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Insulin-Like Growth Factor I Induces Preferential Degradation of Insulin Receptor Substrate-2 through the Phosphatidylinositol 3-Kinase Pathway in Human Neuroblastoma Cells

University of Michigan, Department of Neurology Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: Eva L. Feldman, M.D., Ph.D., Department of Neurology, University of Michigan, 4414 Kresge III, 200 Zina Pitcher Place, Ann Arbor, Michigan 48109-0588. E-mail: efeldman{at}umich.edu.

Insulin receptor substrate (IRS) signaling is regulated through serine/threonine phosphorylation, with subsequent IRS degradation. This study examines the differences in IRS-1 and IRS-2 degradation in human neuroblastoma cells. SH-EP cells are glial-like, express low levels of the type I IGF-I receptor (IGF-IR) and IRS-2 and high levels of IRS-1. SH-SY5Y cells are neuroblast-like, with high levels of IGF-IR and IRS-2 but virtually no IRS-1. When stimulated with IGF-I, IRS-1 expression remains constant in SH-EP cells; however, IRS-2 in SH-SY5Y cells shows time- and concentration-dependent degradation, which requires IGF-IR activation. SH-EP cells transfected with IRS-2 and SH-SY5Y cells transfected with IRS-1 show that only IRS-2 is degraded by IGF-I treatment. When SH-EP cells are transfected with IGF-IR or suppressor of cytokine signaling, IRS-1 is degraded by IGF-I treatment. IRS-1 and -2 degradation are almost completely blocked by phosphatidylinositol 3-kinase inhibitors and partially by proteasome inhibitors. In summary, 1) IRS-2 is more sensitive to IGF-I-mediated degradation; 2) IRS degradation is mediated by phosphatidylinositol 3-kinase and proteasome sensitive pathways; and 3) high levels of IGF-IR, and possibly the subsequent increase in Akt phosphorylation, are required for efficient IRS degradation.

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				C. M. van Golen, T. S. Schwab, B. Kim, M. E. Soules, S. Su Oh, K. Fung, K. L. van Golen, and E. L. Feldman Insulin-Like Growth Factor-I Receptor Expression Regulates Neuroblastoma Metastasis to Bone. Cancer Res., July 1, 2006; 66(13): 6570 - 6578. [Abstract] [Full Text] [PDF]