, Volume 14, Issue 5, pp 665–673 | Cite as

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

  • Bhumsoo KimEmail author
  • Eva L. Feldman
Original Paper


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.


IRS Apoptosis Caspase Neuroblastoma 



This work was supported by a grant from the Juvenile Diabetes Research Foundation Center for the study of complications in diabetes, the Program for Neurology Research and Discovery and the A. Alfred Taubman Medical Research Institute.


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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of NeurologyUniversity of MichiganAnn ArborUSA

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