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Over 30 mutations of the B-RAF gene associated with human cancers have been identified, the majority of which are located within the kinase domain. Here we show that of 22 B-RAF mutants analyzed, 18 have elevated kinase activity and signal to ERK in vivo. Surprisingly, three mutants have reduced kinase activity towards MEK in vitro but, by activating C-RAF in vivo, signal to ERK in cells. The structures of wild type and oncogenic V599EB-RAF kinase domains in complex with the RAF inhibitor BAY43-9006 show that the activation segment is held in an inactive conformation by association with the P loop. The clustering of most mutations to these two regions suggests that disruption of this interaction converts B-RAF into its active conformation. The high activity mutants signal to ERK by directly phosphorylating MEK, whereas the impaired activity mutants stimulate MEK by activating endogenous C-RAF, possibly via an allosteric or transphosphorylation mechanism.

Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF., Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, Jones CM, Marshall CJ, Springer CJ, Barford D, Marais R, Cell. 2004 Mar 19;116(6):855-67. PMID:15035987

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Categories: Homo sapiens | Non-specific serine/threonine protein kinase | Barford, D. | Roe, S M. | Wan, P T.C. | Kinase | Signal transduction | Threonine-protein kinase