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

David Maag, Micah Maxwell, Douglas A. Hardesty, Katie L. Boucher, Namrata Choudhari, Adam G. Hanno, Jenny F. Ma, Adele M 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

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Phosphatidylinositol 3-Kinases
Inositol Phosphates
Cell Proliferation
Intercellular Signaling Peptides and Proteins
Second Messenger Systems
Protein Kinases
inositol polyphosphate multikinase
Phosphotransferases
Phosphorylation
Water
Growth
Pharmaceutical Preparations

Keywords

  • Cancer
  • Signal transduction

ASJC Scopus subject areas

  • General

Cite this

Inositol polyphosphate multikinase is a physiologic PI3-kinase that activates Akt/PKB. / Maag, David; Maxwell, Micah; Hardesty, Douglas A.; Boucher, Katie L.; Choudhari, Namrata; Hanno, Adam G.; Ma, Jenny F.; Snowman, Adele M; Pietropaoli, Joseph W.; Xu, Risheng; Storm, Phillip B.; Saiardi, Adolfo; Snyder, Solomon H; Resnick, Adam C.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 4, 25.01.2011, p. 1391-1396.

Research output: Contribution to journalArticle

Maag, D, Maxwell, M, Hardesty, DA, Boucher, KL, Choudhari, N, Hanno, AG, Ma, JF, Snowman, AM, Pietropaoli, JW, Xu, R, Storm, PB, Saiardi, A, Snyder, SH & Resnick, AC 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, vol. 108, no. 4, pp. 1391-1396. https://doi.org/10.1073/pnas.1017831108
Maag, David ; Maxwell, Micah ; Hardesty, Douglas A. ; Boucher, Katie L. ; Choudhari, Namrata ; Hanno, Adam G. ; Ma, Jenny F. ; Snowman, Adele M ; Pietropaoli, Joseph W. ; Xu, Risheng ; Storm, Phillip B. ; Saiardi, Adolfo ; Snyder, Solomon H ; Resnick, Adam C. / Inositol polyphosphate multikinase is a physiologic PI3-kinase that activates Akt/PKB. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 4. pp. 1391-1396.
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