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 Gbetagamma, PAK-associated guanine nucleotide exchange factor (PIXalpha), 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 Gbetagamma binds PAKI and, via PAK-associated PIXa, activates Cdc42, which in turn activates PAK1. Thus, in this pathway, PAKII is not only an effector for Cdc42, but it also functions as a scaffold protein required for Cdc42 activation. This Gbetagamma-PAK1/PIXalpha/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.