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标题：Blocking ligand occupancy of the αVβ3 integrin inhibits insulin-like growth factor I signaling in vascular smooth muscle cells
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作者：Bo Zheng ; David R. Clemmons
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：1998
卷号：95
期号：19
页码：11217-11222
DOI：10.1073/pnas.95.19.11217
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Blocking V{beta}3 integrin occupancy results in attenuation of the cellular migration response to insulin-like growth factor I (IGF-I). To determine whether integrin antagonists alter other IGF-I-stimulated biologic actions, quiescent smooth muscle cells (SMCs) were exposed to echistatin and their ability to respond to IGF-I was determined. Echistatin (10-7 M) inhibited IGF-I-stimulated DNA synthesis by 80%, and the protein synthesis response also was inhibited. Therefore blocking occupancy of V{beta}3 inhibited multiple target cell actions of IGF-I. To determine whether blocking V{beta}3 occupancy could alter IGF-I receptor-mediated signal transduction, the ability of IGF-I to stimulate phosphorylation of insulin receptor substrate-1 (IRS-1) was analyzed. A 10-min exposure to 100 ng/ml of IGF-I resulted in a substantial increase in phosphorylated IRS-1, and echistatin (10-7 M) blocked the IGF-I-induced IRS-1 phosphorylation response. Echistatin also attenuated downstream signaling because the capacity of the p85 subunit of phosphatidylinositol-3 kinase (PI-3 kinase) to bind to IRS-1 was blocked. In contrast, exposure of SMCs to vitronectin (1.0 {micro}g/cm2) or thrombospondin (0.25 {micro}g/cm2), two known ligands for V{beta}3, resulted in enhancement of the IGF-I-stimulated IRS-1 response. To determine whether these effects were caused by alterations in receptor kinase activity, the IGF-I receptor was immunoprecipitated and then analyzed for phosphotyrosine. Echistatin (10-7 M) significantly reduced IGF-I-stimulated tyrosine phosphorylation of the IGF-I receptor {beta} subunit. We conclude that occupancy of the V{beta}3 integrin is necessary for IGF-I to fully activate the kinase activity of the IGF-I receptor and phosphorylate IRS-1. Activation of the V{beta}3 receptor results in an interaction with the IGF-I signal transduction pathway, which modulates SMCs responsiveness to IGF-I.