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

哺乳动物靶标雷帕霉素(MTOR)信号通路感知生长因子、营养物质和应激信号，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个不同的多蛋白复合体，分别称为mTOR复合体1(MTORC1)和复合体2(MTORC2)。当被激活时，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DEP结构域中含有mTOR相互作用蛋白(DEPTOR)是一种新的结合和抑制mTORC1/2的蛋白。我们观察到，DEPTOR在增殖细胞中低表达，当细胞处于应激状态时，其表达增加。尽管DEPTOR对mTORC1/2信号转导的抑制作用已被证实，但许多关于DEPTOR生物学的基本问题仍未得到解答。例如，DEPTOR的转录是如何受胁迫信号调控的，目前还不清楚。此外，DEPTOR的细胞分布尚未确定，我们也不知道应激信号是否影响该蛋白的定位和功能。最后，虽然DEPTOR在调节mTOR信号通路中的作用已经得到了很好的证实，但目前还不清楚DEPTOR是否在细胞内发挥其他作用。这项建议的总体目标是扩大我们对DEPTOR的了解，以提高我们对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.