Kim Bhumsoo, Feldman Eva L
Department of Neurology, University of Michigan, 5371 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.
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.
胰岛素受体底物（IRS）-1和-2是胰岛素及Ⅰ型胰岛素样生长因子（IGF-Ⅰ）受体（IGF-IR）信号传导的主要底物。在本研究中，SH-EP人神经母细胞瘤细胞被用作模型系统，以研究IRS-1和IRS-2在葡萄糖介导的细胞凋亡中的不同作用。在高糖环境下，IRS-1发生半胱天冬酶介导的降解，随后粘着斑激酶（FAK）和Akt降解并引发细胞凋亡。IRS-2的表达可阻止所有这些变化，而IRS-1的过表达则没有影响。同时，IRS-2的过表达增强了IGF-Ⅰ介导的Akt激活，而不影响细胞外调节激酶信号传导，而IRS-1则无此作用。虽然IRS-1很容易被半胱天冬酶降解，但高血糖介导的IRS-2降解不受半胱天冬酶抑制剂的影响，却被蛋白酶体和钙蛋白酶抑制剂所阻断。我们的数据表明，IRS-1和IRS-2的不同降解方式导致了它们不同的作用模式，本报告中IRS-2增强的神经保护作用部分归因于其对半胱天冬酶介导降解的抗性。
