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Updated: Dec 18, 2025

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The Insulin Receptor Adaptor IRS2 is an APC/C Substrate That Promotes Cell Cycle Protein Expression and a Robust

Sandhya Manohar1, Qing Yu1, Steven P Gygi1

  • 1Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.

Molecular & Cellular Proteomics : MCP
|June 20, 2020
PubMed

Insights

Insulin receptor substrate 2 (IRS2) protein stability is regulated by the Anaphase Promoting Complex/Cyclosome (APC/C). This discovery reveals a new pathway for IRS2 turnover and its role in cell cycle control.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Metabolic Regulation

Background:

  • Insulin receptor substrate 2 (IRS2) is crucial for insulin signaling and metabolic homeostasis.
  • Dysregulation of IRS2 leads to systemic insulin signaling defects.
  • Factors controlling IRS2 protein stability remain largely unknown.

Purpose of the Study:

  • To identify novel substrates of the Anaphase Promoting Complex/Cyclosome (APC/C).
  • To investigate the role of APC/C in regulating IRS2 protein stability.
  • To explore the function of IRS2 in cell cycle control.

Main Methods:

  • Unbiased proteomic screening to identify APC/C substrates.
  • Quantitative proteomic analysis of IRS2-null cells.
  • Assessment of spindle assembly checkpoint function.

Main Results:

  • IRS2 was identified as a direct substrate of APC/C in G1 phase.
  • APC/C activity regulates IRS2 protein levels.
  • IRS2-null cells showed defects in cell cycle progression and spindle assembly checkpoint function.

Conclusions:

  • A novel pathway for IRS2 turnover mediated by APC/C was discovered.
  • IRS2 plays a role in cell cycle regulation beyond its metabolic functions.
  • IRS2 is a component of the cell cycle control system.
Keywords:
Anaphase-promoting complex/cyclosomeG1anaphase promoting complex (APC/C)cell cyclecell divisionenzyme inhibitioninsulin signaling pathwaymitosisubiquitin

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