CONTROL OF CELL POLARITY & PLASMA MEMBRANE FUNCTION BY RHO FAMILY GTPASE

细胞组织和功能的关键方面由以下因素决定： 细胞膜和细胞骨架之间的相互作用。在许多情况下，这些 相互作用由细胞外信号启动，并通过 也负责控制转录的蛋白质家族 活性和细胞周期。虽然不完全理解， 酵母子细胞的极化出芽提供了一个突出的例子 rho家族的GTP酶和相关蛋白如何导致 已知的和新的细胞骨架元件来控制细胞形态发生。 考虑到这些反应的基本性质， 一系列类似的事件负责控制形态发生 和极性。最近的证据显示， 暗示这可能确实如此。我们建议应用新的检测方法， 描述负责启动和维持 极性在哺乳动物细胞，并直接测试的可能性， 酵母和哺乳动物细胞中的极性是由基本相似的 战略布局此外，我们将研究极性之间的关系 和肿瘤发生，因为蛋白质是强有力的候选者， 控制细胞极性的基因是由已知或怀疑的癌基因编码的。我们 具体目标是：（i）了解导致初始 上皮细胞、神经元和淋巴细胞中极性的发展; ii） 说明负责维持不同的 iii）在不存在细胞-细胞接触的情况下， 确定哺乳动物同源基因的细胞内定位 控制酵母中的极化出芽，并评估 来自上皮肿瘤的转移细胞，其中极性似乎具有 iv）表征rho家族蛋白的功能， 相关分子在产生或维持极性中的作用 上皮细胞、神经元和淋巴细胞。

Crucial aspects of cellular organization and function are determined by interactions between membranes and the cytoskeleton. In many cases, these interactions are initiated by extracellular signals and transduced by families of proteins also responsible for controlling transcriptional activity and the cell cycle. Although incompletely understood, the polarized budding of daughter cells in yeast provides a striking example of how rho family of GTPases and related proteins lead to alterations of known and novel cytoskeletal elements to control cellular morphogenesis. Given the fundamental natures of these responses, it is highly likely that a similar cascade of events is responsible for controlling morphogenesis and polarity in mammalian cells. Recent evidence provides provocative hints that this may indeed be the case. We propose to apply novel assays to characterize the mechanisms responsible for initiating and maintaining polarity in mammalian cells, and to directly test the possibility that polarity in yeast and mammalian cells is mediated by fundamentally similar strategies. In addition, we will examine the relationship between polarity and tumorigenesis, since proteins which are strong candidates in controlling cell polarity are encoded by known or suspected oncogenes. Our Specific Aims are: i) to understand the events leading to the initial development of polarity in epithelial cells, neurons and lymphocytes; ii) To characterize the mechanisms responsible for the maintenance of distinct plasma membrane domains in the absence of cell-cell contact; iii) To determine the intracellular localization of mammalian homologs of genes that control polarized budding in yeast, and evaluate alterations in metastatic cells from epithelial tumors where polarity appears to have been lost; and iv) To characterize the function of rho family proteins and related molecules in the generation or maintenance of polarity in epithelia, neurons, and lymphocytes.