Akt/PKB is a crucial regulator of diverse cellular processes and contributes to cancer progression. Activation of Akt is essentially dependent on phosphatidylinositol (PI) 3-kinase signaling. Here, we describe a novel mediator of Akt that is independent of PI 3-kinase. This mediator, PIKE-A, is a PIKE isoform and contains GTPase, pleckstrin homology, ArfGAP, and ankyrin repeats domains. PIKE-A directly binds to activated Akt but not PI 3-kinase in a guanine nucleotide-dependent way and stimulates the kinase activity of Akt. Overexpression of PIKE-A enhances Akt activity and promotes cancer cell invasion, whereas dominant-negative PIKE-A and PIKE-A knockdown markedly inhibit these processes. Our results demonstrate that PIKE-A is a physiologic regulator of Akt and an oncogenic effector of cell invasion.