Publication in detail

PNAS 2011 Jan 25;108(4):1391-6. Epub 2011 Jan

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

Boucher, KL; Choudhari, N; Hanno, AG; Hardesty, DA; Ma, JF; Maag, D; Maxwell, MJ; Pietropaoli, JW; Resnick, AC.; Saiardi, A; Snowman, AS; Snyder, SH.; Storm, PB; Xu, R

The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

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. 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.

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