YEAST PHEROMONE SIGNAL TRANSDUCTION

细胞的行为通常由细胞外环境中的信号控制。其影响可能是 戏剧性的，例如扩散或差异化的决定，因此反应必须非常强烈 监管和精心策划的。而许多信号通路及其分子组件 一些经过充分研究的系统提供了测试多个组件如何 实现统一的细胞响应，集成来自不同亚细胞区域的信息以及 有关细胞生理状态的信息。被激活的信号转导通路 酿酒酵母胞外交配信息素提供了一个理想的模型系统 用来探索细胞反应中的错综复杂的东西。此系统中的信令涉及 质膜定位的信号复合体的动态组装，包括已发现的蛋白质 普遍存在于从酵母到人类的各种信号通路中，例如PAK家族的激酶，一种 异源三聚体G蛋白、MAP激酶级联和支架蛋白。在这里，我们使用了一个富有的 建立信息和遗传试剂来测试几个有趣的机制模型 传播细胞内信号及其与细胞生物结构的接口，特别强调 亚细胞定位的作用。其中一个目标将是确定膜招募地图如何 KK级联支架蛋白Ste5通过KK级联放大信号，以及这是否 信号主要发生在单个支架分子之间或内部。另一个目标将是 解剖交配MAPK级联抑制有丝分裂细胞周期的多种途径，并 确定为什么这个信号通路在细胞分裂时失活是很重要的。也是 正在研究的将是PAK家族激酶Ste20中一个小的膜结合结构域的作用，以及 在其他极化蛋白质中类似结构域的普遍存在。总体而言，我们预计这些研究将有助于 通过揭示信号转导中内置的机制来深入理解信号转导 允许在单元内进行动态和综合响应的系统。

Cellular behavior is commonly controlled by signals in the extracellular environment. The effects can be dramatic, such as the decision to proliferate or to differentiate, and so the responses must be highly regulated and carefully orchestrated. While many signaling pathways and their molecular components have been identified, some well-studied systems offer a unique opportunity to test how multiple components achieve a unified cellular response that integrates information from different subcellular regions as well as information about the physiological status of the cell. The signal transduction pathway that is activated by extracellular mating pheromones in the yeast Saccharomycescerevisiae presents an ideal model system in which to probe the intricacies that are built into a cellular response. Signaling in this system involves the dynamic assembly of plasma membrane-localized signaling complexes, which include proteins found ubiquitously in a variety of signaling pathwaysfrom yeast to humans, such as a PAK-family kinase, a heterotrimeric G protein, a MAP kinase cascade, and a scaffold protein. Here we make use of a rich foundation of information and genetic reagents to test several intriguing models about the mechanisms that propagate intracellular signaling and their interface with cell biological structures, with particular emphasis on the role of subcellular localization. One goal will be to determine how membrane recruitment of the MAP kinase cascade scaffold protein Ste5 amplifies signaling through the kinase cascade, and whether this signaling occurs predominantly between or within individual scaffold molecules. Another goal will be to dissect the multiple routes by which the mating MAP kinase cascade can inhibit the mitotic cell cycle, and to determine why it is important for this signaling pathway to be inactivated as cells commit to division. Also under investigation will be the role of a small membrane-binding domain in the PAK-family kinase Ste20, and the prevalence of similar domains in other polarized proteins. Overall, we expect these studies to contribute to a sophisticated understanding of signal transduction by revealing mechanisms that are built into signaling systems to allow dynamic and integrative responses within a cell.