Abstract
Akt activation relies on the binding of Akt to phosphatidylinositol-3,4,5-trisphosphate (PIP(3)) in the membrane. Here, we demonstrate that Akt activation requires not only PIP(3) but also membrane phosphatidylserine (PS). The extent of insulin-like growth factor-induced Akt activation and downstream signaling as well as cell survival under serum starvation conditions positively correlates with plasma membrane PS levels in living cells. PS promotes Akt-PIP(3) binding, participates in PIP(3)-induced Akt interdomain conformational changes for T308 phosphorylation, and causes an open conformation that allows for S473 phosphorylation by mTORC2. PS interacts with specific residues in the pleckstrin homology (PH) and regulatory (RD) domains of Akt. Disruption of PS-Akt interaction by mutation impairs Akt signaling and increases susceptibility to cell death. These data identify a critical function of PS for Akt activation and cell survival, particularly in conditions with limited PIP(3) availability. The novel molecular interaction mechanism for Akt activation suggests potential new targets for controlling Akt-dependent cell survival and proliferation.