Hepatic signaling by the mechanistic target of rapamycin complex 2 (mTORC2)
Hepatic signaling by the mechanistic target of rapamycin complex 2 (mTORC2)
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DOI：
10.1096/fj.13-237743
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发表时间：
2014-01-01
期刊：
影响因子：
4.8
通讯作者：
Gruppuso, Philip A.
中科院分区：
文献类型：
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作者：
Lamming, Dudley W.;Demirkan, Gokhan;Gruppuso, Philip A.
雷帕霉素 (mTOR) 的机制靶标存在于调节不同细胞过程的两种复合物中。 mTOR 复合物 1 (mTORC1) 是雷帕霉素的典型靶标，已得到充分研究，而 mTORC2 的生理作用仍然相对未知。在肝脏中 mTORC2 成分 Rictor 被删除的小鼠 [Rictor 敲除 (RKO) 小鼠] 中，我们使用基因组和磷酸蛋白质组分析来表征肝脏 mTORC2 在体内的作用。隔夜断食然后重新进食用于激活 mTOR 信号传导。在重新喂食之前施用雷帕霉素以指定 mTORC2 介导的事件。肝脏 mTORC2 调节复杂的基因表达和翻译后网络，影响中间代谢、核糖体生物发生和蛋白酶体生物发生。几乎所有与中间代谢调节相关的基因变化都在培养的胎儿肝细胞中复制，表明 mTORC2 信号传导的细胞自主效应。磷酸化蛋白质组学分析鉴定了 144 种蛋白质的 mTORC2 相关信号传导，其中包括代谢酶和调节因子。 RKO 小鼠中 p38 MAPK 信号传导的减少代表了我们的磷酸蛋白质组学和基因表达结果之间的联系。我们得出的结论是，肝脏 mTORC2 在生理条件下发挥广泛的生物效应。我们的研究结果为开发调节 mTORC2 信号传导的靶向疗法提供了背景。 Lamming, D. W., Demirkan, G., Boylan, J. M., Mihaylova, M. M., Peng, T., Ferreira, J., Neretti, N., Salomon, A., Sabatini, D. M., Gruppuso, P. A. 雷帕霉素复合物机械靶点的肝信号传导2（mTORC2）。
The mechanistic target of rapamycin (mTOR) exists in two complexes that regulate diverse cellular processes. mTOR complex 1 (mTORC1), the canonical target of rapamycin, has been well studied, whereas the physiological role of mTORC2 remains relatively uncharacterized. In mice in which the mTORC2 component Rictor is deleted in liver [Rictor-knockout (RKO) mice], we used genomic and phosphoproteomic analyses to characterize the role of hepatic mTORC2 in vivo. Overnight food withdrawal followed by refeeding was used to activate mTOR signaling. Rapamycin was administered before refeeding to specify mTORC2-mediated events. Hepatic mTORC2 regulated a complex gene expression and post-translational network that affects intermediary metabolism, ribosomal biogenesis, and proteasomal biogenesis. Nearly all changes in genes related to intermediary metabolic regulation were replicated in cultured fetal hepatocytes, indicating a cell-autonomous effect of mTORC2 signaling. Phosphoproteomic profiling identified mTORC2-related signaling to 144 proteins, among which were metabolic enzymes and regulators. A reduction of p38 MAPK signaling in the RKO mice represents a link between our phosphoproteomic and gene expression results. We conclude that hepatic mTORC2 exerts a broad spectrum of biological effects under physiological conditions. Our findings provide a context for the development of targeted therapies to modulate mTORC2 signaling.Lamming, D. W., Demirkan, G., Boylan, J. M., Mihaylova, M. M., Peng, T., Ferreira, J., Neretti, N., Salomon, A., Sabatini, D. M., Gruppuso, P. A. Hepatic signaling by the mechanistic target of rapamycin complex 2 (mTORC2).