PAK1-mediated activation of ERK1/2 regulates lamellipodial dynamics.

PAK1 is a member of the p21-activated kinase (PAK) family of serine/threonine kinases that are activated by the Rho GTPases Rac and Cdc42, and are implicated in regulating morphological polarity, cell migration and adhesion. Here we investigate the function of PAK1 in cell motility using macrophages derived from PAK1-null mice. We show that CSF1, a macrophage chemoattractant, transiently stimulates PAK1 and MAPK activation, and that MAPK activation is reduced in PAK1-/- macrophages. PAK1 regulates the dynamics of lamellipodium extension as cells spread in response to adhesion but is not essential for macrophage migration or chemotaxis towards CSF1. Following adhesion, PAK1-/- macrophages spread more rapidly and have more lamellipodia than wild-type cells; however, these lamellipodia were less stable than those in wild-type macrophages. ERK1/2 activity was reduced in PAK1-/- macrophages during adhesion, and inhibition of ERK1/2 activation in wild-type macrophages was sufficient to increase the spread area and mimic the lamellipodial dynamics of PAK1-/- macrophages. Together, these data indicate that PAK1 signals via ERK1/2 to regulate lamellipodial stability.