Activation of Gαi3 triggers cell migration via regulation of GIV

During migration, cells must couple direction sensing to signal transduction and actin remodeling. We previously identified GIV/Girdin as a G alpha i3 binding partner. We demonstrate that in mammalian cells G alpha i3 controls the functions of GIV during cell migration. We find that G alpha i3 preferentially localizes to the leading edge and that cells lacking G alpha i3 fail to polarize or migrate. A conformational change induced by association of GIV with G alpha i3 promotes Akt-mediated phosphorylation of GIV, resulting in its redistribution to the plasma membrane. Activation of G alpha i3 serves as a molecular switch that triggers dissociation of G beta gamma and GIV from the Gi3-GIV complex, thereby promoting cell migration by enhancing Akt signaling and actin remodeling. G alpha i3-GIV coupling is essential for cell migration during wound healing, macrophage chemotaxis, and tumor cell migration, indicating that the G alpha i3-GIV switch serves to link direction sensing from different families of chemotactic receptors to formation of the leading edge during cell migration.