Insulin receptor substrate (IRS)-2, not IRS-1, protects human neuroblastoma cells against apoptosis

Apoptosis. 2009 May;14(5):665-73. doi: 10.1007/s10495-009-0331-0.


Insulin receptor substrates (IRS)-1 and -2 are major substrates of insulin and type I insulin-like growth factor (IGF-I) receptor (IGF-IR) signaling. In this study, SH-EP human neuroblastoma cells are used as a model system to examine the differential roles of IRS-1 and IRS-2 on glucose-mediated apoptosis. In the presence of high glucose, IRS-1 underwent caspase-mediated degradation, followed by focal adhesion kinase (FAK) and Akt degradation and apoptosis. IRS-2 expression blocked all these changes whereas IRS-1 overexpression had no effect. In parallel, IRS-2, but not IRS-1, overexpression enhanced IGF-I-mediated Akt activation without affecting extracellular regulated kinase signaling. While IRS-1 was readily degraded by caspases, hyperglycemia-mediated IRS-2 degradation was unaffected by caspase inhibitors but blocked by proteasome and calpain inhibitors. Our data suggest that the differential degradation of IRS-1 and IRS-2 contributes to their distinct modes of action and the increased neuroprotective effects of IRS-2 in this report are due, in part, to its resistance to caspase-mediated degradation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis* / drug effects
  • Cell Line, Tumor
  • Cytoprotection* / drug effects
  • Enzyme Activation / drug effects
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism
  • Glucose / pharmacology
  • Humans
  • Insulin Receptor Substrate Proteins / metabolism*
  • Insulin-Like Growth Factor I / pharmacology
  • Neuroblastoma / enzymology*
  • Neuroblastoma / pathology*
  • Peptide Hydrolases / metabolism
  • Phosphorylation / drug effects
  • Protein Processing, Post-Translational / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Transfection


  • IRS1 protein, human
  • IRS2 protein, human
  • Insulin Receptor Substrate Proteins
  • Insulin-Like Growth Factor I
  • Focal Adhesion Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-akt
  • Peptide Hydrolases
  • Glucose