Protein / target
RAF proto-oncogene serine/threonine-protein kinase
Protein at a glance
Biological role
Protein serine/threonine kinase activity
Primary system
Nervous system
Strongest disease association
RASopathy
Therapeutic maturity
Clinically validated target
Druggability
Small molecule
Clinical development
4 approved · 5 in clinical development
Derived from structured UniProt, Open Targets and literature data on this page.
Protein profile
Canonical identity and biological annotation from UniProt.
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
Subcellular location
Domains and Gene Ontology detail (39)Hide
Domains & features
Gene Ontology
- Ccytoplasm
- Ccytosol
- CGolgi apparatus
- Cmitochondrial outer membrane
- Cmitochondrion
- Cnucleus
- Cplasma membrane
- Cpseudopodium
- Fadenylate cyclase activator activity
- FATP binding
- Fenzyme binding
- Fidentical protein binding
Biological roles
What this protein does, drawn together from its UniProt function, Gene Ontology terms and Reactome pathways.
View supporting evidenceHide supporting evidence
Kinase signalling
- ·Serine/threonine-protein kinase that acts as a regulatory link between the membrane-asso…
- ·MAP kinase kinase kinase activity
- ·protein kinase activity
- ·protein serine kinase activity
Apoptosis & cell death
- ·Serine/threonine-protein kinase that acts as a regulatory link between the membrane-asso…
- ·apoptotic process
- ·negative regulation of apoptotic process
- ·regulation of apoptotic process
Immune signalling
- ·Serine/threonine-protein kinase that acts as a regulatory link between the membrane-asso…
Transcriptional regulation
- ·Serine/threonine-protein kinase that acts as a regulatory link between the membrane-asso…
View underlying pathways (17)Hide underlying pathways
Concepts derived from UniProt GO Reactome — each badge above shows which sources supported that role.
Interaction neighbourhood
Proteins with the strongest functional or physical association. Node size and line weight reflect STRING confidence; hover or select a partner to inspect one association.
Functional and physical associations from STRING v12.0. Only associations with this protein are drawn — partner-to-partner links are not part of this evidence.
Drugs targeting this protein
Whether each drug engages this protein directly or through a complex, and how many other targets are recorded for it. Direct binders with few recorded targets are listed first.
Serine/threonine-protein kinase RAF inhibitor
Appears in clinical studies involving colorectal cancer, metastatic colorectal cancer, colorectal neoplasm, neoplasm
ChEMBL mechanism, action type and target identity. Open Targets clinical status and indications.
Translational evidence
Why this target matters therapeutically — disease associations, drugs in development, tractability and safety, from Open Targets.
Strongest genetic associations
Human genetic evidence — the most direct causal link between this target and a disease.
Highest-confidence therapeutic associations
Diseases where a drug acting on this target has already reached clinical development.
Highest overall evidence
Remaining associations by Open Targets' aggregated evidence score.
Show all associationsHide all associations
Open Targets ranks 3,149 associations for this target and we store the top 10 by aggregated score. The long tail is largely literature co-mention and RNA-expression evidence, not evidence that this target drives those diseases.
Known drugs · 9 total
central nervous system neoplasm · central nervous system cancer · melanoma
cancer
colorectal cancer · melanoma
renal cell carcinoma · thyroid gland carcinoma · hepatocellular carcinoma
colorectal cancer · metastatic colorectal cancer · colorectal neoplasm
neoplasm
renal cell carcinoma · hepatocellular carcinoma · renal cell carcinoma
glioma · low grade glioma · low grade glioma
melanoma · non-small cell lung carcinoma · non-small cell lung carcinoma
Tractability
Safety liabilities
Clinical trials
Trials of drugs that target this protein — reached indirectly through those drugs, so a trial listed here studies the drug, not the protein.
Show remaining trials (24)Hide
ClinicalTrials.gov via the drug-target graph.
Forefront confidence
Our own weighting of the evidence behind each disease association. Human genetics and clinical evidence count for most; literature co-mention counts for little, because two entities sharing an abstract is not evidence that one drives the other.
The evidence agreement range shows how closely the independent evidence families agree — it is not a statistical confidence interval, and nothing here is fitted to outcome data. Derived from Open Targets evidence types under Forefront weighting; the underlying per-type scores are shown above so the calculation can be checked.
What's happening now
Recent activity around this target, drawn from one canonical event stream. Every item is reached through a drug that targets this protein, so each event is news about that drug rather than about the protein directly.
- New publicationEfficacy of pembrolizumab in microsatellite-stable, tumor mutational burden-high metastatic colorectal cancer: genomic signatures and clinical outcomes.
- New publicationLenvatinib Plus Pembrolizumab Versus Standard of Care for Previously Treated Metastatic Colorectal Cancer: Final Analysis of the Randomized, Open-Label, Phase III LEAP-017 Study.
- New publicationTargeted therapy for hepatocellular carcinoma.
- New publicationMolecular targeted and immune checkpoint therapy for advanced hepatocellular carcinoma.
- New publicationRandomized Double-Blind Phase II Study of Regorafenib in Patients With Metastatic Osteosarcoma.
- New publicationRegorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial.
- Regulatory approval
Approval: Stivarga (EMA)
Objective event titles are shown unmodified; the event kind and significance line are derived from structured fields. Forefront AttentionEvent stream aggregating Europe PMC Regulatory filings ClinicalTrials.gov.