Novel Components of the mTORC1 and mTORC2 Pathways

mTORC1 和 mTORC2 通路的新成分

• 批准号: 9042919
• 负责人: David M. Sabatini
• 金额: $ 48.75万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9042919
• 关键词: Adipose tissue; Affect; Alleles; Amino Acids; Animals; Antibodies; Autistic Disorder; Back; Binding; Biological Assay; Biological Process; Cell Cycle Progression; Cell Line; Cell Size; Cell Survival; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Communities; Complementary DNA; Complex; Data Set; Diabetes Mellitus; Diet; Disease; EIF4EBP1 gene; Engineering; Eukaryota; FRAP1 gene; Fasting; Feedback; Functional disorder; Future; Genes; Glucose; Goals; Growth; High Fat Diet; In Vitro; Knock-out; Link; Liver; Malignant Neoplasms; Medical; Messenger RNA; Metabolism; Molecular; Molecular Biology; Multiple Myeloma; Mus; Mutation; Normal Cell; Nutrient; Obesity; Organism; Pathway interactions; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological; Positioning Attribute; Process; Progress Reports; Proteins; Proteomics; RNA Interference; Raptors; Research; Role; Signal Transduction; Sirolimus; Starvation; Stimulus; Stress; Structure; System; Technology; Testing; Translations; Variant; Work; biochemical tools; drug development; feeding; genome editing; human disease; in vivo; insight; interest; mTOR Inhibitor; mTOR Signaling Pathway; mTOR inhibition; metabolic phenotype; mouse model; mutant; novel; organ growth; overexpression; protein complex; research study; response; transcriptome

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.

mTOR 激酶是控制真核生物生长途径的核心成分，并且在真核生物中失调。 人类常见疾病，如癌症、糖尿病和自闭症。 mTOR 是两种不同蛋白质复合物的一部分， mTOR 复合物 1 (mTORCI) 和 2 (mT0RC2)。 mTORCI 包含 mTOR、mLSTS、raptor 和 PRAS40，是 对雷帕霉素部分敏感，并通过 S6K1 和 4E-BP1 等翻译调节因子控制细胞大小。 mT0RC2 还包含 mTOR 和 mLSTS，但是它包含 rictor、mSin1 和 ，而不是 raptor 和 PRAS40 普罗托尔。我们对 mT0RC2 的了解少于 mTORCI，但现在人们普遍认为 mT0RC2 是一种激活剂。 Akt/PKB 和 SGK 激酶，因此是控制细胞存活、增殖的 PI3K 通路的一部分， 和新陈代谢。最近，我们发现 DEPTOR（一种以前未知功能的蛋白质）与 直接与 mTOR 结合并抑制细胞中的 mTORCI 和 mT0RC2 信号传导。 DEPTOR 蛋白水平很高 受调节 mTORCI 和 mTORC2 的相同生长刺激和应激调节。过度表达 DEPTOR 抑制 mTORCI 信号传导，而 mTORCI 信号传导又通过抑制已知的 PI3K 通路来激活 PI3K 通路。 mTORCI 到 PI3K 的抑制反馈。在多发性骨髓瘤等癌症中，DEPTOR 高度 PI3K 的过度表达和由此产生的激活是促进细胞存活的新机制。我们的目标 继续：（1）了解 DEPTOR 如何抑制 mTORCI 和 mTORC2 信号传导，特别是通过 纳入我们称之为“基材质量”的新概念； (2)了解其分子机制 调节 DEPTOR 的表达并确定 DEPTOR 如何受到癌症相关 mTOR 的影响 突变； (3)确定DEPTOR和RagA在mTORCI和mTORCI通路中的体内作用 以及控制生长和有机体代谢，特别是当动物面临高脂肪挑战时 饮食。我们将采用多学科方法，利用生物化学、分子生物学等工具 生物学、蛋白质组学、CRISPR 基因组编辑和工程小鼠模型。我们的结果很可能是 对于我们理解临床上重要的 mTOR 通路和信号传导具有重要意义 我们发现的机制可能在未来作为药物开发的目标。