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

doi:10.1073/pnas.1017831108

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

70 Scopus citations

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 language	English (US)
Pages (from-to)	1391-1396
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	108
Issue number	4
DOIs	https://doi.org/10.1073/pnas.1017831108
State	Published - Jan 25 2011

Keywords

Cancer
Signal transduction

ASJC Scopus subject areas

General

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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

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 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

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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.",

keywords = "Cancer, Signal transduction",

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

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AU - Boucher, Katie L.

AU - Choudhari, Namrata

AU - Hanno, Adam G.

AU - Ma, Jenny F.

AU - Snowman, Adele S.

AU - Pietropaoli, Joseph W.

AU - Xu, Risheng

AU - Storm, Phillip B.

AU - Saiardi, Adolfo

AU - Snyder, Solomon H.

AU - Resnick, Adam C.

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N2 - 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.

AB - 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.

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

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