Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF.
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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.
Open access locationhttps://doi.org/10.1016/S0092-8674(04)00215-6
Version of record
Cancer Genome Project
NIH 3T3 Cells
Cell Transformation, Neoplastic
Proto-Oncogene Proteins B-raf
Proto-Oncogene Proteins c-raf
Mitogen-Activated Protein Kinase Kinases
MAP Kinase Kinase 1
Mitogen-Activated Protein Kinases
MAP Kinase Signaling System
Gene Expression Regulation, Enzymologic
Gene & Oncogene Targeting
Cell, 2004, 116 (6), pp. 855 - 867
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/
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