Characterization of the molecular mechanisms regulating DEPTOR expression/localization in response to stress and identification of novel cellular functions of this protein.

哺乳动物雷帕霉素靶点（mTOR）信号通路感知生长因子、营养物质和应激信号，调节许多参与促进细胞生长的生物过程。mTOR与许多蛋白质相互作用形成两种不同的多蛋白复合物，称为mTOR复合物1 （mTORC1）和复合物2 （mTORC2）。激活时，mTORC1促进蛋白质合成和合成代谢，而mTORC2促进细胞存活和代谢。最近，我们发现含有mtor相互作用蛋白（DEPTOR）的dep结构域是一种结合和抑制mTORC1/2的新蛋白。我们观察到detor在增殖细胞中的表达较低，当细胞暴露于应激时，其表达增加。尽管DEPTOR对mTORC1/2信号的抑制作用已经得到了很好的证实，但是许多关于DEPTOR生物学的基本问题仍未得到解答。例如，DEPTOR的转录是如何受应激信号调控的，目前尚不清楚。此外，DEPTOR的细胞分布尚未确定，我们不知道应激信号是否会影响该蛋白的定位和功能。最后，尽管DEPTOR在调控mTOR信号通路中的作用已经被很好地确立，但DEPTOR是否在细胞中发挥其他作用尚不清楚。本提案的总体目标是扩展我们对DEPTOR的认识，以提高我们对应激反应中控制细胞生长和合成代谢的分子机制的理解。

The mammalian target of rapamycin (mTOR) signaling pathway senses growth factors, nutrients, and stress signals to regulate many biological processes involved in the promotion of cell growth. mTOR interacts with many proteins to form two distinct multiprotein complexes named mTOR complex 1 (mTORC1) and complex 2 (mTORC2). When active, mTORC1 promotes protein synthesis and anabolism whereas mTORC2 promotes cell survival and metabolism. Recently, we identified DEP-domain containing mTOR-interacting protein (DEPTOR) as a new protein that binds and represses mTORC1/2. We observed that DEPTOR expression is low in proliferating cells and that its expression increases when cells are exposed to stress. Although the inhibitory role of DEPTOR on mTORC1/2 signaling has been well established, many basic questions regarding the biology of DEPTOR remain unanswered. For example, it is still unknown how the transcription of DEPTOR is regulated by stress signals. Also, the cellular distribution of DEPTOR has not been determined and we do not know if stress signals affect the localization and the function of this protein. Finally, although the role of DEPTOR in regulating the mTOR signaling pathway has been well established, it is unknown if DEPTOR plays other roles into the cells. The general objective of this proposal is to extend our knowledge of DEPTOR to improve our comprehension of the molecular mechanisms controlling cell growth and anabolism in response to stress.