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

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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.