Inositol Polyphosphate Multikinase Is a Nuclear PI3-Kinase with Transcriptional Regulatory Activity
Open accessAbstract
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.
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IPMK generates only PI(3,4,5)P3 as its product, unlike class I PI3K which generates multiple products.
“Specifically, IPMK generates only PI (3,4,5) P3 as its product [26], highlighting its unique enzymatic specificity in lipid kinase activity.”
From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [26]
IPMK uniquely serves as a lipid kinase using PIP2 as a substrate to generate PIP3.
“IPMK uniquely serves as a lipid kinase (Figure 1A), utilizing Phosphatidylinositol 4,5-bisphosphate [PI (4,5) P2] (PIP2) as a substrate to generate [PI (3,4,5) P3] (PIP3).”
From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [26]
IPMK functions as both an inositol kinase and a lipid kinase, converting PIP2 to PIP3.
“It functions as both an inositol kinase and a lipid kinase, capable of converting PIP2 (Phosphoinositide 4,5 bi phosphate) to PIP3 (Phosphoinositide 3,4,5 triphosphate) [26,27].”
From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [26]
Both yeast and mammalian IPMK exhibit lipid kinase properties.
“Both yeast and mammalian IPMK exhibit lipid kinase properties [15,26].”
From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [26]
IPMK is enriched in the nucleus.
“Over-expression studies indicate that IPMK is enriched in the nucleus [26], suggesting that PIP3 production also occurs within the nucleus.”
From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [26]
IPMK is an essential PI3-kinase-generating PIP3 critical for AKT activation.
“Studies by Resnick et al. [26], Maag et al. [15], and Reilly et al. [34] indicated that IPMK is an essential PI3-kinase-generating PIP3, which is critical for AKT activation.”
From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [26]
Cites
The phosphoinositide 3-kinase pathway
Cantley, L. C. (2002) · Science · doi:10.1126/science.296.5573.1655 · Cited by 5,621 · see citing works
A Role for Nuclear Inositol 1,4,5-Trisphosphate Kinase in Transcriptional Control
Odom, A. R., Stahlberg, A., Wente, S. R., & York, J. D. (2000) · Science · doi:10.1126/science.287.5460.2026 · Cited by 394 · see citing works
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-citationNALASKOWSKI, M. M., DESCHERMEIER, C., FANICK, W., & MAYR, G. W. (2002) · Biochemical Journal · doi:10.1042/bj20020327 · Cited by 89 · see citing works
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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
“Both yeast and mammalian IPMK exhibit lipid kinase properties [15,26].”
Influential
- Authors
- Resnick, A. C., Snowman, A. M., Kang, B. N., Hurt, K. J., Snyder, S. H., & Saiardi, A.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Snyder, Solomon H.
- Saiardi, Adolfo
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2005-08-25
- Volume
- 102
- Issue
- 36
- Pages
- 12783-12788
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1200306
- OpenAlex
- W2009772352
- Cited by
- 119
- References
- 4
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 5 · 2023: 4 · 2022: 6 · 2021: 3 · 2020: 3 · 2019: 11 · 2018: 3 · 2017: 13 · 2016: 8 · 2015: 11 · 2014: 1 · 2013: 10 · 2012: 4
- FWCI
- 1.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Drug Abuse (P50DA000266, DA000266)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- inositol polyphosphate multikinase, phosphatidylinositol 3-kinase, phosphatidylinositol 3,4,5-trisphosphate, inositol phosphates, transcriptional regulation, yeast, nuclear localization
- MeSH terms
- Wortmannin, Transaminases, Androstadienes, Animals, Cell Line, Cell Nucleus, Chlorocebus aethiops, Gene Expression Regulation, Humans, RNA, Messenger, Saccharomyces cerevisiae, Transcription, Genetic, Phosphotransferases (Alcohol Group Acceptor), Phosphatidylinositol 3-Kinases, Protein Kinase Inhibitors, Rats
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