YEAST PHEROMONE SIGNAL TRANSDUCTION

细胞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，如决定增殖或分化，因此反应必须高度 精心策划的虽然许多信号通路及其分子组分具有 一些经过充分研究的系统提供了一个独特的机会，可以测试多个组件如何 实现统一的细胞反应，该反应整合了来自不同亚细胞区域的信息， 关于细胞的生理状态的信息。信号转导通路是由 酵母酿酒酵母中的胞外交配信息素提供了一个理想的模型系统， 用来探测细胞反应的复杂性。在这个系统中的信号涉及 质膜定位信号复合物的动态组装，其中包括发现的蛋白质 普遍存在于从酵母到人类的各种信号通路中，如PAK家族激酶， 在一个实施方案中，所述多肽包括异源三聚体G蛋白、MAP激酶级联和支架蛋白。在这里，我们利用丰富的 信息和基因试剂的基础，以测试几个有趣的模型的机制， 传播细胞内信号及其与细胞生物学结构的界面，特别强调 亚细胞定位的作用。一个目标将是确定如何膜募集的MAP 激酶级联支架蛋白Ste5通过激酶级联放大信号传导，并且这是否 信号传导主要发生在单个支架分子之间或内部。另一个目标是 剖析交配MAP激酶级联可抑制有丝分裂细胞周期的多种途径， 确定为什么当细胞致力于分裂时，这种信号通路被灭活是重要的。也 正在研究的将是PAK家族激酶Ste20中小的膜结合结构域的作用， 在其他极化蛋白中类似结构域的普遍性。总的来说，我们希望这些研究有助于 通过揭示信号传导的内在机制， 系统允许细胞内的动态和综合反应。

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.