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

• Published in: Endocrinology (Philadelphia) Vol. 146; no. 12; pp. 5350 - 5357
• Main Authors: Kim, Bhumsoo, van Golen, Cynthia M, Feldman, Eva L
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.12.2005
• Subjects: Biological and medical sciences; Cell Line, Tumor; Enzyme Activation; Fundamental and applied biological sciences. Psychology; Humans; Insulin Receptor Substrate Proteins; Insulin-Like Growth Factor I - pharmacology; Intracellular Signaling Peptides and Proteins; Medical sciences; Neuroblastoma - metabolism; Neuroblastoma - pathology; Neurology; Phosphatidylinositol 3-Kinases - metabolism; Phosphoproteins - metabolism; Phosphorylation - drug effects; Proteasome Endopeptidase Complex - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Receptor, IGF Type 1 - metabolism; Tumors of the nervous system. Phacomatoses; Vertebrates: endocrinology; Human; Nervous system diseases; Enzyme; Transferases; Insulin receptor substrate protein 2; Malignant tumor; Neuroblastoma; Phosphatidylinositol 3-kinase; Autonomic neuropathy; Insulin like growth factor 1; 1-Phosphatidylinositol 3-kinase
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2005-0356

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.