Modulation of insulin-stimulated glycogen synthesis by Src Homology Phosphatase 2

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• 作者：Ouwens ; D. Margriet ; van der Zon ; Gerard C.M. ; Maassen ; J. Antonie
• 关键词：Insulin signalling ; Src homology phosphatase 2 ; Glycogen synthesis ; IRS-1 ; PI 3&prime ; -kinase
• 刊名：Molecular and Cellular Endocrinology
• 出版年：2001
• 出版时间：April 25, 2001
• 年：2001
• 卷：175
• 期：1-2
• 页码：131-140
• 全文大小：185 K

文摘

We have examined the requirement of the protein tyrosine phosphatase Src Homology Phosphatase 2 (SHP2) for insulin-stimulated glycogen synthesis. To this end, 3T3L1 fibroblasts were stably transfected with either wild type or a catalytically inactive C463A-mutant of SHP2, and analysed for insulin-induced glycogen synthesis, tyrosine phosphorylation of the insulin receptor and IRS-1, and activation of phosphatidylinositol 3′-kinase (PI 3′-kinase). Glycogen synthesis was stimulated 9.1±0.9-fold by insulin in untransfected cells. In cells expressing the dominant-negative C463A-SHP2 mutant, the stimulation of glycogen synthesis by insulin was strongly enhanced (18.7±2.7-fold stimulation), while this response was impaired in cells overexpressing wild-type SHP2 (6.6±1.1-fold stimulation). When exploring the early post-receptor signalling pathways that contribute to glycogen synthesis, we found that insulin stimulated the tyrosine phosphorylation of IRS-1, and the activation of IRS-1-associated PI 3′-kinase more strongly in C463A-SHP2 expressing 3T3L1-cells (18.1±4.7-fold) than in parental 3T3L1 cells (6.8±0.5-fold). In 3T3L1 cells overexpressing wild-type SHP2, the insulin stimulation of IRS-1 tyrosine phosphorylation and the activation of PI 3′-kinase (4.5±1.0-fold) were impaired. An enhanced activity of SHP2 leads to negative modulation of insulin signalling by reducing the tyrosine phosphorylation of IRS-1 and the concomitant activation of PI 3′-kinase. This results in an impaired ability of insulin to stimulate glycogen synthesis.