Rapamycin-Insensitive Signaling by Rictor-mTOR

Rictor-mTOR 的雷帕霉素不敏感信号传导

• 批准号: 7209812
• 负责人: David M. Sabatini
• 金额: $ 46.22万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7209812
• 关键词: 3-Phosphoinositide Dependent Protein Kinase-1; Angioplasty; Animal Model; Antineoplastic Agents; BAD gene; Bad protein; Biochemical; Biochemistry; Body Size; Cell Cycle Progression; Cell Size; Cell Survival; Cells; Complex; Cultured Cells; Development; Diabetes Mellitus; Disease; Family; Figs - dietary; Funding; Future; Genes; Genetic; Goals; Growth; Growth Factor; Human; Human Development; Immunosuppressive Agents; In Vitro; Lead; Lipids; Location; Malignant Neoplasms; Mammalian Cell; Mammals; Mediating; Microarray Analysis; Modeling; Molecular; Names; Nutrient; Organ; PTEN gene; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiology; Play; Principal Investigator; Process; Protein Kinase; Proteins; Raptors; Recruitment Activity; Research; Role; Scaffolding Protein; Serine; Signal Transduction; Sirolimus; Site; Source; Stress; Syndrome; Tail; Title; Tuberous sclerosis protein complex; Tumor Suppressor Proteins; Work; Writing; base; cancer type; cell growth; cell type; clinical application; drug development; human disease; human tissue; inhibitor/antagonist; insight; interest; loss of function; member; novel; nutrient metabolism; prevent; programs; response; restenosis; size; tissue culture; transcription factor

DESCRIPTION (provided by applicant): The process of mass accumulation (cell growth) is an important regulator of cell, organ, and body size and can be deregulated in diverse diseases such as cancer and diabetes. Our lab is studying the mammalian TOR (mTOR) pathway, a signaling network that regulates growth in response to growth factors, stress, nutrients, and metabolism. The mTOR pathway is medically important, as it is the target of the FDA-approved immunosuppressant rapamycin that also prevents vessel restenosis after angioplasty and has potential as an anti-cancer agent. Moreover, recent work suggests that in the cancer-prone genetic syndrome tuberous sclerosis complex the mTOR pathway becomes hyperactive and deregulated. Over the last few years we have been studying the biochemistry of the mTOR pathway in human tissue culture cells and have discovered two distinct mTOR-containing protein complexes. The first contains mTOR and two novel proteins, raptor and GbL, and mediates the rapamycin-sensitive roles of mTOR (like S6K1 phosphorylation). The second complex also contains mTOR and GbetaL but, instead of raptor, another novel protein that we named rictor. Our proposed work focuses on understanding the biochemical, cellular and organismal functions of the rictor protein, the central component of the rapamycin-insensitive mTOR pathway. Although we know little about this pathway compared to the rapamycin-sensitive branch, our preliminary results suggest that rictor plays critical roles in the control of cell survival and proliferation by regulating the activity of known effectors of these processes. Our unexpected discovery that mTOR has rapamycin-insensitive functions suggests that direct inhibitors of the mTOR kinase activity will likely have different pharmacological effects and clinical applications than rapamycin. Therefore, our proposed work will lead to an important advance in our understanding of the molecular mechanisms that regulate cell growth and survival and that may be exploited to tackle diseases in which these processes are deregulated.

描述（由申请人提供）：质量积累（细胞生长）过程是细胞、器官和身体大小的重要调节因素，并且在癌症和糖尿病等多种疾病中可能会失调。我们的实验室正在研究哺乳动物 TOR (mTOR) 通路，这是一种信号网络，可响应生长因子、压力、营养物质和新陈代谢来调节生长。 mTOR 通路在医学上很重要，因为它是 FDA 批准的免疫抑制剂雷帕霉素的靶标，雷帕霉素还可以防止血管成形术后血管再狭窄，并具有作为抗癌药物的潜力。此外，最近的研究表明，在易患癌症的遗传综合征结节性硬化症中，mTOR 通路变得过度活跃和失调。 在过去的几年里，我们一直在研究人类组织培养细胞中 mTOR 通路的生物化学，并发现了两种不同的含有 mTOR 的蛋白质复合物。第一个包含 mTOR 和两种新蛋白 raptor 和 GbL，并介导 mTOR 的雷帕霉素敏感作用（如 S6K1 磷酸化）。第二个复合物还包含 mTOR 和 GbetaL，但不是 raptor，而是另一种新蛋白质，我们将其命名为 rictor。我们提出的工作重点是了解 rictor 蛋白的生化、细胞和有机体功能，rictor 蛋白是雷帕霉素不敏感 mTOR 通路的核心成分。尽管与雷帕霉素敏感分支相比，我们对该途径知之甚少，但我们的初步结果表明，rictor 通过调节这些过程的已知效应子的活性，在控制细胞存活和增殖中发挥着关键作用。我们意外地发现 mTOR 具有雷帕霉素不敏感功能，这表明 mTOR 激酶活性的直接抑制剂可能具有与雷帕霉素不同的药理作用和临床应用。因此，我们提出的工作将导致我们对调节细胞生长和存活的分子机制的理解取得重要进展，并可用于解决这些过程失调的疾病。