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

被引：88

作者：

Maag, David ^{[1
]}

Maxwell, Micah J. ^{[1
]}

Hardesty, Douglas A. ^{[4
]}

Boucher, Katie L. ^{[4
]}

Choudhari, Namrata ^{[4
]}

Hanno, Adam G. ^{[4
]}

Ma, Jenny F. ^{[4
]}

Snowman, Adele S. ^{[1
]}

Pietropaoli, Joseph W. ^{[1
]}

Xu, Risheng ^{[1
,2
]}

Storm, Phillip B. ^{[4
]}

Saiardi, Adolfo ^{[5
,6
]}

Snyder, Solomon H. ^{[1
,2
,3
]}

Resnick, Adam C. ^{[4
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA

[2] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA

[3] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA

[4] Childrens Hosp Philadelphia, Dept Neurosurg, Philadelphia, PA 19104 USA

[5] UCL, MRC, Mol Cell Biol Lab, Cell Biol Unit, London WC1E 6BT, England

[6] UCL, Dept Cell & Dev Biol, London WC1E 6BT, England

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2011年 / 108卷 / 04期

关键词：

signal transduction; cancer; HEXAKISPHOSPHATE KINASE-2; PHOSPHATE MULTIKINASE; HUMAN HOMOLOG; PROTEIN; PATHWAY; PENTAKISPHOSPHATE; PYROPHOSPHORYLATION; PYROPHOSPHATES; LOCALIZATION; INHIBITOR;

D O I：

10.1073/pnas.1017831108

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP3), 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.

引用

页码：1391 / 1396

页数：6

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