RAF proto-oncogene serine/threonine...
Raf1
205Annotation score:
A0A0N4SV36A0A0N4SV36_MOUSE
RAF proto-oncogene serine/threonine...
Raf1
118Annotation score:

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti522D → N in AAH92040 (PubMed:15489334).Curated1
Sequence conflicti543A → T in AAH92040 (PubMed:15489334).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_034629278E → ESNSLNASPRACSRRFCLRG R in isoform 2. Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB057655 mRNA Translation: BAB39748.1
AB057663 mRNA Translation: BAB39743.2
AK141745 mRNA Translation: BAE24820.1
BC015273 mRNA Translation: AAH15273.1
BC092040 mRNA Translation: AAH92040.1
X55432 Genomic DNA No translation available.
CCDSiCCDS20441.1 [Q99N57-1]
RefSeqiNP_084056.1, NM_029780.3 [Q99N57-1]
XP_006505426.1, XM_006505363.3
XP_006505427.1, XM_006505364.2 [Q99N57-2]
XP_006505428.1, XM_006505365.2
UniGeneiMm.184163

Genome annotation databases

EnsembliENSMUST00000000451; ENSMUSP00000000451; ENSMUSG00000000441 [Q99N57-1]
ENSMUST00000112949; ENSMUSP00000108571; ENSMUSG00000000441 [Q99N57-1]
GeneIDi110157
KEGGimmu:110157
UCSCiuc009dix.1 mouse [Q99N57-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiRAF1_MOUSE
AccessioniPrimary (citable) accession number: Q99N57
Secondary accession number(s): Q3UR68
, Q58E75, Q91WH1, Q99N58, Q9QUU8
Entry historyiIntegrated into UniProtKB/Swiss-Prot: August 15, 2003
Last sequence update: March 1, 2002
Last modified: September 12, 2018
This is version 172 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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