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Cited by 1Microtubule and mitosis dynamicsCancer-related Molecular PathwaysPI3K/AKT/mTOR signaling in cancer

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Interaction of IRS2 with PLK1 protects cells from mitotic stress

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Lee, Ji-Sun, Bui, Quyen Thu, Jo, Minjeong, Morgan, Jennifer S., Nasa, Isha, Kettenbach, Arminja N., Shaw, Leslie M.·2026·Cell Death & Disease
DOI 10.1038/s41419-026-08706-0PMC PMC12330483

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Abstract

In this study we identify a role for IRS2 in the protection of cells from mitotic stress through its interaction with PLK1. IRS2 is an adapter protein for the insulin and IGF-1 receptors that mediates their signaling functions. In this capacity, IRS2 is tyrosine phosphorylated to recruit signaling effectors that control cellular outcomes. A role for IRS2 in mitotic regulation has been reported, but the mechanism of IRS2 action in this regulation has not been determined. Here we report that IRS2 interacts with PLK1 in a CDK1-dependent manner. In response to mitotic stress, cells that lack IRS2 or express a PLK1-binding deficient mutant exhibit reduced centrosome separation and a shortened mitotic arrest that leads to reduced tumor cell viability. In contrast, cells expressing an IRS2 mutant that is not tyrosine phosphorylated display normal mitotic function. Together, our findings establish a mechanistic connection between IRS2 and mitotic regulation that is distinct from its function as a signaling adapter protein.

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Metadata

Authors
Lee, J.-S., Bui, Q. T., Jo, M., Morgan, J. S., Nasa, I., Kettenbach, A. N., & Shaw, L. M.
Affiliations
  • University of Massachusetts Chan Medical School (US)
  • Dartmouth College (US)
Corresponding author
  • Lee, Ji-Sun
  • Shaw, Leslie M.
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2026-04-08
Volume
17
Issue
1
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/s41419-026-08706-0
PMC
PMC12330483
OpenAlex
W4412516136
Cited by
1
References
2
Citations by year
2026: 1
FWCI
3.40
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed Central (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Research Foundation of Korea (RS-2024-00406114)
  • U.S. Department of Health & Human Services | National Institutes of Health (GM119455, CA229910, CA227993, CA290778)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords
insulin receptor substrate 2, PLK1, mitotic stress, mitotic regulation, tyrosine phosphorylation, centrosome separation, mitotic arrest, tumor cell viability, insulin receptor substrate, adaptor proteins

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