Theme C

主题C： 细胞内的空间控制 信令 主题领袖：Bard Well 其他项目部：全， 科马罗娃、刘、涅、易 正确的成长、发展和 有机体的生存需要 广博精准 它们之间的交流 有机体细胞。相应地，细胞 对各种各样的刺激做出反应， 它们提供了关于 营养，有害的侮辱，状态 相邻单元格等。许多 首先识别传入的刺激 通过细胞表面受体，然后 传播到里面的不同地方 细胞通过一连串的信号传递 蛋白质。这样的信号转导 “路径”是连接 信号和细胞反应。 准确高效的信号转导是 具有挑战性，因为(I)有多个输入 它必须路由到正确的输出，(Ii) 输入在时间和空间上不同，(Iii)噪声是 无处不在，以及(Iv)途径可能共享类似的或 相同的组件。的中心假设 这一主题是(1)准确而高效的信号 传输需要复杂的监管 信令网络的空间动力学；(2) 实现从信号到细胞反应的特异性 在高度互联的网络中需要 多个绝缘机构的协同作用 (其中一些依赖或利用空间 方面)。为了研究这些假设，我们 建议研究两国之间的关系 信令和方向感知的空间控制 (项目C.1)，不同的网络架构 可以增强专用性(项目C.2)， 转录本的业绩目标 对空间信号的回应(C.3项目)和 空间局部化在信号传递和分析中的作用 特殊性(项目D.4) 酵母交配途径作为模式系统的应用。 我们将集中我们的理论和实践相结合 交配信息素的实验研究 酿酒酵母的反应途径， 因为这是最好理解的信号之一 在真核生物中的途径，因此适合于 试图系统地理解。单倍体酵母 细胞对多肽交配的存在做出反应 通过经历一系列的信息素 事件导致了与一个 附近的交配伙伴[已回顾 作者：Bardwell，2005]。信息素 结合在一个七跨膜上， G蛋白偶联受体(Ste2) 导致激活一个 膜结合异三聚体 G蛋白(见图1)。 激活的G(3(Ste4)然后结合到 Ste5适配器/脚手架和 Ste20激酶。结果, Ste20磷酸化和 激活Ste11激酶，这是 已经被拖到了膜上 由Ste5。Ste11是最顶端的 一种典型的有丝分裂原激活的蛋白激酶 蛋白激酶(MAPK) 级联：Ste11(MAP3K.或 Mekk)使Ste7磷酸化 (MAP2K或MEK)，进而 使Fus3和Kss1磷酸化 (MAPK)。信号传输 STE5增强了MAPK级联的下行 结合Ste11、Ste7和Ste7的支架蛋白 Fus3，并被认为在一个 紧密且高效的配置。Fus3和Kss1 然后是磷光体/晚期几种衬底，包括 Dig1、Dig2和STE12转录调控因子。AS 结果，Dig1/2与STE12和STE12分离 激活细胞融合所需的一系列基因。 该途径的其他组件包括 CDC42 G蛋白周期及其相关调节因子。 MAPK的级联效应和特异性。MAPK级联 在所有动物、植物和真菌中都有发现，在那里它们 参与监管正常和非政府组织 细胞生长、分裂的病理方面， 分化和死亡(约翰逊和拉帕达特， 2002年)。MAPK级联是如何使用的 无所不在，多才多艺，但在某种程度上 保持专一性？不同的信号是如何引发的 当它们由 相同的组件？ 酵母菌就是这样研究的杰出典范 问题，因为同一个MAPK的元素 调节交配的级联也调节另外两个 不同的反应-丝状侵入性生长 差异化计划和猪压力 响应路径(见图C2)。交配和交配 丝状侵袭性生长都是由 Ste2QPAK、Ste11MEKK和STE？MEK|n加法， Ste2QPAK和Ste11 Mekk也在 渗透胁迫。如上所述，FusSMAPK和 Kss1MApK在交配过程中被激活。此外, Kss1在侵袭性生长过程中也被激活 (HoglMAPK在应激反应期间被激活)。 尽管关键组件共享，但这三个 道路彼此之间隔绝良好： 细胞暴露在交配信息素下不会 导致丝状化或应激过度激活 例如，反应基因。如何实现这一目标 是一个积极调查的领域(施瓦茨和 Madhani，2004；Bardwell，2006)，是 这一主题的主要重点。 建立信号转导模型。数量上的 对细胞内信号处理的理解将 大大增加我们对生物学的理解 并可能催化方式发生根本性的变化 疾病是被理解和治疗的。因此，在这里 最近越来越努力地分析 单元格内的信息流和处理 (Endy和Brent，2001；Ferrell，2002； Neves和Lyengar，2002；Schuster等人，2002； Kholodenko，2003；Wiley等人，2003；Sauro和 Kholodenko，2004；Orton等人，2005)。最多的 第二部分，对蛋白激酶信号转导的理论治疗 使用过常微分方程式，但没有 明确考虑了空间动力学。这些努力 也没有明确考虑到重要的方面 信号的特异性。正是这些元素让我们 把注意力放在这里。

Theme C: Spatial Control of Intracellular Signaling Theme Leader: Bard well Other Project Faculty: Jeon, Komarova, Liu, Nie, Yi The proper growth, development and survival of an organism requires extensive and accurate communication between that organism's cells. Accordingly, cells react to a wide variety of stimuli, which deliver information about nutrients, harmful insults, the state of neighboring cells, etc. Many incoming stimuli are first recognized by a cell surface receptor, and then transmitted to various locations inside the cell by a cascade of signaling proteins. Such 'signal transduction pathways' are the connection between signal and cellular response. Accurate and efficient signal transduction is challenging because (i) there are multiple inputs which must be routed to the correct output, (ii) the inputs vary in time and space, (iii) noise is ubiquitous, and (iv) pathways may share similar or identical components. The central hypotheses of this theme are (1) that accurate and efficient signal transmission requires sophisticated regulation of the spatial dynamics of the signaling network; (2) that achieving specificity from signal to cellular response in a highly interconnected network requires the cooperative action of multiple insulating mechanism (some of which depend upon or exploit spatial aspects). To investigate these hypotheses we propose to examine the relationship between the spatial control of signaling and directional sensing (Project C.1), how different network architectures can enhance specificity (Project C.2), the performance objectives of the transcriptional response to a spatial signal (Project C.3) and the role of spatial localization in signal transmission and specificity (Project D.4) Utility of yeast mating pathway as a model system. We will focus our combined theoretical and experimental effort on the mating pheromone response pathway of the yeast S. cerevisiae, because it is one of the best understood signaling pathways in eukaryotes, and is thus suited for attempts at systematic understanding. Haploid yeast cells respond to the presence of peptide mating pheromone by undergoing a series of events resulting in fusion with a nearby mating partner [reviewed by Bardwell, 2005]. Pheromone binds to a seven-transmembrane, G-protein-coupled receptor (Ste2) resulting in the activation of a membrane-bound heterotrimeric G-protein (see Figure C1). Activated G(3 (Ste4) then binds to the Ste5 adapter/scaffold and to the Ste20 kinase. As a result, Ste20 phosphorylates and activates the Ste11 kinase, which has been towed to the membrane by Ste5. Ste11 is the topmost kinase in a prototypical mitogenactivated protein kinase (MAPK) cascade: Ste11 (MAP3K. or MEKK) phosphorylates Ste7 (MAP2K, or MEK), which in turn phosphorylates Fus3 and Kss1 (MAPKs). Signal transmission down the MAPK cascade is enhanced by the Ste5 scaffold protein, which binds to Ste11, Ste7 and Fus3, and is thought to tether these kinases in a close and productive configuration. Fus3 and Kss1 then phosphor/late several substrates, including the Dig1, Dig2 and Ste12 transcriptional regulators. As a result, Dig1/2 dissociate from Ste12, and Ste12 activates a battery of genes required for cell fusion. Additional components of this pathway include a Cdc42 G-protein cycle and associated regulators. MAPK cascades and specificity. MAPK cascades are found in all animals, plants and fungi, where they participate in the regulation of normal and pathological aspects of cell growth, division, differentiation, and death (Johnson and Lapadat, 2002). How are MAPK cascades used so ubiquitously and versatilely yet in a way that maintains specificity? How do different signals elicit distinct responses when they are transmitted by the same components? Yeast is and outstanding model to study such questions, because elements of the same MAPK cascade that regulate mating also regulate two other distinct responses - the filamentous invasive growth differentiation program, and the HOG stress response pathway (see Fig C2). Mating and filamentous invasive growth are both regulated by Ste2QPAK, ste11MEKK and Ste?MEK |n addition, Ste2QPAK and Ste11 MEKK are also activated during osmotic stress. As stated above, FusSMAPK and Kss1MApK are activated during mating. In addition, Kss1 is also activated during invasive growth (HoglMAPK is activated during the stress response). Despite this sharing of key components, the three pathways are well insulated from one another: exposure of cells to mating pheromone does not result in the hyperactivation of filamentation or stress response genes, for example. How this is achieved is an area of active investigation (Schwartz and Madhani, 2004; Bardwell, 2006), and is one of the major emphases of this Theme. Modeling signal transduction. A quantitative understanding of intracellular signal processing will substantially increase our understanding of biological systems and may catalyze radical changes in how diseases are understood and treated. Hence, there has recently been a growing effort to analyze the flow and processing of information within cells (reviewed by Endy and Brent, 2001; Ferrell, 2002; Neves and lyengar, 2002; Schuster et al., 2002; Kholodenko, 2003; Wiley et al., 2003; Sauro and Kholodenko, 2004; Orton et al., 2005). For the most part, theoretical treatments of kinase signaling have used ordinary differential equations, and have not explicitly considered spatial dynamics. These efforts have also not explicitly considered important aspects of signaling specificity. It is these elements that we focus on here.