An Essential Role for an Inositol Polyphosphate Multikinase, Ipk2, in Mouse Embryogenesis and Second Messenger Production
Open accessAbstract
Phospholipase C and several inositol polyphosphate kinase (IPK) activities generate a branched ensemble of inositol polyphosphate second messengers that regulate cellular signaling pathways in the nucleus and cytoplasm. Here, we report that mice deficient for Ipk2 (also known as inositol polyphosphate multikinase), an inositol trisphosphate and tetrakisphosphate 6/5/3-kinase active at several places in the inositol metabolic pathways, die around embryonic day 9.5 with multiple morphological defects, including abnormal folding of the neural tube. Metabolic analysis of Ipk2 -deficient cells demonstrates that synthesis of the majority of inositol pentakisphosphate, hexakisphosphate and pyrophosphate species are disrupted, although the presence of 10% residual inositol hexakisphosphate indicates the existence of a minor alternative pathway. Agonist induced inositol tris- and bis-phosphate production and calcium release responses are present in homozygous mutant cells, indicating that the observed mouse phenotypes are a result of failure to produce higher inositol polyphosphates. Our data demonstrate that Ipk2 plays a major role in the synthesis of inositol polyphosphate messengers derived from inositol 1,4,5-trisphosphate and uncovers a role for their production in embryogenesis and normal development.
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Among all enzymes in the HOIP pathway, IPMK is the only one whose deletion leads to embryonic lethality in mice.
“Notably, among all enzymes in the HOIP pathway, IPMK stands out as the only one whose deletion leads to embryonic lethality in mice, underscoring its critical role in mammalian development [25].”
From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [25]
The Discussion (page not supplied) confirms that Ipk2/IPMK deletion is embryonically lethal, but explicitly reports a similar lethal phenotype for Ipk1-null mice. Thus the paper contradicts the claim that IPMK is the only enzyme in this pathway whose deletion causes embryonic lethality. (LLM, conf=0.93)
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Experimental — accuracy not yet measuredDeletion of IPMK results in severe developmental defects across various model organisms.
“The physiological significance of IPMK is highlighted by studies across various model organisms, where its deletion results in severe developmental defects [24,25].”
From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [25]
The Results report that Ipk2-null mouse embryos have severe developmental abnormalities and are embryonically lethal. The paper does not establish that deletion of IPMK causes developmental defects across various model organisms; its mention of zebrafish abnormalities concerns a different kinase, Ipk1. No page number is available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIPMK is essential for mammalian embryonic development.
“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 [25]
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Cites
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
Self-citationModulation of ATP-Dependent Chromatin-Remodeling Complexes by Inositol Polyphosphates
Shen, X., Xiao, H., Ranallo, R., Wu, W.-H., & Wu, C. (2003) · Science · doi:10.1126/science.1078068 · Cited by 338 · see citing works
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NALASKOWSKI, M. M., DESCHERMEIER, C., FANICK, W., & MAYR, G. W. (2002) · Biochemical Journal · doi:10.1042/bj20020327 · Cited by 89 · see citing works
El 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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Research works printed but not linked: 4
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A role for a lithium-inhibited Golgi nucleotidase in skeletal development and sulfation
Frederick, J. P., Tafari, A. T., Wu, S.-M., Megosh, L. C., Chiou, S.-T., Irving, R. P., & York, J. D. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0801182105 · Cited by 67 · see citing works
Self-citationFrom 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
- Authors
- Frederick, J. P., Mattiske, D., Wofford, J. A., Megosh, L. C., Drake, L. Y., Chiou, S.-T., Hogan, B. L. M., & York, J. D.
- Affiliations
- Howard Hughes Medical Institute (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2005-06-06
- Volume
- 102
- Issue
- 24
- Pages
- 8454-8459
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1150869
- OpenAlex
- W2071737785
- Cited by
- 139
- References
- 5
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 5 · 2023: 3 · 2022: 5 · 2021: 4 · 2020: 7 · 2019: 9 · 2018: 5 · 2017: 9 · 2016: 4 · 2015: 4 · 2014: 2 · 2013: 9 · 2012: 10
- FWCI
- 3.51
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (T32HL007538, R01HL055672, HL55672)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- inositol polyphosphate multikinase, embryonic development, inositol trisphosphate, inositol tetrakisphosphate, inositol pentakisphosphate, phytic acid, inositol metabolism, calcium release, phospholipase C, mouse mutants
- MeSH terms
- Animals, Genetic Complementation Test, Genetic Vectors, Transfection, Second Messenger Systems, Signal Transduction, Phosphotransferases (Alcohol Group Acceptor), Gene Targeting, Gene Expression Regulation, Developmental, Mice
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