Role of the TSC1-TSC2 Complex in the Integration of Insulin and Glucose Signaling Involved in Pancreatic β-Cell Proliferation
Role of the TSC1-TSC2 Complex in the Integration of Insulin and Glucose Signaling Involved in Pancreatic β-Cell Proliferation
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DOI：
10.1210/en.2010-0048
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发表时间：
2010-07-01
期刊：
影响因子：
4.8
通讯作者：
Benito, Manuel
中科院分区：
文献类型：
--
作者：
Bartolome, Alberto;Guillen, Carlos;Benito, Manuel
脑硬化复合蛋白1-2（TSC 1-TSC 2）复合物整合了营养和激素信号，是哺乳动物雷帕霉素靶蛋白（mTOR）复合物1的关键负调节因子。使用表达或不表达胰岛素受体（IR（+/+）和IR-/-）或重建表达IR亚型A或B（Rec A和Rec B）的不同β-细胞系揭示了磷脂酰肌醇3-激酶/Akt/TSC/mTOR复合物1和MAPK激酶/ERK途径均介导IR（+/+）-、伊拉-或IRB-表达细胞中的胰岛素信号传导。然而，在IR（-/-）细胞中，葡萄糖信号传导由MAPK激酶/ERK和AMP活化的蛋白激酶途径介导。在IR（+/+）和Rec B细胞中，使用磷脂酰肌醇3-激酶抑制剂wortmannin可完全抑制胰岛素对Akt磷酸化的作用，在RecA细胞系中观察到部分抑制作用。TSC 2表达的敲低上调70-kDa核糖体蛋白S6激酶（p70 S6 K）和mTOR的下游基础磷酸化。更重要的是，在IR（+/+）和Rec B细胞系中，p70 S6 K信号的上调损害了胰岛素刺激的Akt Ser（473）和p70 S6 K的磷酸化，但在Rec A细胞系中没有。事实上，在胰岛素作用过程中，Rec B细胞中胰岛素受体底物1 Ser（307）磷酸化信号比RecA细胞中更强。在血清刺激期间，RecA细胞与Rec B或IR（+/+）相比诱导更高的增殖率。因此，我们认为胰岛素或葡萄糖对TSC 2磷酸化的调节独立地整合了β细胞增殖信号，胰腺β细胞中伊拉或IRB亚型的相对表达起着主要作用。（内分泌学151：3084-3094，2010）
Tuberous sclerosis complex proteins 1-2 (TSC1-TSC2) complex integrates both nutrient and hormonal signaling and is a critical negative regulator of mammalian target of rapamycin (mTOR) complex 1. The use of different beta-cell lines expressing or not the insulin receptor (IR(+/+) and IR-/-) or with a reconstituted expression of IR isoform A or B (Rec A and Rec B) revealed that both phosphatidylinositol 3-kinase/Akt/TSC/mTOR complex 1 and MAPK kinase/ERK pathways mediate insulin signaling in IR(+/+)-, IRA-, or IRB-expressing cells. However, glucose signaling was mediated by MAPK kinase/ERK and AMP-activated protein kinase pathways as assessed in IR(-/-) cells. The effect of insulin on Akt phosphorylation was completely inhibited by the use of the phosphatidylinositol 3-kinase inhibitor wortmannin in IR(+/+) and Rec B cells, a partial inhibitory effect being observed in RecA cell line. The knockdown of TSC2 expression up-regulated the downstream basal phosphorylation of 70-kDa ribosomal protein S6 kinase (p70S6K) and mTOR. More importantly, upregulation of p70S6K signaling impaired insulin-stimulated phosphorylation of Akt Ser(473) and p70S6K in IR(+/+) and Rec B but not in Rec A cell lines. In fact, insulin receptor substrate-1 Ser(307) phosphorylation signal in Rec B was stronger than in RecA cell line during insulin action. RecA cells induced a higher proliferation rate compared with Rec B or IR(+/+) during serum stimulation. Thus, we propose that the regulation of TSC2 phosphorylation by insulin or glucose independently integrates beta-cell proliferation signaling, the relative expression of IRA or IRB isoforms in pancreatic beta cells playing a major role. (Endocrinology 151: 3084-3094, 2010)