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

David Maag, Micah J. Maxwell, Douglas A. Hardesty, Katie L. Boucher, Namrata Choudhari, Adam G. Hanno, Jenny F. Ma, Adele S. Snowman, Joseph W. Pietropaoli, Risheng Xu, Phillip B. Storm, Adolfo Saiardi, Solomon H. Snyder, Adam C. Resnick

Research output: Contribution to journalArticle

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 PIP3 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 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.

Original languageEnglish (US)
Pages (from-to)1391-1396
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number4
DOIs
StatePublished - Jan 25 2011

Keywords

  • Cancer
  • Signal transduction

ASJC Scopus subject areas

  • General

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  • Cite this

    Maag, D., Maxwell, M. J., Hardesty, D. A., Boucher, K. L., Choudhari, N., Hanno, A. G., Ma, J. F., Snowman, A. S., Pietropaoli, J. W., Xu, R., Storm, P. B., Saiardi, A., Snyder, S. H., & Resnick, A. C. (2011). Inositol polyphosphate multikinase is a physiologic PI3-kinase that activates Akt/PKB. Proceedings of the National Academy of Sciences of the United States of America, 108(4), 1391-1396. https://doi.org/10.1073/pnas.1017831108