Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

PNAS 102 (36): 12783-12788

Copyright © 2005 by the National Academy of Sciences.


Inositol polyphosphate multikinase is a nuclear PI3-kinase with transcriptional regulatory activity

Adam C. Resnick *, Adele M. Snowman *, Bingnan N. Kang {dagger}, K. Joseph Hurt *, Solomon H. Snyder *, {dagger}, {ddagger}, §, and Adolfo Saiardi * ¶, §

Departments of *Neuroscience, {dagger}Pharmacology, and {ddagger}Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205

Contributed by Solomon H. Snyder, July 21, 2005

Abstract: Phosphatidylinositol 3,4,5-trisphosphate is a major intracellular messenger molecule thought to be formed almost exclusively by cytosolic, wortmannin-inhibited phosphoinositide 3-kinase family members. Inositol polyphosphate multikinase was identified as an enzyme that generates a series of water-soluble inositol phosphates. We now report the robust, physiologic, and evolutionarily conserved phosphoinositide 3-kinase activity of inositol polyphosphate multikinase, which is localized to nuclei and unaffected by wortmannin. In yeast, this inositol lipid kinase activity physiologically regulates transcription.

Key Words: lipids • nucleus • wortmannin

Author contributions: A.C.R., B.N.K., S.H.S., and A.S. designed research; A.C.R., A.M.S., B.N.K., K.J.H., and A.S. performed research; A.C.R., B.N.K., S.H.S., and A.S. analyzed data; and A.C.R., S.H.S., and A.S. wrote the paper.

Abbreviations: IP3, inositol 1,4,5-trisphosphate; PI(4,5)P2, inositol phosphatidylinositol 4,5-bisphosphate; PLC, phospholipase C; IPK, inositol polyphosphate kinase; IPMK, inositol polyphosphate multikinase; PI3K, phosphoinositide 3-kinase; PI(3,4,5)P3, phosphatidylinositol 3,4,5-trisphosphate.

Present address: Medical Research Council (MRC) Cell Biology Unit and Laboratory for Molecular Cell Biology, Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom.

§ To whom correspondence may be addressed. E-mail: dmcbado{at} or ssnyder{at}

© 2005 by The National Academy of Sciences of the USA

Inositol polyphosphate multikinase is a coactivator for serum response factor-dependent induction of immediate early genes.
E. Kim, R. Tyagi, J.-Y. Lee, J. Park, Y.-r. Kim, J. Beon, P. Y. Chen, J. Y. Cha, S. H. Snyder, and S. Kim (2013)
PNAS 110, 19938-19943
   Abstract »    Full Text »    PDF »
Inositol polyphosphate multikinase is a transcriptional coactivator required for immediate early gene induction.
R. Xu, B. D. Paul, D. R. Smith, R. Tyagi, F. Rao, A. B. Khan, D. J. Blech, M. S. Vandiver, M. M. Harraz, P. Guha, et al. (2013)
PNAS 110, 16181-16186
   Abstract »    Full Text »    PDF »
Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation.
T. Balla (2013)
Physiol Rev 93, 1019-1137
   Abstract »    Full Text »    PDF »
Regulation of mRNA export by the PI3 kinase/AKT signal transduction pathway.
A. J. C. Quaresma, R. Sievert, and J. A. Nickerson (2013)
Mol. Biol. Cell 24, 1208-1221
   Abstract »    Full Text »    PDF »
Inositol Polyphosphate Multikinase Is a Coactivator of p53-Mediated Transcription and Cell Death.
R. Xu, N. Sen, B. D. Paul, A. M. Snowman, F. Rao, M. S. Vandiver, J. Xu, and S. H. Snyder (2013)
Science Signaling 6, ra22
   Abstract »    Full Text »    PDF »
Arginine Transcriptional Response Does Not Require Inositol Phosphate Synthesis.
D. Bosch and A. Saiardi (2012)
J. Biol. Chem. 287, 38347-38355
   Abstract »    Full Text »    PDF »
Direct Modification and Activation of a Nuclear Receptor-PIP2 Complex by the Inositol Lipid Kinase IPMK.
R. D. Blind, M. Suzawa, and H. A. Ingraham (2012)
Science Signaling 5, ra44
   Abstract »    Full Text »    PDF »
Inositol Pyrophosphates as Mammalian Cell Signals.
A. Chakraborty, S. Kim, and S. H. Snyder (2011)
Science Signaling 4, re1
   Abstract »    Full Text »    PDF »
Inositol polyphosphate multikinase is a physiologic PI3-kinase that activates Akt/PKB.
D. Maag, M. J. Maxwell, D. A. Hardesty, K. L. Boucher, N. Choudhari, A. G. Hanno, J. F. Ma, A. S. Snowman, J. W. Pietropaoli, R. Xu, et al. (2011)
PNAS 108, 1391-1396
   Abstract »    Full Text »    PDF »
New Endogenous Regulators of Class I Histone Deacetylases.
A. Riccio (2010)
Science Signaling 3, pe1
   Abstract »    Full Text »    PDF »
Localization of agonist-sensitive PtdIns(3,4,5)P3 reveals a nuclear pool that is insensitive to PTEN expression.
Y. Lindsay, D. McCoull, L. Davidson, N. R. Leslie, A. Fairservice, A. Gray, J. Lucocq, and C. P. Downes (2006)
J. Cell Sci. 119, 5160-5168
   Abstract »    Full Text »    PDF »
Crystal Structure of Inositol Phosphate Multikinase 2 and Implications for Substrate Specificity.
W. Holmes and G. Jogl (2006)
J. Biol. Chem. 281, 38109-38116
   Abstract »    Full Text »    PDF »
Multiple Endoplasmic Reticulum-to-Nucleus Signaling Pathways Coordinate Phospholipid Metabolism with Gene Expression by Distinct Mechanisms.
S. A. Jesch, P. Liu, X. Zhao, M. T. Wells, and S. A. Henry (2006)
J. Biol. Chem. 281, 24070-24083
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882