4E-BP2/SH2B1/IRS2 Are Part of a Novel Feedback Loop That Controls β-Cell Mass.
4E-BP2/SH2B1/IRS2 Are Part of a Novel Feedback Loop That Controls β-Cell Mass.
复制标题
DOI：
10.2337/db15-1443
复制
发表时间：
2016-08
期刊：
影响因子：
7.7
通讯作者：
Bernal-Mizrachi E
中科院分区：
文献类型：
--
作者：
Blandino-Rosano M;Scheys JO;Jimenez-Palomares M;Barbaresso R;Bender AS;Yanagiya A;Liu M;Rui L;Sonenberg N;Bernal-Mizrachi E
哺乳动物雷帕霉素靶点复合物 1 (mTORC1) 调节多种生物过程，但负责这些作用的关键下游机制尚不清楚。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通过增加胰岛素受体底物 2 (IRS2) 水平来调节葡萄糖稳态和 β 细胞质量、增殖和存活的主要调节因子，并确定了 mTORC1 信号传导增加 IRS2 水平的新反馈机制。在这个反馈环中，我们发现 4E-BP2 缺失会诱导接头蛋白 SH2B1 的翻译，并促进与 IRS2 和 Janus 激酶 2 形成复合物，从而阻止 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 缺失导致对体外细胞因子治疗的抵抗。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 联系起来的新型反馈机制，并确定 4E-BP2 是 β 细胞增殖和存活的主要调节因子。
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.