RAF protein kinases (B-Raf, C-Raf, A-Raf) (RAF)

The RAF protein kinases (B-Raf, C-Raf, and A-Raf) are serine/threonine kinases that act as downstream effectors of RAS GTPases, initiating the MAPK/ERK signaling cascade crucial for regulating cell growth, survival, and differentiation. These kinases share a common structural organization, including an N-terminal regulatory region with a RAS-binding domain (RBD) and a cysteine-rich domain (CRD), and a C-terminal catalytic kinase domain. Activation involves RAS-mediated recruitment to the cell membrane and subsequent conformational changes leading to MEK phosphorylation and downstream ERK activation. Oncogenic mutations, particularly in BRAF (most famously V600E), drive constitutive pathway activation in many cancers. RAF proteins are validated drug targets, with multiple inhibitors in clinical use, but therapeutic resistance and paradoxical pathway activation remain significant clinical challenges.

Other names

BRAFB-Raf kinaseRAF1c-RafARAFA-Raf kinaseRAF protein kinasesRAF kinases

Drugs targeting RAF proteins primarily inhibit their kinase activity, thereby blocking the phosphorylation of downstream MEK and ERK proteins in the RAS/MAPK signaling pathway. Some mechanisms also involve disrupting RAF dimerization or activation, thus regulating the overall MAPK pathway output.