Working model. (1) GIV preferentially and avidly binds to inactive GDP-bound Gαi3. Interaction with Gαi3 induces a change in conformation of GIV (dotted arrow). In a quiescent cell, this step is likely to occur predominantly on vesicles near the Golgi where Gαi3 and GIV were previously shown to colocalize. (2) Upon a chemotactic stimulus, Akt signaling is initiated and results in phosphorylation of GIV at S1416. This critical phosphorylation step is facilitated by the favorable conformation of GIV induced by direct interaction with Gαi3. Phosphorylation at S1416 was previously shown to be necessary for GIV's functions during cell migration (Enomoto et al., 2005). (3) Upon phosphorylation, GIV continues to preferentially and avidly bind to Gαi3; however, it selectively loses its affinity for PI4P (Enomoto et al., 2005), a phosphoinositide that is enriched in the Golgi, and redistributes from Golgi membranes to the peripheral actin bed near the PM. (4) Activation of Gαi3 occurs, likely downstream of ligand occupied receptors, and is the key event that mediates simultaneous dissociation of Gβγ and GIV from the Gi3–GIV complexes. (5) Released Gβγ activates PI3K-dependent Akt signaling (Lilly and Devreotes, 1995). (6) Released phospho-GIV enhances the initial Akt signaling (Anai et al., 2005), remodels actin, and promotes migration. (7) This second phase of Akt signal enhancement is critical for formation of the leading edge during polarized cell migration. Cyclical activation and inactivation of Gαi in vivo thus contributes to progressive Akt enhancement, which promotes further cycles of GIV phosphorylation (8 and 2), redistribution of phosphorylated GIV from Golgi to PM/actin (3), and subsequent release from the Gi3–GIV complexes upon activation of Gαi3 (4). This contributes to the previously observed accumulation of phosphorylated GIV at the leading edge (Enomoto et al., 2005) where GIV rapidly remodels actin to generate pseudopods.