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，遗传和生化方法来了解控制细胞大小的分子机制。用果蝇黑腹果蝇作为实验模型，我的实验室已经确定了两个重要的信号通路，它们协同作用来调节细胞大小。其中之一是胰岛素受体/PI3K途径。另一条通路是Tsc1/Tsc2/TOR信号通路。激活任何一条通路都会导致细胞大小增加。胰岛素通路通常用于将细胞生长与胰岛素等细胞间激素偶联，而Tsc1/Tsc2/TOR通路主要受营养可利用性调节。我的实验室最近的研究已经确定了Rheb， Ras超家族的一个小GTPase，作为Tsc1/Tsc2/TOR营养传感途径的一个新组成部分，从而为理解该途径的分子结构提供了一个新的切入点。当前提案的重点是了解Rheb在Tsc1/Tsc2/TOR通路方面的功能和调控。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。其次，我们将确定Rheb的鸟嘌呤核苷酸交换因子(s)。第三，将进行遗传筛选，以确定细胞生长中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.