Inositol polyphosphate multikinase is a physiologic PI3-kinase that activates Akt/PKB

The second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP3), formed by the p110 family of PI3-kinases, promotes cellular growth, proliferation and survival, in large part by activating the protein kinase Akt/PKB. We show that the inositol polyphosphate multikinase (IPMK) physiologically generates PIP3 as well as water soluble inositol phosphates. IPMK deletion markedly reduces growth factor-elicited Akt signaling and cell proliferation caused uniquely by the loss of its PI3-kinase activity. Inhibition of the p110 PI3-kinases by wortmannin prevents IPMK phosphorylation and activation. Thus, growth factor stimulation of Akt signaling involves PIP3 generation through the sequential activations of the p110 PI3-kinases and IPMK. As inositol phosphates inhibit Akt signaling, IPMK appears to act as a molecular switch, inhibiting or stimulating Akt via its inositol phosphate kinase or PI3-kinase activities, respectively. Drugs regulating IPMK may have therapeutic relevance in influencing cell proliferation.