Research ArticleCell Biology

RAF1/BRAF dimerization integrates the signal from RAS to ERK and ROKα

See allHide authors and affiliations

Sci. Signal.  07 Mar 2017:
Vol. 10, Issue 469, eaai8482
DOI: 10.1126/scisignal.aai8482

You are currently viewing the editor's summary.

View Full Text

Coordinating proliferation and migration with RAF1

The kinase RAF1 is the mitogen-activated protein kinase kinase kinase (MAPKKK) that sits at the top of the proliferative pathway activated by growth factors. Growth factors stimulate a transient increase in the kinase activity of RAF1 through a complex set of phosphorylation and dephosphorylation events. Through a kinase-independent mechanism, RAF1 is also an inhibitor of the kinase ROKα, thereby coupling growth factor signaling to the cytoskeleton. Varga et al. identified how these two activities are controlled by the formation of specific phosphorylated forms of RAF1, as this kinase interacts with the signaling complex that activates the MAPK cascade. By combining the analysis of protein interactions detected by immunoprecipitation with computational modeling, the authors determined that the interaction with BRAF as part of the MAPK signaling complex stimulated the formation of the RAF1 phosphorylated form that signaled as a MAPKKK and also the formation of a distinct form that inhibited ROKα. Given the importance of RAF signaling in development, physiology, and various pathologies, such as cancer, this finding provides valuable insight into the molecular events controlling the output of this protein.