Insulin receptor substrate (IRS)-2, not IRS-1, protects human neuroblastoma cells against apoptosis.
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.
Kim
Bhumsoo
B
Department of Neurology, University of Michigan, 5371 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA. bhumsoo@umich.edu
Feldman
Eva L
EL
D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D019610:Cytoprotection / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D009447:Neuroblastoma / Q000201:enzymology* / Q000473:pathology*; D010447:Peptide Hydrolases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014162:Transfection
C526292:IRS1 protein, human; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010447:Peptide Hydrolases; D005947:Glucose