RAF1
entrez
5894
canonical
uniprot
P04049
canonical
ensembl
ENSG00000132155
resolver
ensp
ENSP00000251849
resolver
ensp
ENSP00000401888
resolver
ensp
ENSP00000508763
resolver
ensp
ENSP00000508794
resolver
ensp
ENSP00000509612
resolver
ensp
ENSP00000509669
resolver
ensp
ENSP00000570436
resolver
ensp
ENSP00000570438
resolver
ensp
ENSP00000570442
resolver
ensp
ENSP00000593116
resolver
ensp
ENSP00000593117
resolver
ensp
ENSP00000611555
resolver
ensp
ENSP00000611556
resolver
enst
ENST00000685437
resolver
enst
ENST00000688543
resolver
enst
ENST00000692093
resolver
enst
ENST00000900379
resolver
enst
ENST00000923057
resolver
enst
ENST00000923058
resolver
genesymbol
RAF1
resolver
genesymbol_syn
RAF
resolver
hgnc
HGNC:9829
resolver
uniprot
A0A024R2G5
resolver
uniprot
A0A0S2Z4L5
resolver
uniprot
A0A0S2Z559
resolver
uniprot
A0ACI8T5E0
resolver
uniprot
B0LPH8
resolver
uniprot
B2R5N3
resolver
uniprot
B4E0X2
resolver
uniprot
L7RRS6
resolver
uniprot
Q15278
resolver
uniprot
Q9UC20
resolver
uniprot_entry
A0A0S2Z4L5_HUMAN
resolver
uniprot_entry
A0A0S2Z559_HUMAN
resolver
uniprot_entry
A0ACI8T5E0_HUMAN
resolver
uniprot_entry
B4E0X2_HUMAN
resolver
uniprot_entry
L7RRS6_HUMAN
resolver
uniprot_entry
RAF1_HUMAN
resolver
uniprot_sec
A0A024R2G5
resolver
uniprot_sec
B0LPH8
resolver
uniprot_sec
B2R5N3
resolver
uniprot_sec
Q15278
resolver
uniprot_sec
Q9UC20
resolver
activity_regulation
ACTIVITY REGULATION: 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. {ECO:0000269|PubMed:10576742, ECO:0000269|PubMed:10801873, ECO:0000269|PubMed:11447113, ECO:0000269|PubMed:11733498, ECO:0000269|PubMed:12717443, ECO:0000269|PubMed:16892053, ECO:0000269|PubMed:18294816, ECO:0000269|PubMed:19710016}.
uniprot
proteins
amino_acid_sequence
MEHIQGAWKTISNGFGFKDAVFDGSSCISPTIVQQFGYQRRASDDGKLTDPSKTSNTIRVFLPNKQRTVVNVRNGMSLHDCLMKALKVRGLQPECCAVFRLLHEHKGKKARLDWNTDAASLIGEELQVDFLDHVPLTTHNFARKTFLKLAFCDICQKFLLNGFRCQTCGYKFHEHCSTKVPTMCVDWSNIRQLLLFPNSTIGDSGVPALPSLTMRRMRESVSRMPVSSQHRYSTPHAFTFNTSSPSSEGSLSQRQRSTSTPNVHMVSTTLPVDSRMIEDAIRSHSESASPSALSSSPNNLSPTGWSQPKTPVPAQRERAPVSGTQEKNKIRPRGQRDSSYYWEIEASEVMLSTRIGSGSFGTVYKGKWHGDVAVKILKVVDPTPEQFQAFRNEVAVLRKTRHVNILLFMGYMTKDNLAIVTQWCEGSSLYKHLHVQETKFQMFQLIDIARQTAQGMDYLHAKNIIHRDMKSNNIFLHEGLTVKIGDFGLATVKSRWSGSQQVEQPTGSVLWMAPEVIRMQDNNPFSFQSDVYSYGIVLYELMTGELPYSHINNRDQIIFMVGRGYASPDLSKLYKNCPKAMKRLVADCVKKVKEERPLFPQILSSIELLQHSLPKINRSASEPSLHRAAHTEDINACTLTTSPRLPVF
uniprot
proteins
disease_involvement
DISEASE: 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. {ECO:0000269|PubMed:17603482, ECO:0000269|PubMed:17603483, ECO:0000269|PubMed:20683980}. Note=The disease is caused by variants affecting the gene represented in this entry.; DISEASE: LEOPARD syndrome 2 (LPRD2) [MIM:611554]: A disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness. {ECO:0000269|PubMed:17603483}. Note=The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, dilated, 1NN (CMD1NN) [MIM:615916]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:24777450}. Note=The disease is caused by variants affecting the gene represented in this entry.
uniprot
proteins
ec_number
2.7.11.1
uniprot
proteins
function
FUNCTION: 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. {ECO:0000269|PubMed:11427728, ECO:0000269|PubMed:11719507, ECO:0000269|PubMed:15385642, ECO:0000269|PubMed:15618521, ECO:0000269|PubMed:15849194, ECO:0000269|PubMed:16892053, ECO:0000269|PubMed:16924233, ECO:0000269|PubMed:9360956}.
uniprot
proteins
mass_dalton
73052
uniprot
proteins
mutagenesis
MUTAGEN 338..339; /note="SS->AA: Reduced kinase activity; when associated with 340-D-D-341."; /evidence="ECO:0000269|PubMed:16892053"; MUTAGEN 338..339; /note="SS->DE: Non-inhibited by PPP5C. Constitutively active and non-inhibited by PPP5C; when associated with 340-D-D-341."; /evidence="ECO:0000269|PubMed:16892053"; MUTAGEN 340..341; /note="YY->DD: Constitutively active and highly phosphorylated on S-338, inhibited by PPP5C. Reduced kinase activity; when associated with 338-A-A-339. Constitutively active and non-inhibited by PPP5C; when associated with 338-D-E-339."; /evidence="ECO:0000269|PubMed:16892053"; MUTAGEN 375; /note="K->W: Catalytically inactive."; /evidence="ECO:0000269|PubMed:20956560"; MUTAGEN 491; /note="T->D: Increased kinase activity but can still be inhibited by PPP5C; when associated with D-494."; /evidence="ECO:0000269|PubMed:16892053"; MUTAGEN 494; /note="S->D: Increased kinase activity but can still be inhibited by PPP5C; when associated with D-491."; /evidence="ECO:0000269|PubMed:16892053"; MUTAGEN 563; /note="R->K: Loss of methylation. Increased stability and catalytic activity in response to EGF treatment."; /evidence="ECO:0000269|PubMed:21917714
uniprot
proteins
post_translational_modification
PTM: 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 SHOC2-MRAS-PP1c (SMP) complex consisting of SHOC2, GTP-bound M-Ras/MRAS and the catalytic subunit of protein phosphatase 1 (PPP1CA, PPP1CB or PPP1CC); this relieves inactivation and stimulates kinase activity (PubMed:35768504, PubMed:35831509, PubMed:35830882). Phosphorylation at Ser-338 by PAK1 and 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 an activity decrease. {ECO:0000269|PubMed:10576742, ECO:0000269|PubMed:10801873, ECO:0000269|PubMed:11447113, ECO:0000269|PubMed:11733498, ECO:0000269|PubMed:11756411, ECO:0000269|PubMed:15047712, ECO:0000269|PubMed:15849194, ECO:0000269|PubMed:16093354, ECO:0000269|PubMed:16630891, ECO:0000269|PubMed:16892053, ECO:0000269|PubMed:18465753, ECO:0000269|PubMed:21917714, ECO:0000269|PubMed:35768504, ECO:0000269|PubMed:35830882, ECO:0000269|PubMed:35831509, ECO:0000269|PubMed:7477354, ECO:0000269|PubMed:8349614, ECO:0000269|PubMed:9823899}.; PTM: Methylated at Arg-563 in response to EGF treatment. This modification leads to destabilization of the protein, possibly through proteasomal degradation. {ECO:0000269|PubMed:21917714}.
uniprot
proteins
protein_family
Protein kinase superfamily
uniprot
proteins
protein_family
RAF subfamily
uniprot
proteins
protein_family
TKL Ser/Thr protein kinase family
uniprot
proteins
pubmed
10576742
uniprot
proteins
pubmed
10801873
uniprot
proteins
pubmed
11427728
uniprot
proteins
pubmed
11447113
uniprot
proteins
pubmed
11719507
uniprot
proteins
pubmed
11733498
uniprot
proteins
pubmed
11756411
uniprot
proteins
pubmed
11784866
uniprot
proteins
pubmed
12717443
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15047712
uniprot
proteins
pubmed
15385642
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15618521
uniprot
proteins
pubmed
15849194
uniprot
proteins
pubmed
15935327
uniprot
proteins
pubmed
15943972
uniprot
proteins
pubmed
16093354
uniprot
proteins
pubmed
16508002
uniprot
proteins
pubmed
16630891
uniprot
proteins
pubmed
16892053
uniprot
proteins
pubmed
16924233
uniprot
proteins
pubmed
17218791
uniprot
proteins
pubmed
17344846
uniprot
proteins
pubmed
17525332
uniprot
proteins
pubmed
17603482
uniprot
proteins
pubmed
17603483
uniprot
proteins
pubmed
18220336
uniprot
proteins
pubmed
18294816
uniprot
proteins
pubmed
18465753
uniprot
proteins
pubmed
18669648
uniprot
proteins
pubmed
18691976
uniprot
proteins
pubmed
1886707
uniprot
proteins
pubmed
19298812
uniprot
proteins
pubmed
19690332
uniprot
proteins
pubmed
19710016
uniprot
proteins
pubmed
20068231
uniprot
proteins
pubmed
20674547
uniprot
proteins
pubmed
20683980
uniprot
proteins
pubmed
20956560
uniprot
proteins
pubmed
21269460
uniprot
proteins
pubmed
21406692
uniprot
proteins
pubmed
21779496
uniprot
proteins
pubmed
21917714
uniprot
proteins
pubmed
22538822
uniprot
proteins
pubmed
22886302
uniprot
proteins
pubmed
23186163
uniprot
proteins
pubmed
23327923
uniprot
proteins
pubmed
23509299
uniprot
proteins
pubmed
24275569
uniprot
proteins
pubmed
24777450
uniprot
proteins
pubmed
29127155
uniprot
proteins
pubmed
2993863
uniprot
proteins
pubmed
3003687
uniprot
proteins
pubmed
30368668
uniprot
proteins
pubmed
31024343
uniprot
proteins
pubmed
35768504
uniprot
proteins
pubmed
35830882
uniprot
proteins
pubmed
35831509
uniprot
proteins
pubmed
7477354
uniprot
proteins
pubmed
7766599
uniprot
proteins
pubmed
7791872
uniprot
proteins
pubmed
8349614
uniprot
proteins
pubmed
8710867
uniprot
proteins
pubmed
8756332
uniprot
proteins
pubmed
9360956
uniprot
proteins
pubmed
9823899
uniprot
proteins
sequence_length
648
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: 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.
uniprot
proteins