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

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.

Pubmed ID: 21220345

Authors

  • 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

Journal

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

Publication Data

January 25, 2011

Associated Grants

  • Agency: NIDA NIH HHS, Id: DA-00074
  • Agency: NIDA NIH HHS, Id: DA-00266
  • Agency: NCI NIH HHS, Id: K99 CA134914
  • Agency: NCI NIH HHS, Id: K99 CA134914-01
  • Agency: Medical Research Council, Id: MC_U122680443
  • Agency: NCI NIH HHS, Id: R00 CA134914
  • Agency: NCI NIH HHS, Id: R00 CA134914-02
  • Agency: NCI NIH HHS, Id: R00 CA134914-03

Mesh Terms

  • Androstadienes
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Cells, Cultured
  • Embryo, Mammalian
  • Enzyme Activation
  • Female
  • Fibroblasts
  • HEK293 Cells
  • Humans
  • Immunoblotting
  • Inositol Phosphates
  • Intercellular Signaling Peptides and Proteins
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Biological
  • Phosphatidylinositol 3-Kinases
  • Phosphatidylinositol Phosphates
  • Phosphorylation
  • Phosphotransferases (Alcohol Group Acceptor)
  • Proto-Oncogene Proteins c-akt