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.
KeywordsIRS 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.
- 13.Van Golen CM, Feldman EL (2000) Insulin-like growth factor I is the key growth factor in serum that protects neuroblastoma cells from hyperosmotic-induced apoptosis. J Cell Physiol 182:24–32. doi: 10.1002/(SICI)1097-4652(200001)182:1<24::AID-JCP3>3.0.CO;2-6 CrossRefPubMedGoogle Scholar
- 22.Lee AV, Gooch JL, Oesterreich S, Guler RL, Yee D (2000) Insulin-like growth factor I-induced degradation of insulin receptor substrate 1 is mediated by the 26S proteasome and blocked by phosphatidylinositol 3′-kinase inhibition. Mol Cell Biol 20:1489–1496. doi: 10.1128/MCB.20.5.1489-1496.2000 CrossRefPubMedGoogle Scholar
- 29.Sonoda Y, Matsumoto Y, Funakoshi M, Yamamoto D, Hanks SK, Kasahara T (2000) Anti-apoptotic role of focal adhesion kinase (FAK). Induction of inhibitor-of-apoptosis proteins and apoptosis suppression by the overexpression of FAK in a human leukemic cell line, HL-60. J Biol Chem 275:16309–16315. doi: 10.1074/jbc.275.21.16309 CrossRefPubMedGoogle Scholar
- 44.Briaud I, Dickson LM, Lingohr MK, McCuaig JF, Lawrence JC, Rhodes CJ (2005) Insulin receptor substrate-2 proteasomal degradation mediated by a mammalian target of rapamycin (mTOR)-induced negative feedback down-regulates protein kinase B-mediated signaling pathway in beta-cells. J Biol Chem 280:2282–2293. doi: 10.1074/jbc.M412179200 CrossRefPubMedGoogle Scholar
- 55.Kim B, Leventhal PS, White MF, Feldman EL (1998) Differential regulation of insulin receptor substrate-2 and mitogen-activated protein kinase tyrosine phosphorylation by phosphatidylinositol 3-kinase inhibitors in SH-SY5Y human neuroblastoma cells. Endocrinology 139:4881–4889. doi: 10.1210/en.139.12.4881 CrossRefPubMedGoogle Scholar