Passa al contenuto
Merck

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

Cell (2004-03-24)
Paul T C Wan, 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
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.

MATERIALI
N° Catalogo
Marchio
Descrizione del prodotto

Sigma-Aldrich
Sorafenib, ≥98% (HPLC)