Blandino-Rosano Manuel, Scheys Joshua O, Jimenez-Palomares Margarita, Barbaresso Rebecca, Bender Aaron S, Yanagiya Akiko, Liu Ming, Rui Liangyou, Sonenberg Nahum, Bernal-Mizrachi Ernesto
Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI.
Diabetes, Obesity and Metabolism Institute, The Icahn School of Medicine at Mount Sinai, New York, NY.
Diabetes. 2016 Aug;65(8):2235-48. doi: 10.2337/db15-1443. Epub 2016 May 23.
The mammalian target of rapamycin complex 1 (mTORC1) regulates several biological processes, although the key downstream mechanisms responsible for these effects are poorly defined. Using mice with deletion of eukaryotic translation initiation factor 4E-binding protein 2 (4E-BP2), we determine that this downstream target is a major regulator of glucose homeostasis and β-cell mass, proliferation, and survival by increasing insulin receptor substrate 2 (IRS2) levels and identify a novel feedback mechanism by which mTORC1 signaling increases IRS2 levels. In this feedback loop, we show that 4E-BP2 deletion induces translation of the adaptor protein SH2B1 and promotes the formation of a complex with IRS2 and Janus kinase 2, preventing IRS2 ubiquitination. The changes in IRS2 levels result in increases in cell cycle progression, cell survival, and β-cell mass by increasing Akt signaling and reducing p27 levels. Importantly, 4E-BP2 deletion confers resistance to cytokine treatment in vitro. Our data identify SH2B1 as a major regulator of IRS2 stability, demonstrate a novel feedback mechanism linking mTORC1 signaling with IRS2, and identify 4E-BP2 as a major regulator of proliferation and survival of β-cells.
雷帕霉素靶蛋白复合物1（mTORC1）调节多种生物学过程，尽管导致这些效应的关键下游机制尚不清楚。通过使用缺失真核翻译起始因子4E结合蛋白2（4E-BP2）的小鼠，我们确定该下游靶点是葡萄糖稳态以及β细胞质量、增殖和存活的主要调节因子，其通过提高胰岛素受体底物2（IRS2）水平来实现，并鉴定出一种新的反馈机制，通过该机制mTORC1信号传导增加IRS2水平。在这个反馈回路中，我们表明4E-BP2缺失诱导衔接蛋白SH2B1的翻译，并促进其与IRS2和Janus激酶2形成复合物，从而防止IRS2泛素化。IRS2水平的变化通过增加Akt信号传导和降低p27水平，导致细胞周期进程、细胞存活和β细胞质量增加。重要的是，4E-BP2缺失赋予体外细胞因子治疗抗性。我们的数据确定SH2B1是IRS2稳定性的主要调节因子，证明了一种将mTORC1信号传导与IRS2联系起来的新反馈机制，并确定4E-BP2是β细胞增殖和存活的主要调节因子。
