Phosphoinositol lipids bind to phosphaticlylinositol 3 (P13)-kinase enhancer GTPase and mediate its stimulatory effect on P13-kinase and Akt signalings

Phosphaticlylinositol 3 (P13)-kinase enhancer (PIKE) is a nuclear GTPase that enhances P13-kinase activity in a GTP-dependent manner. Both PIKE-L and -A isoforms contain GTPase, pleckstrin homology (PH), ADP ribosylation factor-GTPase-activating protein, and two ankyrin repeats domains, and C-terminal ADP ribosylation factor-GTPase-activating protein activates its internal GTPase activity. However, whether PH domain modulates the intramolecular action and subsequently influences its downstream signalings remains elusive. Here we show that PH domain from PIKE-L robustly binds PI(3,4,5)P-3 and exclusively resides in the nucleus. By contrast, the mutant (K679,687N), unable to bind phosphoinositol lipids, translocates to the cytoplasm. This mutation substantially compromises the stimulatory effects on P13-kinase by PIKE-L. Surprisingly, PH domain from PIKE-A distributes in the cytoplasm. Similar mutation in PH domain of PIKE-A abolishes its binding to PI(3,4,5)P3 and significantly decreases its activation of Akt. Moreover, amplified PIKE-A from human cancers contains mutations and highly stimulates Akt kinase activity, correlating with its GTPase activity. Thus, phosphaticlylinositols regulate PIKE GTPase activity, mediating its downstream P13-kinase/Akt signaling through a feedback mechanism by binding to its PH domain.