RagD调控mTORC2溶酶体定位的机制及功能研究

mTORC2是细胞感应胰岛素的关键通路，与细胞代谢及肿瘤发生发展密切相关。既往研究主要集中于mTORC2在细胞质膜上的功能及机制，但是关于mTORC2在溶酶体上的定位及其调控机制尚不清楚。申请人前期数据发现溶酶体是mTORC2活化的重要场所；mTORC2的组分蛋白SIN1和Rictor能够特异性与定位在溶酶体上的RagD结合；RagD能够促进mTORC2与其底物AKT1的结合；因此我们推断RagD是调控mTORC2溶酶体定位及激活的关键蛋白。进一步研究发现胰岛素不仅能够调控mTOR的溶酶体定位；还能增强RagD与Rictor、SIN1及AKT1的结合，且RagD参与了胰岛素介导的mTORC2的激活。基于此，申请人拟进一步阐释RagD调控mTORC2的溶酶体定位及激活的机理，并通过肿瘤模型探究mTORC2的溶酶体定位对肿瘤生长的影响，以期为临床上肿瘤相关疾病的诊疗提供理论基础。

mTORC2 is a key pathway in sensing insulin and is closely related to cell metabolism and tumor growth. Previous research has been focused on the function and mechanism of the plasma membrane localized mTORC2, but the lysosomal localization of mTORC2 and its regulatory mechanism are unclear. The previous data of the applicant revealed that lysosome is an important organelle for mTORC2 activation. Further screening analysis revealed that SIN1, Rictor, the component proteins of mTORC2, can specifically bind to RagD, and the lysosomal localizated RagD can promote the interaction between mTORC2 and AKT1. Taken together, RagD may play an important role in lysosomal localization and activation of mTORC2. Moreover, we found that insulin can not only promote the localization of mTOR on lysosome, but enhance the interaction between RagD and SIN1, Rictor and AKT1. Besides, we found RagD was involved in insulin-mediated activation of mTORC2. Based on these, we plan to clarify the mechanism of growth factor in regulating lysosomal localization and activation of mTORC2, and explore the biological functions of lysosomal localization of mTORC2 on tumor growth, to provide theoretical basis for molecular diagnosis and treatment of tumors.