The RAF-mitogen-activated protein kinase/extracellular signal regulated (ERK) kinase (MEK)-ERK signaling cascade mediates mitogenic and antiapoptotic signals from the cell surface to intracellular effector molecules. It is preferentially activated through binding of growth factors to receptor tyrosine kinases (RTK) that associate with the 21-kDa small G-protein RAS. The serine-threonine kinases A-RAF, B-RAF, and RAF-1 require RAS binding for activation and are additionally regulated through phosphorylation and binding to lipids and other protein regulators. Activated RAF phosphorylates MEK1/2, which in turn phosphorylate and thus activate ERK1/2. Constitutive activation of this pathway as a result of mutations is considered to be a key event in the development of several human cancers including acute myeloid leukemia (AML). RTKs like FLT3 are frequently mutated in AML, leading to ligand-independent pathway activation. Mutations have also been described in RAS, which is constitutively active in f20% of all human cancers and in up to 25% of AML cases. Recently, activating mutations of B-RAF have been detected in 66% of melanomas and at lower frequency in a wide range of human solid cancers. All mutations were located within the kinase domain of B-RAF with a single substitution (V600E, formerly V599E) accounting for 80% of the. Until now, more than 60 different mutations have been identified in this RAF isoform, most of them exhibiting elevated kinase activity and the ability to transform NIH 3T3 cells. Some of these B-RAF mutants, however, have impaired kinase activity but nevertheless activate ERK by stimulating RAF-1 . a very limited number of cases of activated RAF-1 have been reported. several studies addressing the mechanism of kinase activation for the Raf family point to differences between family members that allow B-Raf to be activated by a single mutation, while c- and A-Raf require multiple mutational events.
Khazak V, Astsaturov I, Serebriiskii I G, et al. Selective Raf inhibition in cancer therapy[J]. Expert opinion on therapeutic targets, 2007, 11(12): 1587-1609.
Zebisch A, Staber P B, Delavar A, et al. Two transforming C-RAF germ-line mutations identified in patients with therapy-related acute myeloid leukemia[J]. Cancer research, 2006, 66(7): 3401-3408.