Novel Components of the mTORC1 and mTORC2 Pathways

MTOR激酶是控制真核生物生长的途径的中心组成部分，在 人类常见的疾病，如癌症、糖尿病和自闭症。MTOR是两种不同的蛋白质复合体的一部分， MTOR复合体1(MTORCI)和2(MT0RC2)。MTORCI包含mTOR、mLSTS、Raptor和PRAS40，IS 对雷帕霉素部分敏感，并通过S6K1和4E-BP1等翻译调控因子控制细胞大小。 MT0RC2还包含mTOR和mLSTS，但它不包含Raptor和PRAS40，而包含Rictor、mSin1和 普罗特。我们对mT0RC2的了解比mTORCI少，但现在人们普遍认为mT0RC2是一种激活 Akt/PKB和SGK的激酶，因此是控制细胞存活、增殖的PI3K途径的一部分， 和新陈代谢。最近，我们发现DEPTOR，一种以前未知的功能蛋白质，可以相互作用 直接与mTOR结合，抑制细胞内mTORCI和mT0RC2信号转导。DEPTOR蛋白水平很高 受相同的生长刺激和压力调节，调节mTORCI和mTORC2。过度表达 Of DEPTOR抑制mTORCI信号，进而通过抑制已知的PI3K途径激活PI3K途径 从mTORCI到PI3K的抑制反馈。在多发性骨髓瘤等癌症中，DEPTOR高度 PI3K的过度表达和激活是促进细胞存活的一种新机制。我们的目标 继续：(1)了解DEPTOR如何抑制mTORCI和mTORC2信号，特别是通过 引入了一个新的概念，我们称之为‘底物质量’；(2)了解 调节DEPTOR的表达并确定癌症相关mTOR对DEPTOR的影响 突变；以及(3)确定DEPTOR和RAGA在mTORCI和mTORCI通路中的体内作用 在控制生长和机体新陈代谢方面，特别是当动物面临高脂肪挑战时 节食。我们将使用一种多学科的方法，利用生物化学、分子 生物学、蛋白质组学、CRISPR基因组编辑和转基因小鼠模型。我们的结果很可能会有 对我们理解临床上重要的mTOR通路和信号的重要结果 我们发现的机制可能在未来成为药物开发的目标。

The mTOR kinase is the central component of a pathway controls growth in eukaryotes and is deregulated in common human diseases like cancer, diabetes, and autism. mTOR is part of two distinct protein complexes, mTOR Complex 1 (mTORCI) and 2 (mT0RC2). mTORCI contains mTOR, mLSTS, raptor, and PRAS40, is partially sensitive to rapamycin, and controls cell size through translational regulators like S6K1 and 4E-BP1. mT0RC2 also contains mTOR and mLSTS, but, instead of raptor and PRAS40, it contains rictor, mSin1, and protor. We know less about mT0RC2 than mTORCI but it is now accepted that mT0RC2 is an activating kinase for Akt/PKB and SGK and therefore part of the PI3K pathway that controls cell survival, proliferation, and metabolism. Recently, we discovered that DEPTOR, a protein of previously unknown function, interacts directly with mTOR and inhibits mTORCI and mT0RC2 signaling in cells. DEPTOR protein levels are highly regulated by the same growth stimuli and stresses that regulate mTORCI and mTORC2. Overexpression of DEPTOR inhibits mTORCI signaling, which, in turn, activates the PI3K pathway by suppressing a known inhibitory feedback from mTORCI to PI3K. In cancers like Multiple Myeloma, DEPTOR is highly overexpressed and the resulting activation of PI3K is a new mechanism for promoting cell survival. Our goals continue to be to: (1) understand how DEPTOR inhibits mTORCI and mTORC2 signaling, particularly by incorporating a new concept we call 'substrate quality'; (2) understand the molecular mechanisms that regulate the expression of DEPTOR and determine how DEPTOR is affected by cancer-associated mTOR mutations; and (3) determine the in vivo role of DEPTOR and RagA in the mTORCI and mTORCI pathways and in controlling growth and organismal metabolism, particularly when animals are challenged with a high-fat diet. We will use a multi-disciplinary approach that exploits the tools of biochemistry, molecular biology, proteomics, CRISPR-genome editing, and engineered mouse models. Our results are likely to have important consequences for our understanding of the clinically important mTOR pathway and the signaling mechanisms we uncover may serve in the future as targets for drug development.