Directional Sensing Requires Gβγ-Mediated PAK1 and PIXα-Dependent Activation of Cdc42

Efficient chemotaxis requires directional sensing and cell polarization. We describe a signaling mechanism involving Gβγ, PAK-associated guanine nucleotide exchange factor (PIXα), Cdc42, and p21-activated kinase (PAK) 1. This pathway is utilized by chemoattractants to regulate directional sensing and directional migration of myeloid cells. Our results suggest that Gβγ binds PAK1 and, via PAK-associated PIXα, activates Cdc42, which in turn activates PAK1. Thus, in this pathway, PAK1 is not only an effector for Cdc42, but it also functions as a scaffold protein required for Cdc42 activation. This Gβγ-PAK1/PIXα/Cdc42 pathway is essential for the localization of F-actin formation to the leading edge, the exclusion of PTEN from the leading edge, directional sensing, and the persistent directional migration of chemotactic leukocytes. Although ligand-induced production of PIP3 is not required for activation of this pathway, PIP3 appears to localize the activation of Cdc42 by the pathway.