Inositol polyphosphate multikinase is a physiologic PI3-kinase that activates Akt/PKB.
Journal:
Proc. Natl. Acad. Sci. U.S.A. 2011 JanAuthors:
Maag D, Maxwell MJ, Hardesty DA, Boucher KL, Choudhari N, Hanno AG, Ma JF, Snowman AS, Pietropaoli JW, Xu R, Storm PB, Saiardi A, Snyder SH, Resnick AC
Abstract
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. Inhib
...[more]ition 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.[less]
Mesh Headings:
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