Global Phosphoproteomic Analysis of Insulin/Akt/mTORC1/S6K Signaling in Rat Hepatocytes.
Global Phosphoproteomic Analysis of Insulin/Akt/mTORC1/S6K Signaling in Rat Hepatocytes.
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DOI：
10.1021/acs.jproteome.7b00140
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发表时间：
2017-08-04
影响因子：
4.4
通讯作者：
Yu Y
中科院分区：
文献类型：
--
作者：
Zhang Y;Zhang Y;Yu Y
胰岛素抵抗是2型糖尿病的标志。虽然多种遗传和生理因素相互作用导致胰岛素抵抗，但磷酸化信号失调是一种常见的潜在机制。特别是，胰岛素的特异性磷酸化依赖性调节机制和信号输出在肝细胞中知之甚少，肝细胞是最重要的胰岛素应答细胞类型之一。以原代大鼠肝细胞为模型系统，进行了基于还原二甲基化（ReDi）的定量质谱分析，并表征了受胰岛素调节的磷酸化蛋白质组及其关键下游激酶，包括Akt，mTORC 1和S6 K。我们在这种单细胞类型中鉴定了总共12，294个独特的、确信定位的磷酸化位点和3，805个磷酸化蛋白质。对每个单独数据集的详细生物信息学分析确定了这一关键胰岛素下游效应器途径的已知和之前未识别的靶点。此外，肝Akt/mTORC 1/S6 K信号轴的综合分析允许描绘胰岛素信号通路内几种密切相关的激酶的底物特异性。我们期望这些数据集将作为一个宝贵的资源，为未来的假设驱动的研究提供基础，帮助描述2型糖尿病和相关代谢综合征发病机制的分子机制。
Insulin resistance is a hallmark of type 2 diabetes. Although multiple genetic and physiological factors interact to cause insulin resistance, deregulated signaling by phosphorylation is a common underlying mechanism. In particular, the specific phosphorylation-dependent regulatory mechanisms and signaling outputs of insulin is poorly understood in hepatocytes, which represents one of the most important insulin-responsive cell types. Using primary rat hepatocytes as a model system, we performed reductive di-methylation (ReDi)-based quantitative mass spectrometric analysis, and characterized the phosphoproteome that is regulated by insulin, as well as its key downstream kinases including Akt, mTORC1 and S6K. We identified a total of 12,294 unique, confidently localized phosphorylation sites and 3,805 phosphorylated proteins in this single cell type. Detailed bioinformatic analysis on each individual dataset identified both known and previously unrecognized targets of this key insulin downstream effector pathway. Furthermore, integrated analysis of the hepatic Akt/mTORC1/S6K signaling axis allowed the delineation of the substrate specificity of several close-related kinases within the insulin signaling pathway. We expect that the datasets will serve as an invaluable resource, providing the foundation for future hypothesis-driven research that helps delineate the molecular mechanisms that underlie the pathogenesis of type 2 diabetes and related metabolic syndrome.
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影响因子：
64.5
作者：
Huttlin EL;Jedrychowski MP;Elias JE;Goswami T;Rad R;Beausoleil SA;Villén J;Haas W;Sowa ME;Gygi SP
通讯作者：
Gygi SP
DOI：
10.1073/pnas.0914798107
发表时间：
2010-02-23
影响因子：
11.1
作者：
Li, Shijie;Brown, Michael S.;Goldstein, Joseph L.
通讯作者：
Goldstein, Joseph L.
影响因子：
1.3
作者：
Iyer, SS;Zhang, ZP;Karnes, HT
通讯作者：
Karnes, HT
DOI：
10.1073/pnas.0404297101
发表时间：
2004-08-03
影响因子：
11.1
作者：
Chen, GX;Liang, GS;Brown, MS
通讯作者：
Brown, MS
影响因子：
4.8
作者：
Kovacina, KS;Park, GY;Roth, RA
通讯作者：
Roth, RA