Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK; UK Dementia Research Institute, Cambridge, UK.
Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK; UK Dementia Research Institute, Cambridge, UK.
Cell Rep. 2020 Dec 29;33(13):108564. doi: 10.1016/j.celrep.2020.108564.
The mechanistic target of rapamycin complex 2 (mTORC2) controls cell metabolism and survival in response to environmental inputs. Dysregulation of mTORC2 signaling has been linked to diverse human diseases, including cancer and metabolic disorders, highlighting the importance of a tightly controlled mTORC2. While mTORC2 assembly is a critical determinant of its activity, the factors regulating this event are not well understood, and it is unclear whether this process is regulated by growth factors. Here, we present data, from human cell lines and mice, describing a mechanism by which growth factors regulate ubiquitin-specific protease 9X (USP9X) deubiquitinase to stimulate mTORC2 assembly and activity. USP9X removes Lys63-linked ubiquitin from RICTOR to promote its interaction with mTOR, thereby facilitating mTORC2 signaling. As mTORC2 is central for cellular homeostasis, understanding the mechanisms regulating mTORC2 activation toward its downstream targets is vital for our understanding of physiological processes and for developing new therapeutic strategies in pathology.
雷帕霉素靶蛋白复合物 2（mTORC2）的机械靶标控制细胞代谢和存活以响应环境输入。mTORC2 信号的失调与多种人类疾病有关，包括癌症和代谢紊乱，突出了严格控制 mTORC2 的重要性。虽然 mTORC2 的组装是其活性的关键决定因素，但调节此事件的因素尚不清楚，也不清楚该过程是否受生长因子调节。在这里，我们提供了来自人类细胞系和小鼠的数据，描述了生长因子调节泛素特异性蛋白酶 9X（USP9X）去泛素酶以刺激 mTORC2 组装和活性的机制。USP9X 从 RICTOR 上去除 Lys63 连接的泛素，以促进其与 mTOR 的相互作用，从而促进 mTORC2 信号传导。由于 mTORC2 对于细胞内稳态至关重要，因此理解调节 mTORC2 向其下游靶标的激活的机制对于我们理解生理过程以及在病理学中开发新的治疗策略至关重要。
