Research ArticleCell Biology

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

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

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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.

Abstract

Downstream of growth factor receptors and of the guanine triphosphatase (GTPase) RAS, heterodimers of the serine/threonine kinases BRAF and RAF1 are critical upstream kinases and activators of the mitogen-activated protein kinase (MAPK) module containing the mitogen-activated and extracellular signal–regulated kinase kinase (MEK) and their targets, the extracellular signal–regulated kinase (ERK) family. Either direct or scaffold protein–mediated interactions among the components of the ERK module (the MAPKKKs BRAF and RAF1, MEK, and ERK) facilitate signal transmission. RAF1 also has essential functions in the control of tumorigenesis and migration that are mediated through its interaction with the kinase ROKα, an effector of the GTPase RHO and regulator of cytoskeletal rearrangements. We combined mutational and kinetic analysis with mathematical modeling to show that the interaction of RAF1 with ROKα is coordinated with the role of RAF1 in the ERK pathway. We found that the phosphorylated form of RAF1 that interacted with and inhibited ROKα was generated during the interaction of RAF1 with the ERK module. This mechanism adds plasticity to the ERK pathway, enabling signal diversification at the level of both ERK and RAF. Furthermore, by connecting ERK activation with the regulation of ROKα and cytoskeletal rearrangements by RAF1, this mechanism has the potential to precisely coordinate the proper timing of proliferation with changes in cell shape, adhesion, or motility.

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