Rapidly accelerated fibrosarcoma family kinase (RAF) (RAF)

The Rapidly accelerated fibrosarcoma (RAF) family kinase, comprising A-Raf, B-Raf, and C-Raf (Raf-1), is an essential group of serine/threonine-specific protein kinases that function as key mediators in the highly conserved Ras-Raf-MEK-ERK (MAPK) signaling pathway [1, 2, 7]. These kinases are recruited to the plasma membrane and activated by Ras-GTPases in response to extracellular growth factors, subsequently phosphorylating and activating MEK1/2 [5, 9]. This signaling cascade is a fundamental regulator of vital cellular processes, including proliferation, differentiation, survival, and apoptosis [4, 7]. Dysregulation of RAF kinases, particularly through activating mutations in the BRAF gene (such as the V600E substitution), is a major driver of oncogenesis in various human malignancies, including melanoma, colorectal cancer, and thyroid cancer [7, 10, 11]. In the clinical setting, RAF kinases are prominent therapeutic targets, with several small-molecule inhibitors approved for the treatment of BRAF-mutant cancers [6, 9]. These drugs typically act as ATP-competitive inhibitors that block the kinase activity of mutant B-Raf, thereby suppressing the downstream MAPK pathway [6, 10]. However, the use of first-generation RAF inhibitors is often complicated by the "RAF paradox," where the drug induces paradoxical activation of the MAPK pathway in cells with wild-type BRAF and mutant RAS, potentially leading to secondary skin cancers [10, 11]. Ongoing research focuses on developing next-generation "paradox-breaker" inhibitors and pan-RAF inhibitors to overcome resistance mechanisms and improve safety profiles [6, 8].

Other names

A-RafB-RafC-RafRaf-1v-Rafv-MilProto-oncogene A-Raf-1v-raf murine sarcoma viral oncogene homolog B1

Inhibition of kinase activity through ATP-competitive binding, prevention of RAF dimerization, and disruption of the RAS-RAF-MEK-ERK signaling cascade.