Activation of Gαi3 triggers cell migration via regulation of GIV

Abstract

During migration, cells must couple direction sensing to signal transduction and actin remodeling. We previously identified GIV/Girdin as a Gαi3 binding partner. We demonstrate that in mammalian cells Gαi3 controls the functions of GIV during cell migration. We find that Gαi3 preferentially localizes to the leading edge and that cells lacking Gαi3 fail to polarize or migrate. A conformational change induced by association of GIV with Gαi3 promotes Akt-mediated phosphorylation of GIV, resulting in its redistribution to the plasma membrane. Activation of Gαi3 serves as a molecular switch that triggers dissociation of Gβγ and GIV from the Gi3-GIV complex, thereby promoting cell migration by enhancing Akt signaling and actin remodeling. Gαi3-GIV coupling is essential for cell migration during wound healing, macrophage chemotaxis, and tumor cell migration, indicating that the Gαi3-GIV switch serves to link direction sensing from different families of chemotactic receptors to formation of the leading edge during cell migration. © 2008 Ghosh et al.