Pak3 inhibits local actin filament formation to regulate global cell polarity

Lamellipodia are broad actin-based structures that define the protruding edge of many motile animal cells. Here we identify a Drosophila homolog of the p21-activated kinases (Paks) as a novel inhibitor of Rac-mediated lamellipodial formation: Pak3 overexpression mimics a loss of Rac activity, while Pak3 RNAi-mediated silencing enhances lamellipodial dynamics. Strikingly, the depletion of Pak3 also polarizes the cellular distribution of actin filaments, is sufficient to induce nonmotile cells to migrate, and, in cells firmly attached to the substrate, gives rise to a wave of high actin filament density that encircles the cell periphery at a steady pace. To better understand these systems level phenomena, we developed a model of the cortical actin network as an active gel whose behavior is dominated by the rate of actin filament bundling and polymer synthesis. In the presence of filament treadmilling, this system generates a propagating density wave of actin filaments like that seen in Pak3 RNAi cells. This analysis reveals an intimate relationship between local regulation of actin filament dynamics and global cytoskeletal polarity, and suggests a role for negative regulators of lamellipodial formation, like Pak3, in the maintenance of a poised state, in which regulated directional cell movement can occur.