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Cited by 29PI3K/AKT/mTOR signaling in cancerProtein Kinase Regulation and GTPase SignalingMetabolism, Diabetes, and Cancer

Loss of PI3k Activity of Inositol Polyphosphate Multikinase Impairs PDK1-Mediated AKT Activation, Cell Migration, and Intestinal Homeostasis

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Reilly, Luke, Semenza, Evan R., Koshkaryan, George, Mishra, Subrata, Chatterjee, Sujan, Abramson, Efrat, Mishra, Pamela, Sei, Yoshitasu +4 more·2023·iScience
DOI 10.1016/j.isci.2023.106623PMC PMC10197106

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Abstract

Abstract Inositol polyphosphate multikinase (IPMK) is a rate-limiting enzyme in the inositol phosphate (IP) pathway which converts IP3 to IP4 and IP5. In mammalian cells, IPMK can also act as a phosphoinositol-3-kinase (PI3-kinase). We previously found that IPMK is a critical PI3-kinase activator of AKT. Here, we show that IPMK mediates AKT activation by promoting membrane localization and activation of PDK1. The PI3-kinase activity of IPMK is dispensable for membrane localization of AKT, which is entirely controlled by classical PI3-kinase (p110 α ,ß, γ, δ ). By contrast, we found that PDK1 membrane localization was largely independent of classical PI3-kinase. Membrane localization of PDK1 stimulates cell migration by dissociating ROCK1 from inhibitory binding to RhoE and promoting ROCK1-mediated myosin light chain (MLC) phosphorylation. Deletion of IPMK impairs cell migration associated with the abolition of PDK1-mediated ROCK1 disinhibition and subsequent MLC phosphorylation. To investigate the physiological relevance of IPMK-mediated AKT activation, we generated mice selectively lacking IPMK in epithelial cells of the intestine, where IPMK is highly expressed. Deletion of IPMK in intestinal epithelial cells markedly reduced AKT phosphorylation and diminished numbers of Paneth cells – a crypt-resident epithelial cell type that generates the physiological niche for intestinal stem cells. Ablation of IPMK impaired intestinal epithelial cell regeneration basally and after; chemotherapy-induced damage, suggesting a broad role for IPMK in the activation of AKT and intestinal tissue regeneration. In summary, the PI3-kinase activity of IPMK promotes membrane localization of PDK1, a critical kinase whereby AKT maintains intestinal homeostasis. One Sentence Summary PI3-kinase activity of IPMK is essential for activation of AKT.

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  • IPMK is implicated in neurodegeneration, cancer, and inflammation.

    “Over two decades, multidisciplinary research has unveiled its far-reaching biological roles and implications in diverse diseases, including neurodegeneration, cancer, and inflammation.”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [34]

    The Introduction (page not provided) links an IPMK mutation to familial intestinal carcinoids and describes IPMK as a putative risk gene for inflammatory bowel disease. The Discussion (page not provided) also suggests IPMK activity may affect Crohn disease risk. The paper does not link IPMK to neurodegeneration, so it supports only part of the attributed disease list. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • IPMK is involved in inflammatory disorders, obesity, Alzheimer's disease, inflammatory bowel disease, and intestinal neuroendocrine tumors.

    “Over the past two decades, research utilizing animal models and human mutation analyses has revealed IPMK’s involvement in a wide array of human diseases, including inflammatory disorders [28,29], obesity [30,31], Alzheimer’s disease [32], inflammatory bowel disease [33,34], and intestinal neuroendocrine tumors [35].”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [34]

  • Loss of IPMK's kinase activity impairs membrane localization of PDK1 and subsequently affects phosphorylation of MLC by ROCK1.

    “In addition to integrin regulation, Reilly et al. [34] proposed an alternative mechanism whereby the loss of IPMK’s kinase activity impairs the membrane localization of 3-phosphoinositide-dependent protein kinase 1 (PDK1) and subsequently affects the phosphorylation of myosin light chain (MLC) by Rho-associated protein kinase 1 (ROCK1).”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [34]

  • Deletion of IPMK or inhibition of its kinase activity results in impaired cell migration.

    “Deletion of IPMK or inhibition of its kinase activity resulted in impaired cell migration, indicating its essential function in this process.”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [34]

  • 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 [34]

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Authors
Reilly, L., Semenza, E. R., Koshkaryan, G., Mishra, S., Chatterjee, S., Abramson, E., Mishra, P., Sei, Y., Wank, S. A., Donowitz, M., Snyder, S. H., & Guha, P.
Affiliations
  • Johns Hopkins University (US)
  • University of Nevada, Las Vegas (US)
  • Memorial Sloan Kettering Cancer Center (US)
  • National Institutes of Health (US)
Corresponding author
  • Snyder, Solomon H.
  • Guha, Prasun
ORCID
Venue
iScience
Publisher
Elsevier BV
Published
2023-05
Volume
26
Issue
5
Pages
106623
ISSN
2589-0042 (ISSN-L)
DOI
10.1016/j.isci.2023.106623
PMC
PMC10197106
OpenAlex
W4364380532
Cited by
29
References
2
Citations by year
2026: 6 · 2025: 10 · 2024: 5 · 2023: 5 · 2022: 2 · 2021: 1
FWCI
2.32
Type
journal article
Language
en
Open access
Licence
Locations
  • iScience (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health
  • NIGMS (P20GM121325, 5R01MH018501-48)
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, PDK1, Akt activation, cell migration, intestinal homeostasis, intestinal epithelial cells, Paneth cells, ROCK1, myosin light chain phosphorylation, intestinal regeneration, chemotherapy-induced intestinal damage, lipid kinase activity

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