BRAF belongs to a family of serine-threonine protein kinases that includes ARAF, BRAF, and CRAF (RAF1). RAF kinases are central mediators in the MAP kinase signaling cascade and exert their effect predominantly through phosphorylation and activation of MEK. This occurs following the dimerization (hetero- or homo-) of the RAF molecules. As part of the MAP kinase pathway, RAF is involved in many cellular processes, including cell proliferation, differentiation, and transcriptional regulation.
BRAF is a serine/threonine protein kinase activating the MAP kinase/ERK-signaling pathway. About 50 % of melanomas harbors activating BRAF mutations (over 90 % V600E). BRAFV600E has been implicated in different mechanisms underlying melanomagenesis, most of which due to the deregulated activation of the downstream MEK/ERK effectors.
Somatic activating BRAF mutations were first described by Davies et al. in 2002. Genomic DNA from 545 cancer cell lines and the corresponding matched lymphoblastoid cell lines from the same individuals were screened for sequence variants through the coding exons and intron-exon junctions of the BRAF gene. They reported an incidence of 8% across all cancers (43/545) and 3% in lung cancer (all adenocarcinomas) (4/131) . All BRAF somatic mutations found in the cancer lines were in exons 11 and 15. RAS and BRAF mutations usually occur in the same cancer types, but these mutations are found in a mutually exclusive fashion.