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
Monomer. Homodimer. Heterodimerizes with BRAF and this heterodimer possesses a highly increased kinase activity compared to the respective homodimers or monomers (PubMed:16508002).
Heterodimerization is mitogen-regulated and enhanced by 14-3-3 proteins (PubMed:16508002). MAPK1/ERK2 activation can induce a negative feedback that promotes the dissociation of the heterodimer (PubMed:16508002). Forms a multiprotein complex with Ras (M-Ras/MRAS), SHOC2 and protein phosphatase 1 (PPP1CA, PPP1CB and PPP1CC) (PubMed:16630891).
Interacts with LZTR1 (PubMed:30368668). Interacts with Ras proteins; the interaction is antagonized by RIN1 (PubMed:11784866). 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). 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 (PubMed:29127155). Interacts with STK3/MST2; the interaction inhibits its pro-apoptotic activity (PubMed:15618521).
Interacts (when phosphorylated at Ser-259) with YWHAZ (unphosphorylated at 'Thr-232') (PubMed:31024343, PubMed:9360956). 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 (PubMed:11427728).
Interacts with PAK1 (via kinase domain) (PubMed:11733498). The phosphorylated form interacts with PIN1 (By similarity). The Ser-338 and Ser-339 phosphorylated form (by PAK1) interacts with BCL2 (PubMed:15849194).
Interacts with PEBP1/RKIP and this interaction is enhanced if RAF1 is phosphorylated on residues Ser-338, Ser-339, Tyr-340 and Tyr-341 (PubMed:18294816). Interacts with ADCY2, ADCY5, ADCY6, DGKH, RCAN1/DSCR1, PPP1R12A, PKB/AKT1, PPP2CA, PPP2R1B, SPRY2, SPRY4, CNKSR1/CNK1, KSR2 and PHB/prohibitin (PubMed:10576742, PubMed:10801873, PubMed:11719507, PubMed:12717443, PubMed:15385642, PubMed:15935327, PubMed:19710016). Interacts with ROCK2 (By similarity).
In its active form, interacts with PRMT5 (PubMed:21917714). Interacts with FAM83B; displaces 14-3-3 proteins from RAF1 and activates RAF1 (PubMed:22886302). Interacts with PDE8A; the interaction promotes RAF1 activity (PubMed:23509299).
Interacts with MFHAS1 (PubMed:23327923). Interacts with GLS (PubMed:22538822). Interacts with NEK10 and MAP2K1; the interaction is direct with NEK10 and required for ERK1/2-signaling pathway activation in response to UV irradiation (PubMed:20956560)
In skeletal muscle, isoform 1 is more abundant than isoform 2
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.
A disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness.
A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.
| Cancer Type | Mutation Percentage |
|---|---|
| Central Nervous System Astrocytoma Grade Iv | 0.38% |
| Lung Adenocarcinoma | 1.05% |
| Lung Small Cell Carcinoma | 0.89% |
| Lung Squamous Cell Carcinoma | 0.54% |
| Oesophagus Squamous Cell Carcinoma | 0.35% |
| Pancreas Ductal Carcinoma | 0.65% |
Genes with an experimentally identified or computationally predicted synthetic-lethal relationship to RAF1, aggregated across our SSL data sources. Click any partner node to view that gene’s page.
Nodes and edges are coloured by the SSL data source. Partners appearing in more than one source are shown in grey.
Total Trials Found: 477
| NCT ID | Condition | Brief Title | Phase | Status |
|---|---|---|---|---|
| NCT04534283 | Cancer, Cancer Metastatic, BRAF V600E, MEK1 Gene Mutation, MEK2 Gene Mutation, ERK Mutation, RAF1 Gene Mutation | A Basket Trial of an ERK1/2 Inhibitor (LY3214996) in Combination With Abemaciclib. | PHASE2 | TERMINATED |
| NCT04985604 | Melanoma, Solid Tumor, CRAF Gene Amplification, RAF1 Gene Amplification, BRAF Gene Fusion, BRAF Fusion, CRAF Gene Fusion, CRAF Fusion, RAF1 Gene Fusion, RAF1 Fusion, Thyroid Cancer, Papillary, Spitzoid Melanoma, Pilocytic Astrocytoma, Pilocytic Astrocytoma, Adult, Non Small Cell Lung Cancer, Non-Small Cell Adenocarcinoma, Colorectal Cancer, Pancreatic Acinar Carcinoma, Spitzoid Malignant Melanoma, Bladder Cancer, Bladder Urothelial Carcinoma, MAP Kinase Family Gene Mutation, RAF Mutation | Tovorafenib (DAY101) Monotherapy for Patients With Melanoma and Other Solid Tumors | PHASE2 | TERMINATED |
| NCT01584778 | Behçet's Disease | Behçet's Disease and Eosinophil Cationic Protein | N/A | COMPLETED |
| NCT03673384 | Allergic Rhinitis | Effect of Health Promotion on Allergic Rhinitis by Infrared-C Ray Irradiation | NA | COMPLETED |
| NCT03856840 | Pemphigoid, Bullous | Cytokines in Blister Fluids of Bullous Pemphigoid (BP) | N/A | COMPLETED |
| NCT04913285 | Solid Tumor, Adult, Non-small Cell Lung Cancer, Melanoma | A Study to Evaluate KIN-2787 in Participants With BRAF and/or NRAS Mutation Positive Solid Tumors | PHASE1 | ACTIVE_NOT_RECRUITING |
| NCT01552161 | Coronary Artery Disease, Allergy, Asthma | Prevalence of Allergic Diseases and Atopy in Subjects With Coronary Artery Disease | N/A | COMPLETED |