Mechanism of ERK-mediated Rho Activation and Stress Fiber Assembly for Cell Migration

The growth factor-activated RAS/Extracellular Regulated Kinase (ERK) pathway is a fundamental regulatory pathway that induces cell migration. ERK supports protrusion of a leading edge and also activates the small GTPase Rho, which induces actin assembly into contractile stress fibers that pull the cell body forward. Yet, the mechanism behind ERK's induction of Rho in the cell body has remained elusive. We discover here that ERK controls Rho activity and contractile stress fibers by inhibiting Ezrin, a protein that physically links proximal actin filaments to the plasma membrane, but which also inhibits Rho by recruiting and activating ARHGAP18. ERK specifically reduces Ezrin activity in the cell body by phosphorylating the C-terminal tail of the Ezrin-activating kinase lymphocyte-oriented kinase (LOK). This phosphorylation inhibits LOK's activation of Ezrin, thereby releases Ezrin's inhibition of Rho and stress fibers. The ERK-LOK-Ezrin-ARHGAP18-Rho signal provides key mechanistic insight into how ERK, activated during development, wound healing, and cancer, induces Rho activity and stress fibers for cell migration.