The mechanistic target of rapamycin, mTOR, controls cell metabolism in response to growth signals and stress stimuli. The cellular functions of mTOR are mediated by two distinct protein complexes, mTOR complex 1 (mTORC1) and mTORC2. Rapamycin and its analogs are currently used in the clinic to treat a variety of diseases and have been instrumental in delineating the functions of its direct target, mTORC1. Despite the lack of a specific mTORC2 inhibitor, genetic studies that disrupt mTORC2 expression unravel the functions of this more elusive mTOR complex. Like mTORC1 which responds to growth signals, mTORC2 is also activated by anabolic signals but is additionally triggered by stress. mTORC2 mediates signals from growth factor receptors and G-protein coupled receptors. How stress conditions such as nutrient limitation modulate mTORC2 activation to allow metabolic reprogramming and ensure cell survival remains poorly understood. A variety of downstream effectors of mTORC2 have been identified but the most well-characterized mTORC2 substrates include Akt, PKC, and SGK, which are members of the AGC protein kinase family. Here, we review how mTORC2 is regulated by cellular stimuli including how compartmentalization and modulation of complex components affect mTORC2 signaling. We elaborate on how phosphorylation of its substrates, particularly the AGC kinases, mediates its diverse functions in growth, proliferation, survival, and differentiation. We discuss other signaling and metabolic components that cross-talk with mTORC2 and the cellular output of these signals. Lastly, we consider how to more effectively target the mTORC2 pathway to treat diseases that have deregulated mTOR signaling.

中文翻译：

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mTORC2 信号网络：目标和串扰

雷帕霉素的机制靶标 mTOR 控制细胞代谢以响应生长信号和应激刺激。mTOR 的细胞功能由两种不同的蛋白质复合物介导，即 mTOR 复合物 1 (mTORC1) 和 mTORC2。雷帕霉素及其类似物目前在临床上用于治疗多种疾病，并有助于描述其直接靶标 mTORC1 的功能。尽管缺乏特定的 mTORC2 抑制剂，但破坏 mTORC2 表达的遗传学研究揭示了这种更难以捉摸的 mTOR 复合物的功能。与响应生长信号的 mTORC1 一样，mTORC2 也会被合成代谢信号激活，但也会被压力触发。mTORC2 介导来自生长因子受体和 G 蛋白偶联受体的信号。营养限制等应激条件如何调节 mTORC2 激活以允许代谢重编程并确保细胞存活仍然知之甚少。多种 mTORC2 下游效应子已被鉴定，但最充分表征的 mTORC2 底物包括 Akt、PKC 和 SGK，它们是 AGC 蛋白激酶家族的成员。在这里，我们回顾了 mTORC2 如何受到细胞刺激的调节，包括复杂成分的区室化和调节如何影响 mTORC2 信号传导。我们详细阐述了其底物（特别是 AGC 激酶）的磷酸化如何介导其生长、增殖、存活和分化的多种功能。我们讨论了与 mTORC2 串扰的其他信号传导和代谢成分以及这些信号的细胞输出。最后，我们考虑如何更有效地靶向 mTORC2 通路来治疗 mTOR 信号传导失调的疾病。