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 膜与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 蛋白质家族也负责控制转录 活跃度和细胞周期。尽管不能完全理解，但 酵母子细胞的极化萌发提供了一个引人注目的例子 Rho家族的GTP酶和相关蛋白如何导致 控制细胞形态发生的已知和新的细胞骨架元件。 鉴于这些反应的基本性质，很有可能 一系列类似的事件负责控制形态发生 和哺乳动物细胞中的极性。最近的证据提供了挑衅性的 暗示情况可能确实如此。我们建议应用新的分析方法 描述负责启动和维护的机制的特征 在哺乳动物细胞中的极性，并直接测试 酵母和哺乳动物细胞中的极性是由基本相似的 战略。此外，我们还将研究极性之间的关系 和肿瘤发生，因为蛋白质是很强的候选 控制细胞极性的基因是由已知或可疑的癌基因编码的。我们的 具体目标是：i)了解导致最初 上皮细胞、神经元和淋巴细胞的极性发育；ii) 描述负责维护不同的 在没有细胞-细胞接触的情况下的质膜结构域； 确定哺乳动物基因同源物的细胞内定位 控制酵母中的极化萌发，并评估在 来自上皮性肿瘤的转移细胞，其极性似乎有 以及iv)鉴定Rho家族蛋白的功能和 与极性的产生或维持有关的分子 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.