Inositol Polyphosphate Multikinase Is a Physiologic PI3-Kinase That Activates Akt/PKB
Open accessAbstract
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.
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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 [15]
The introduction and Results and Discussion support IPMK’s role in growth factor–dependent Akt signaling, and the paper notes that IPMK deletion is lethal early in mouse embryogenesis. Our copy does not establish roles in nutrient sensing or mRNA transport. Transcriptional regulation appears in the title of an earlier study in the references, not as a finding established by this paper; yeast appears only in a referenced title. (LLM, conf=0.88)
Experimental — accuracy not yet measuredBoth 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 [15]
The Results and Discussion report PI3K lipid-kinase activity for mouse IPMK, including reduced PIP3 generation in IPMK-deleted mouse embryonic fibroblasts. The passages found do not establish lipid-kinase activity for yeast IPMK, so the yeast half of the claim is unsupported by this paper. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIPMK's lipid kinase enzymatic (PI3-kinase) activity is essential for activating AKT.
“Notably, research suggests that IPMK’s lipid kinase enzymatic (PI3-kinase) activity is essential for activating AKT [15], also known as PKB (protein kinase B), a crucial kinase involved in cell survival and proliferation.”
From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [15]
The Results and Discussion report that IPMK’s PI3-kinase activity is predominantly responsible for its contribution to Akt signaling: wild-type IPMK rescued Akt activation in IPMK-deleted cells, whereas a form lacking PI3-kinase activity did not. But deletion reduced activation by 40–50%, rather than eliminating it, so the paper does not establish that IPMK’s activity is essential for all Akt activation. (LLM, conf=0.90)
Experimental — accuracy not yet measuredIPMK 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 [15]
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 [15]
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 [15]
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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 complex interplay between Akt, TSC2 and the two mTOR complexes
Huang, J., & Manning, B. D. (2009) · Biochemical Society Transactions · doi:10.1042/bst0370217 · Cited by 724 · 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
- Maag, D., Maxwell, M. J., Hardesty, D. A., Boucher, K. L., Choudhari, N., Hanno, A. G., Ma, J. F., Snowman, A. S., Pietropaoli, J. W., Xu, R., Storm, P. B., Saiardi, A., Snyder, S. H., & Resnick, A. C.
- Affiliations
- The Solomon H. Snyder Department of Neuroscience,
- Children's Hospital of Philadelphia (US)
- MRC Laboratory for Molecular Cell Biology (GB)
- Johns Hopkins University (US)
- Corresponding author
- Snyder, Solomon H.
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-01-10
- Volume
- 108
- Issue
- 4
- Pages
- 1391-1396
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3029688
- OpenAlex
- W2162760085
- Cited by
- 122
- References
- 4
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 6 · 2023: 8 · 2022: 8 · 2021: 5 · 2020: 4 · 2019: 11 · 2018: 4 · 2017: 10 · 2016: 3 · 2015: 10 · 2014: 4 · 2013: 12 · 2012: 20
- FWCI
- 5.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Damon Runyon Cancer Research Foundation
- National Institute on Drug Abuse (P50DA000266, DA 00074, DA.00266, K05DA000074)
- National Cancer Institute (R00CA134914, K99CA134914)
- 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 › Metabolism, Diabetes, and Cancer
- Keywords
- inositol polyphosphate multikinase, PI3-kinase, Akt signaling, phosphatidylinositol 3,4,5-trisphosphate, inositol phosphates, wortmannin, growth factor signaling, cell proliferation
- MeSH terms
- Wortmannin, Phosphoinositide-3 Kinase Inhibitors, Androstadienes, Animals, Cells, Cultured, Embryo, Mammalian, Enzyme Activation, Female, Fibroblasts, Humans, Inositol Phosphates, Male, Mice, Inbred C57BL, Models, Biological, Phosphorylation, Immunoblotting, Phosphotransferases (Alcohol Group Acceptor), Phosphatidylinositol Phosphates, Mice, Knockout, Phosphatidylinositol 3-Kinases, Intercellular Signaling Peptides and Proteins, Cell Line, Tumor, Cell Proliferation, Proto-Oncogene Proteins c-akt, Mice, Mice, 129 Strain, HEK293 Cells
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