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Cited by 20Metabolism, Diabetes, and CancerCell Adhesion Molecules ResearchCellular Mechanics and Interactions

Inositol Polyphosphate Multikinase Is a Metformin Target That Regulates Cell Migration

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Tu‐Sekine, Becky, Padhi, Abinash, Jin, Sunghee, Kalyan, Srivathsan, Singh, Karanpreet, Apperson, Matthew, Kapania, Rakesh, Hur, Soojung Claire +2 more·2019·The FASEB Journal
DOI 10.1096/fj.201900717rrPMC PMC6894044
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Abstract

Metformin has been shown to alter cell adhesion protein expression, which is thought to play a role in its observed antitumor properties. We found that metformin treatment down‐regulated integrin β1 concomitant with the loss of inositol polyphosphate multikinase (IPMK) in murine myocytes, adipocytes, and hepatocytes. To determine if IPMK was upstream of integrin β1 expression, we examined IPMK ‐/‐ mouse embryonic fibroblast cells and found that integrins β1and β3 gene expression was reduced by half, relative to wild‐type cells, whereas focal adhesion kinase (FAK) activity and Rho/Rac/Cdc42 protein levels were increased, resulting in migration defects. Using nanonet force microscopy, we determined that cell:extracellular matrix adhesion and cell contractility forces were decreased, confirming the functional relevance of integrin and Rho protein dysregulation. Pharmacological studies showed that inhibition of both FAK1 and proline‐rich tyrosine kinase 2 partially restored integrin β1 expression, suggesting negative regulation of integrin β1 by FAK. Together our data indicate that IPMK participates in the regulation of cell migration and provides a potential link between metformin and wound healing impairment.—Tu‐Sekine, B., Padhi, A., Jin, S., Kalyan, S., Singh, K., Apperson, M., Kapania, R., Hur, S. C., Nain, A., Kim, S. F. Inositol polyphosphate multikinase is a metformin target that regulates cell migration. FASEB J. 33, 14137‐14146 (2019). www.fasebj.org

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  • IPMK's lipid kinase activity promotes cell migration in immortalized mouse embryonic fibroblast cells.

    “Studies by Sekine et al. [54] and Reilly et al. [34] have highlighted the significant role of IPMK’s lipid kinase activity in promoting cell migration in immortalized mouse embryonic fibroblast cells (MEFs).”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [54]

    The Results (page unavailable) report that IPMK-deficient MEFs migrated more slowly than wild-type cells and that active IPMK, but not kinase-dead IPMK, accelerated wound closure. These experiments support a role for IPMK’s catalytic activity in MEF migration, but they do not isolate its lipid kinase activity from its other catalytic activity or establish that the MEFs were immortalized. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • IPMK plays a crucial role in migration.

    “It plays a crucial role in cell proliferation [34], metabolism [58], autophagy [14,64], and migration [34,53,54].”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [54]

  • 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 [54]

  • Attempts to rescue cell migration in IPMK-deleted MEFs by overexpressing β1 integrin were unsuccessful.

    “However, attempts to rescue cell migration in IPMK-deleted MEFs by overexpressing β1 integrin were unsuccessful [54], suggesting that integrin-independent pathways likely play a role in IPMK-mediated cell migration.”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [54]

  • In Dictyostelium, cells with cPI3K genetically eliminated still migrate but are substantially retarded.

    “However, studies conducted in the model organism Dictyostelium, where cPI3K was genetically eliminated, revealed that cells still migrate but are substantially retarded [53,54].”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [54]

    The Results (page unavailable) report that mouse embryonic fibroblasts lacking IPMK still migrated, but more slowly than wild-type cells. Searches for Dictyostelium and genetically eliminated cPI3K found no passage addressing migration in those cells; the reported result concerns a different organism and gene. (LLM, conf=0.77)

    Experimental — accuracy not yet measured

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Authors
Tu‐Sekine, B., Padhi, A., Jin, S., Kalyan, S., Singh, K., Apperson, M., Kapania, R., Hur, S. C., Nain, A., & Kim, S. F.
Affiliations
  • Johns Hopkins University (US)
  • Virginia Tech (US)
Corresponding author
Kim, Sangwon F.
ORCID
Venue
The FASEB Journal
Publisher
Wiley
Published
2019-10-30
Volume
33
Issue
12
Pages
14137-14146
ISSN
  • 0892-6638 (ISSN-L)
  • 1530-6860
DOI
10.1096/fj.201900717rr
PMC
PMC6894044
OpenAlex
W2981346204
Cited by
20
References
1
Citations by year
2026: 1 · 2025: 3 · 2024: 2 · 2023: 3 · 2022: 5 · 2021: 2 · 2020: 2 · 2019: 2
FWCI
0.91
Type
journal article
Language
en
Update notices
correction (2020-08-28)
Open access
Licence
Locations
  • The FASEB Journal (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (DA568921)
  • American Heart Association (17SFRN33610014)
  • National Science Foundation (1437101, 1462916)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
Keywords
inositol polyphosphate multikinase, metformin, cell migration, beta1 integrin, CD61, focal adhesion kinase, cell adhesion, cell contractility, wound healing, PRK2, antitumor drug targets
MeSH terms
Animals, Cell Movement, Fibroblasts, Hypoglycemic Agents, Metformin, Down-Regulation, Gene Expression Regulation, Enzymologic, Phosphotransferases (Alcohol Group Acceptor), Mice, Knockout, Integrin beta1, Mice, Focal Adhesion Kinase 1

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