mTORC2是细胞增殖、代谢和稳态的枢纽，其调控异常导致肿瘤和代谢综合征等重大疾病的发生。mTORC2的活化与细胞膜密切相关，然而调控机制不清楚。鉴定调控mTORC2活化的膜分子并阐明作用机制是mTOR领域亟待解决的重要问题。申请者前期系列研究建立了以膜受体CD146为核心的分子网络；在此基础上新近发现CD146与mTORC2互作并直接调控其活化，形成CD146-mTORC2信号轴。因此，申请者大胆提出CD146是调控mTORC2活化的重要细胞膜分子。本项目拟以CD146-mTORC2信号轴为全新视角，利用分子、细胞、生物物理等方法，鉴定CD146-mTORC2互作表位，揭示CD146调控Rictor蛋白稳定性及膜定位的途径，探讨胞外因子调控该信号轴的机制及其在细胞增殖和代谢中的作用。这一新发现不仅会极大拓宽mTORC2的上游调控网络，并且为mTORC2相关疾病的治疗提供新的理论启示。

mTORC2 emerges as a master regulator of cell proliferation, metabolism, and homeostasis. Deregulation of mTORC2 leads to a variety of human diseases, including metabolic disorders and cancer. Previous studies indicated that the activation of mTORC2 requires the regulations from plasma membrane. However, the mechanism of how mTORC2 is activated by plasma membrane is largely unknown. Our previous studies have established a signaling network with CD146 at the core. Moreover, in our recent experiments, we observed a close correlation and interaction between CD146 and mTORC2 through Rictor, thereby establishing CD146-mTORC2 axis. In this project, we are aiming to determine the following important issues: 1. the relationship between CD146 expression and mTORC2 activation; 2. identification of the structural epitope required for CD146-mTORC2 interaction; 3. the mechanism of CD146 in mediating Rictor expression and mTORC2 membrane targeting; 4. the mechanism of growth factors in regulating CD146-mTORC2 axis during cell proliferation. Our study will not only greatly expands the spectrum of upstream regulators of mTORC2, but also provides important theoretical strategies for treating mTORC2-related diseases.