The serine/threonine kinase Akt is involved in a variety of cellular processes including cell proliferation, survival and gene expression.Akt has also been shown to be required for cell migration in different organisms.However, the mechanism by which Akt functions to promote cell migration is not fully understood.We identified a new Akt substrate,Girdin (girders of actin filament) which is an actin-binding protein, and found that Girdin is essential for the integrity of the actin cytoskeleton and cell migration.Girdin is expressed in some types of cancer cells, such as breast cancer and glioblastoma, and immature endothelial cells.Akt phosphorylates serine at position 1416 in Girdin, and phosphorylated Girdin accumulates at the leading edge of migrating cells.Cells expressing mutant Girdin, in which serine 1416 was replaced with alanine, exhibited limited migration and lamellipodia formation.Depletion of Girdin resulted in severe impairment of cancer cell migration and invasion in vitro and in vivo.Furthermore, we obtained evidence that Aktmediated phosphorylation of Girdin promotes VEGF-dependent migration and capillary formation of cultured endothelial cells.A significant observation is that Girdin, although v.ital for.cancer progression and postnatal vascular remodeling,is dispensable for cell migratory events during embryonic development.These findings suggest that Girdin and its interacting proteins are potential pharmaceutical targets for cancer therapies and pathological angiogenesis, including tumor angiogenesis.