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


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.

SUBMITTER: Maag D 

PROVIDER: S-EPMC3029688 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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

Maag David D   Maxwell Micah J MJ   Hardesty Douglas A DA   Boucher Katie L KL   Choudhari Namrata N   Hanno Adam G AG   Ma Jenny F JF   Snowman Adele S AS   Pietropaoli Joseph W JW   Xu Risheng R   Storm Phillip B PB   Saiardi Adolfo A   Snyder Solomon H SH   Resnick Adam C AC  

Proceedings of the National Academy of Sciences of the United States of America 20110110 4


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]

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