Mechanism of Activation of the RAF-ERK Signaling Pathway by Oncogenic Mutations of B-RAF

Content Provider	Semantic Scholar
Author	Wan, Paul T. C. Garnett, Mathew J. Roe, S. Mark Lee, Sharlene S. W. Niculescu-Duvaz, Dan Good, Valerie M. Jones, C. Michael Marshall, Christopher J. Barford, David Marais, Richard
Copyright Year	2004
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.
Starting Page	855
Ending Page	867
Page Count	13
File Format	PDF HTM / HTML
DOI	10.1016/S0092-8674(04)00215-6
PubMed reference number	15035987
Journal	Medline
Volume Number	116
Alternate Webpage(s)	http://faculty.evansville.edu/be6/b48055/PS2F05/Wan.pdf
Alternate Webpage(s)	http://www.unc.edu/courses/2006spring/envr/230/001/Cell%202004%20v-Raf%20V599E.pdf
Alternate Webpage(s)	https://api.elsevier.com/content/article/pii/S0092867404002156
Alternate Webpage(s)	https://www.sciencedirect.com/science/article/pii/S0092867404002156
Alternate Webpage(s)	https://doi.org/10.1016/S0092-8674%2804%2900215-6
Journal	Cell
Language	English
Access Restriction	Open
Content Type	Text
Resource Type	Article