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蛋白（mTOR）信号传导途径感知生长因子、营养物质和应激信号，以调节参与促进细胞生长的许多生物学过程。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（mTORC 1）和复合物2（mTORC 2）。当活跃时，mTORC 1促进蛋白质合成和抗凋亡，而mTORC 2促进细胞存活和代谢。最近，我们发现了一种新的结合和抑制mTORC 1/2的蛋白，即DEP-domain containing mTOR-interacting protein（DEPTOR）。我们观察到DEPTOR在增殖细胞中的表达较低，而当细胞暴露于应激时，其表达增加。虽然DEPTOR对mTORC 1/2信号传导的抑制作用已经得到很好的确立，但关于DEPTOR生物学的许多基本问题仍然没有答案。例如，目前还不清楚DEPTOR的转录是如何被应激信号调节的。此外，DEPTOR的细胞分布尚未确定，我们不知道应激信号是否影响这种蛋白质的定位和功能。最后，虽然DEPTOR在调节mTOR信号通路中的作用已经得到很好的确立，但尚不清楚DEPTOR是否在细胞中发挥其他作用。这个建议的总体目标是扩展我们对DEPTOR的了解，以提高我们对控制细胞生长和应激反应的分子机制的理解。

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.