Function of the Small GTPase Rheb in Cell Growth

小 GTP 酶 Rheb 在细胞生长中的功能

• 批准号: 7086362
• 负责人: DUOJIA PAN
• 金额: $ 25.55万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7086362
• 关键词: Drosophilidae; biological signal transduction; cell growth regulation; cell proliferation; genetic screening; guanine nucleotide binding protein; guanine nucleotide exchange factors; guanosinetriphosphatases; nutrient bioavailability; nutrition related tag

DESCRIPTION (provided by applicant): My laboratory is taking molecular, genetic and biochemical approaches to understand the molecular mechanisms that control cell size. Using the fruitfly Drosophila melanogaster as an experimental model, my laboratory has identified two prominent signaling pathways that act in concert to regulate cell size. One of them is the insulin receptor/PI3K pathway. The other pathway is the Tsc1/Tsc2/TOR signaling pathway. Activation of either pathway leads to increased cell size. Unlike the insulin pathway, which is normally used to couple cell growth to intercellular hormones such as insulin, the Tsc1/Tsc2/TOR pathway is mainly regulated by nutrient availability. Recent studies from my laboratory have identified Rheb, a small GTPase of the Ras superfamily, as a novel component of the Tsc1/Tsc2/TOR nutrient-sensing pathway, thus providing a new entry point to understand the molecular architecture of this pathway. The focus of the current proposal is to understand the function and regulation of Rheb with respect to the Tsc1/Tsc2/TOR pathway. Three specific aims are proposed. First, we will determine the molecular mechanisms by which TOR is regulated by Rheb. Second, we will identify the guanine nucleotide exchange factor(s) for Rheb. Third, a genetic screen will be conducted to identify additional components of the Rheb signaling pathway in cell growth. These studies should not only help us understand basic developmental mechanisms, but also provide insights into human diseases and cancer.

描述(申请人提供)：我的实验室正在采用分子、遗传和生物化学方法来了解控制细胞大小的分子机制。以果蝇黑腹果蝇为实验模型，我的实验室发现了两条共同作用于调节细胞大小的重要信号通路。其中之一是胰岛素受体/PI3K途径。另一条途径是TSC1/TSC2/TOR信号通路。任何一条途径的激活都会导致细胞大小的增加。与通常用于将细胞生长与胰岛素等细胞间激素结合起来的胰岛素途径不同，TSC1/TSC2/TOR途径主要受营养物质可获得性的调节。我的实验室最近的研究发现，Rheb是Ras超家族的一个小GTP酶，是TSC1/TSC2/TOR营养传感途径的一个新的组成部分，从而为理解这一途径的分子结构提供了一个新的切入点。目前建议的重点是了解Rheb在TSC1/TSC2/TOR途径中的功能和调节。提出了三个具体目标。首先，我们将确定Rheb调控TOR的分子机制。其次，我们将确定Rheb的鸟核苷酸交换因子(S)。第三，将进行基因筛查，以确定Rheb信号通路在细胞生长中的其他成分。这些研究不仅应该帮助我们了解基本的发育机制，还应该为我们提供对人类疾病和癌症的见解。