Rapidly Accelerated Fibrosarcoma kinase family (RAF family) (RAF)

The Rapidly Accelerated Fibrosarcoma (RAF) kinase family consists of three highly conserved serine/threonine-specific protein kinases: A-RAF, B-RAF, and C-RAF (also known as RAF-1) [1.4.1, 1.4.3]. These enzymes are essential components of the mitogen-activated protein kinase (MAPK/ERK) signaling pathway, where they function as MAP kinase kinase kinases (MAP3Ks) [1.3.1, 1.4.2]. Upon activation by upstream RAS GTPases, RAF proteins undergo complex regulatory processes, including dimerization and phosphorylation, to activate downstream MEK and ERK kinases [1.4.1, 1.4.3]. This signaling cascade is a primary regulator of fundamental cellular activities such as proliferation, differentiation, and survival [1.4.2, 1.4.3]. Dysregulation of the RAF family is a hallmark of many human cancers, with somatic mutations in BRAF—particularly the V600E mutation—occurring in over 50% of melanomas and significant portions of colorectal and thyroid cancers [1.4.1, 1.4.4]. Germline mutations in RAF genes are also implicated in developmental disorders known as RASopathies, such as Noonan syndrome [1.4.2]. Therapeutic targeting of RAF kinases has led to the approval of several small-molecule inhibitors, such as vemurafenib and dabrafenib, which have significantly improved outcomes for patients with BRAF-mutant tumors [1.3.4, 1.4.4]. However, clinical challenges persist, including the development of drug resistance and the paradoxical activation of the MAPK pathway in cells with wild-type RAF, which can lead to secondary cutaneous malignancies [1.4.1, 1.4.2].

Other names

RAF kinasesA-RAFB-RAFC-RAFRaf-1Proto-oncogene c-RAFSerine/threonine-protein kinase RAF

ATP-competitive inhibition of RAF kinases, leading to the disruption of the MAPK/ERK signaling pathway and inhibition of downstream MEK and ERK activation.