Inositol polyphosphate multikinase is a physiologic PI3-kinase that activates Akt/PKB.
The second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP(3)), 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 inositol polyphosphate multikinase (IPMK) physiologically generates PIP(3) as well as water soluble inositol phosphates. IPMK deletion reduces growth factor-elicited Akt signaling and cell proliferation caused uniquely by loss of its PI3-kinase activity. Inhibition of p110 PI3-kinases by wortmannin prevents IPMK phosphorylation and activation. Thus, growth factor stimulation of Akt signaling involves PIP(3) 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.
Pubmed ID: 21220345 RIS Download
Androstadienes | Animals | Cell Line, Tumor | Cell Proliferation | Cells, Cultured | Embryo, Mammalian | Enzyme Activation | Female | Fibroblasts | HEK293 Cells | Humans | Immunoblotting | Inositol Phosphates | Intercellular Signaling Peptides and Proteins | Male | Mice | Mice, 129 Strain | Mice, Inbred C57BL | Mice, Knockout | Models, Biological | Phosphatidylinositol 3-Kinases | Phosphatidylinositol Phosphates | Phosphorylation | Phosphotransferases (Alcohol Group Acceptor) | Proto-Oncogene Proteins c-akt