Function of the Small GTPase Rheb in Cell Growth

描述（由申请人提供）： 我的实验室正在采取分子，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Drosophila melanogaster为实验模型，我的实验室已经确定了两条重要的信号通路，它们共同作用于调节细胞大小。其中之一是胰岛素受体/PI 3 K通路。另一条途径是Tsc 1/Tsc 2/TOR信号通路。任何一种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细胞间激素（如胰岛素）偶联的胰岛素途径不同，Tsc 1/Tsc 2/TOR途径主要受营养物质可用性调节。我的实验室最近的研究已经确定Rheb，Ras超家族的一个小的GTdR，作为Tsc 1/Tsc 2/TOR营养感应途径的一个新的组成部分，从而提供了一个新的切入点，以了解这一途径的分子结构。本研究的重点是了解Rheb在Tsc 1/Tsc 2/TOR通路中的功能和调控。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。第二，我们将鉴定Rheb的鸟嘌呤核苷酸交换因子。第三，将进行遗传筛选以识别细胞生长中Rheb信号通路的其他成分。这些研究不仅可以帮助我们了解基本的发育机制，还可以为人类疾病和癌症提供见解。

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.