PLEKHG3 guides directed cell migration by activating branched actin networks

Abstract

Cells migrate by directing Rac1 and Cdc42 activities as well as actin polymerization towards their front. Previous studies proposed that this polarization process requires a local positive feed-back in the front involving Rac small GTPase and actin polymerization with PI3K likely playing a coor-dinating role. Here we show that PLEKHG3 is a PI3K-regulated RhoGEF for Rac1 and Cdc42 that se-lectively binds to newly polymerized actin in the front of migrating fibroblasts. Optogenetic inactiva-tion of PLEKHG3 showed that PLEKHG3 is indispensable not only for inducing but also for maintain-ing cell polarity. By selectively binding to newly polymerized actin, PLEKHG3 promotes local Rac1/ Cdc42 activation to induce more local actin polymerization which in turn promotes recruitment of more PLEKHG3 to induce and maintain frontness. Thus, autocatalytic reinforcement of PLEKHG3 localiza-tion to the front provides a molecular basis for the proposed positive feedback loop that is required for cell polarization and directed migration.