BRAF
BRAF is a serine/threonine kinase immediately downstream of KRAS in the MAPK cascade, and the carrier of the most common activating kinase mutation in melanoma.
Function
BRAF is one of three RAF kinases. Activated RAS recruits BRAF to the membrane, where it dimerizes and phosphorylates MEK, which phosphorylates ERK; ERK then drives the transcriptional program of proliferation. BRAF depends on RAS for activation, but its position one step downstream makes it accessible to ATP-competitive inhibitors.
In cancer
The V600E mutation — a single glutamate-for-valine substitution in the activation loop — occurs in about half of melanomas, most hairy cell leukemias, and a large share of papillary thyroid cancers. V600E activates the kinase without RAS, and the mutant protein can signal as a monomer, which is why selective BRAF inhibitors (vemurafenib, dabrafenib) work in V600E melanoma. Two resistance routes shape therapy: BRAF-wild-type tumors dimerize and escape monomer-selective inhibition, and treated tumors frequently reactivate upstream signaling, which is why BRAF inhibitors are combined with MEK inhibitors in practice. In RAS-mutant tumors, BRAF inhibitors are harmful — the drug drives BRAF–CRAF heterodimerization and accelerates the pathway.
Notes
- Human gene symbol: BRAF; UniProt P15056; 766 amino acids; RAF kinase family.