Pivotal role of mTORC2 and involvement of ribosomal protein S6 in cardioprotective signaling.
Pivotal role of mTORC2 and involvement of ribosomal protein S6 in cardioprotective signaling.
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DOI：
10.1161/circresaha.114.303562
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发表时间：
2014-04-11
影响因子：
20.1
通讯作者：
Steenbergen C
中科院分区：
文献类型：
--
作者：
Yano T;Ferlito M;Aponte A;Kuno A;Miura T;Murphy E;Steenbergen C
Akt的激活和抑制细胞死亡之间存在紧密的耦合关系。Akt的完全激活需要mTOR复合体2(MTORC2)，但mTORC2的调控尚不清楚。以获得对mTORC2/Akt信号转导机制的新见解。检测mTORC2在心脏保护中的作用。在灌流的小鼠心脏中，缺血预适应(IPC)增加mTORC2的活性，导致Ser473上Akt的磷酸化。预先给予双mTORC抑制剂后，IPC的保护作用消失，但不能被mTORC2抑制剂雷帕霉素所阻断，这表明mTORC2激活在心脏保护中的基础作用。接下来，对mTORC2/Akt信号的调控和下游靶点进行了探讨。我们发现IPC和其他Akt激动剂(胰岛素和阿片类药物)导致小鼠心脏和新生大鼠心肌细胞核糖体蛋白S6(Rps6)Ser235/236处的磷酸化。Rps6与mTORC2的组成成分相互作用，siRNA介导的Rps6的敲除减弱了胰岛素诱导的mTORC2激活和Akt-Ser473的磷酸化。另一方面，Rps6的过表达增强了Akt-Ser473的磷酸化，表明Rps6的激活放大了mTORC2/Akt信号。Rps6/mTORC2通路被Rps6或Rictor基因敲除后，胰岛素诱导的细胞保护作用被破坏。虽然雷帕霉素阻断了依赖Rps6的mTORC2的激活，但mTORC2仍然被另一条信号通路激活，这表明心脏保护信号中存在冗余。MTORC2的激活在心脏保护中起着关键作用，而Rps6是心肌保护信号的汇聚点，为mTORC2/Akt信号提供正反馈调节。
There is tight coupling between Akt activation and suppression of cell death. Full Akt activation requires mTOR complex 2 (mTORC2), but the regulation of mTORC2 is unclear. To gain new insights into mechanisms of mTORC2/Akt signaling. The role of mTORC2 in cardioprotection was examined. In perfused mouse hearts, ischemic preconditioning (IPC) increased mTORC2 activity, leading to phosphorylation of Akt on Ser473. The protective effect of IPC was lost by pretreatment with dual mTORC inhibitors but not with rapamycin, a mTORC1 inhibitor, which indicates the fundamental role of mTORC2 activation in cardioprotection. Next, the regulation and downstream targets of mTORC2/Akt signaling were explored. We have found that IPC and other Akt activators (insulin and opioids) result in phosphorylation of ribosomal protein S6 (Rps6) at Ser235/236 in mouse hearts and neonatal rat ventricular myocytes. Rps6 interacts with components of mTORC2, and siRNA-mediated knockdown of Rps6 attenuates insulin-induced mTORC2 activation and Akt-Ser473 phosphorylation. On the other hand, Rps6 overexpression enhanced Akt-Ser473 phosphorylation, indicating that Rps6 activation amplifies mTORC2/Akt signaling. Disruption of the Rps6/mTORC2 pathway by knockdown of Rps6 or rictor abrogated insulin-induced cytoprotection against oxidative stress. Although rapamycin blocks Rps6-dependent mTORC2 activation, mTORC2 is still activated by an alternative signaling pathway, demonstrating the redundancy in cardioprotective signaling. Activation of mTORC2 plays a pivotal role in cardioprotection, and Rps6 is a convergence point of cardioprotective signaling, providing positive feedback regulation of mTORC2/Akt signaling.