Content area
Full Text
Apoptosis (2009) 14:665673 DOI 10.1007/s10495-009-0331-0
ORIGINAL PAPER
Insulin receptor substrate (IRS)-2, not IRS-1, protects human neuroblastoma cells against apoptosis
Bhumsoo Kim Eva L. Feldman
Published online: 4 March 2009 Springer Science+Business Media, LLC 2009
Abstract 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.
Keywords IRS Apoptosis Caspase Neuroblastoma
Introduction
Insulin-like growth factor-I (IGF-I) plays crucial roles in the regulation of growth, survival, and normal metabolism of many cell types [1]. IGF signaling plays important roles in the malignant transformation of many tumors, including
neuroblastoma [2]. Most of the physiological effects of IGF-I are mediated by the type I IGF receptor (IGF-IR) [3]. Ligand binding of IGF-IR causes IGF-IR autophosphorylation, which subsequently initiates the binding of specic docking molecules to the phosphorylated receptor. One such docking molecule is insulin receptor substrate (IRS), which binds to phosphotyrosine residues on IGF-IR b-subunits. Receptor-IRS binding is required for IGF-I-mediated downstream signal transduction [4].
The most thoroughly characterized members of the IRS protein family are IRS-1 and IRS-2. Even though they display similar structural and functional characteristics, IRS-1 and IRS-2 mediate distinctly different cellular responses. IRS-2 knockout mice, but not IRS-1 decient mice, develop diabetes [5, 6], and disruption of the IRS-2 gene results in reduced neuronal proliferation and impaired brain growth [7]. In hepatocellular carcinoma, IRS-1 mediates the mitogenic effects of IGF-I [8], whereas IRS-2 is responsible for the metabolic and...