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. 2004 Mar 19;116(6):855-67.
doi: 10.1016/s0092-8674(04)00215-6.

Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF

Paul T C Wan  1 , Mathew J Garnett, S Mark Roe, Sharlene Lee, Dan Niculescu-Duvaz, Valerie M Good, C Michael Jones, Christopher J Marshall, Caroline J Springer, David Barford, Richard Marais; Cancer Genome Project
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Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF (V体育官网入口)

Paul T C Wan et al. Cell. .
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Abstract

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 VSports手机版. .

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