Inositol Polyphosphate Multikinase Is a Transcriptional Coactivator Required for Immediate Early Gene Induction
Open accessAbstract
Significance: The induction of immediate early genes (IEGs) by neural stimuli underlies much of the plasticity of brain function, but regulatory mechanisms have been obscure. Inositol polyphosphate multikinase (IPMK) is a notably pleiotropic enzyme that displays inositol phosphate kinase activity and phosphatidylinositol kinase activity and exhibits physiologically noncatalytic actions such as stabilizing the mammalian target of rapamycin complex 1 complex. We report that IPMK is required for IEG induction by neural activation and neurotrophic stimuli. We have elucidated the molecular mechanisms responsible for IPMK influences; namely, that it enhances the transcriptional coactivation ability of Creb-binding protein (CBP). This epigenetic regulation of IEGs may have both neural and nonneural implications, as IPMK and CBP are broadly expressed in a variety of tissues.
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IPMK functions in mRNA export, chromatin remodeling, transcription, nutrient sensing, and growth factor signaling.
“Its diverse functions span a wide range of cellular processes, including mRNA export [17,18], chromatin remodeling [19,20], transcription [21,22], nutrient sensing [23], and growth factor signaling [15].”
From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [22]
IPMK has roles in nutrient sensing, growth factor signaling, mRNA transport, and transcription regulation.
“Initially identified in yeast and later recognized as essential for mammalian embryonic development, IPMK has transitioned from a niche interest to a focal point in studies of nutrient sensing, growth factor signaling, mRNA transport, and transcription regulation.”
From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [22]
Cites
Widespread transcription at neuronal activity-regulated enhancers
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CBP/p300 in cell growth, transformation, and development
Goodman, R. H., & Smolik, S. (2000) · Genes & Development · doi:10.1101/gad.14.13.1553 · Cited by 1,778 · see citing works
Structure of Hdac3 Bound to Co-Repressor and Inositol Tetraphosphate
Watson, P. J., Fairall, L., Santos, G. M., & Schwabe, J. W. R. (2012) · Nature · doi:10.1038/nature10728 · Cited by 505 · cited 1× · see citing works
“Recently, transcriptional repressive functions have been implicated for inositol 1,4,5,6-tetrakisphosphate (39).”
BackgroundA Role for Nuclear Inositol 1,4,5-Trisphosphate Kinase in Transcriptional Control
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Saiardi, A., Nagata, E., Luo, H. R., Sawa, A., Luo, X., Snowman, A. M., & Snyder, S. H. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.041614598 · Cited by 110 · see citing works
Self-citationEl Alami, M., Messenguy, F., Scherens, B., & Dubois, E. (2003) · Molecular Microbiology · doi:10.1046/j.1365-2958.2003.03562.x · Cited by 83 · see citing works
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Insights into the activation mechanism of class I HDAC complexes by inositol phosphates
Watson, P. J., Millard, C. J., Riley, A. M., Robertson, N. S., Wright, L. C., Godage, H. Y., Cowley, S. M., Jamieson, A. G., Potter, B. V. L., & Schwabe, J. W. R. (2016) · Nature Communications · doi:10.1038/ncomms11262 · Cited by 244 · see citing works
Association between genetic traits for immune-mediated diseases and Alzheimer disease
Yokoyama, J. S., Wang, Y., Schork, A. J., Thompson, W. K., Karch, C. M., Cruchaga, C., McEvoy, L. K., Witoelar, A., Chen, C.-H., Holland, D., et al. (2016) · JAMA Neurology · doi:10.1001/jamaneurol.2016.0150 · Cited by 176 · see citing works
From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease
Mishra, S. H., Chatterjee, S., Viera-Preval, L., & Guha, P. (2025) · Biomolecules · doi:10.3390/biom15091266 · Cited by 1 · see citing works
“1–75 Dominant-negative Mouse IPMK [22] Chromatin remodeling complex SWI/SNF The substrate binding pocket for HsIPMK is more constrained than its plant and yeast orthologs.”
InfluentialSelf-citation
- Authors
- Xu, R., Paul, B. D., Smith, D. R., Tyagi, R., Rao, F., Khan, A. B., Blech, D. J., Vandiver, M. S., Harraz, M. M., Guha, P., Ahmed, I., Sen, N., Gallagher, M., & Snyder, S. H.
- Affiliations
- Johns Hopkins University (US)
- The Solomon H. Snyder Department of Neuroscience,
- Augusta University (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-09-16
- Volume
- 110
- Issue
- 40
- Pages
- 16181-16186
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3791727
- OpenAlex
- W1972770584
- Cited by
- 36
- References
- 6
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 1 · 2020: 1 · 2019: 4 · 2018: 2 · 2017: 6 · 2016: 4 · 2015: 5 · 2014: 2 · 2013: 1
- FWCI
- 1.96
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (R01MH018501, R37MH018501, MH-18501)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- inositol polyphosphate multikinase, transcriptional coactivator, immediate early genes, CBP, histone acetyltransferase, electroconvulsive stimulation, neuronal activity, spatial memory, epigenetic regulation, gene induction
- MeSH terms
- Analysis of Variance, Animals, Brain, Gene Expression Regulation, Transcriptional Activation, Genes, Immediate-Early, Phosphotransferases (Alcohol Group Acceptor), Maze Learning, Recognition, Psychology, Epigenesis, Genetic, Chromatin Immunoprecipitation, CREB-Binding Protein, Mice
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