Second RAF paralogue (BRAF) is a proto-oncogene that encodes a serine/threonine kinase that transduces regulatory signals through the Rat Sarcoma (RAS)/RAF/ mitogen-activated protein kinase extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway. This pathway is hyperactivated in approximately 30% of human cancers.1 Activating mutations in the RAS oncogenes occur in 15%–30% of cancers.2 Kirsten murine sarcoma virus oncogene (KRAS) is an important and frequently mutated member of this group of oncogenes. Gain-of-function BRAF mutations results in aberrant activation of ERK signalling that is involved in several cancers such as thyroid papillary carcinoma, melanoma and colon carcinoma mainly but also as demonstrated in animal models in ovarian, skin, lung cancers and glioblastoma multiforme.3 ,4

Structure

There are three related RAF genes in mammals: first RAF paralogue (ARAF), BRAF and human homologue of v-RAF (CRAF) (RAF-1). The BRAF gene, located at 7q34, contains 18 exons and encodes a serine–threonine kinase in the RAS/RAF/MAPK signalling pathway.5 All the main RAF proteins share three highly conserved regions: CR1, CR2 and CR3; however, BRAF has a number of structural differences from the other RAF proteins (ARAF and CRAF). CR1 contains the RAS binding domain and the cysteine-rich domain.6–10 CR2 is rich in serine and threonine and contains regulatory phosphorylation sites. CR3 contains the P-loop and the important kinase …