Regulation of Cell Polarity and Exocytosis

描述（由申请人提供）：本提案的总体目标是了解真核细胞将极化生长和分泌导向细胞表面特定位点的机制，以及这如何与整体细胞极性协调。从我们的实验室和其他人以前的工作已经牵连的Lgl/Sro 7和Rho/Cdc 42蛋白家族的成员的因素，在两个膜运输到细胞表面和细胞极性在一些系统中具有重要作用。在酵母细胞表面上的运输的空间调节需要Rho/Cdc 42定位的特定模式以及Lgl/Sro 7蛋白的囊泡束缚和融合功能的紧密调节。在本建议中，我们将审查结构 Cdc 42和Rho 3 GT3蛋白中的元件，其对于其不同的定位模式至关重要，并且限定了用于Cdc 42再循环和运输至细胞表面的特定内吞因子和途径。最后，我们将建立在我们最近发现的一个Rab-dependent囊泡对接功能的Sro 7解剖内和分子间的调节Sro 7的囊泡对接和融合的双重功能。 公共卫生相关性：我们对Rho GTP酶和Lgl肿瘤抑制因子家族成员在细胞极性中发挥作用的基本机制的研究可能与我们对肿瘤发展和其他疾病如II型糖尿病的理解有关，因为这些家族中的缺陷与人类中的许多癌症和胰岛素反应有关。最终了解这些过程的分子细节可能会允许开发新的方法和新的治疗方法来对抗癌症或II型糖尿病，以及其他疾病，其中细胞表面运输的调节是疾病病因的中心。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to understand the mechanism by which eukaryotic cells direct polarized growth and secretion to specific sites on the cell surface and how this is coordinated with overall cell polarity. Previous work from our laboratory and others has implicated members of the Lgl/Sro7 and Rho/Cdc42 protein families as factors that have important roles in both membranes trafficking to the cell surface and cell polarity in a number of systems. Spatial regulation of trafficking on the cell surface in yeast requires specific patterns of Rho/Cdc42 localization as well as tight regulation of vesicle tethering and fusion functions of Lgl/Sro7 protein. In this proposal we will examine the structural elements in Cdc42 and Rho3 GTPase proteins that are critical for their distinct patterns of localization and define the specific endocytic factors and pathways utilized for recycling and trafficking of Cdc42 to the cell surface. Finally we will build on our recent discovery of a Rab-dependent vesicle docking function of Sro7 to dissect both the intra and intermolecular regulation of Sro7's dual functions in vesicle docking and fusion. PUBLIC HEALTH RELEVANCE: Our investigation into the fundamental mechanisms by which Rho GTPases and Lgl tumor suppressor family members function in cell polarity is likely to be relevant to our understanding of tumor development and other diseases such as Type II diabetes as defects in these families have been associated with a number of cancers and insulin response in humans. Ultimately understanding the molecular details of these processes may allow the development of new approaches and novel therapeutics to combating cancer, or type II diabetes, as well as other diseases in which regulation of cell surface trafficking is cental to the etiology of the disease.