Systematic approaches to reveal novel regulatory functions of tyrosine phosphorylation

项目摘要 许多细胞信号网络依赖于酪氨酸磷酸化将细胞外信号转换为细胞表型 结果。酪氨酸磷酸化(PTyr)在不同的细胞过程中是重要的，并经常与 疾病。PTyr的Identifi阳离子有爆炸性增长，目前已知存在46,000个pTyr位点 在人类蛋白质组中，我们只了解其中一小部分的功能。这项工作是为了- 引起一种独特的酪氨酸现象的磷酸化-25%的pTyr属于蛋白质结构域，这些结构域是 PTyr介导的信号网络的中心。我们建议利用蛋白质结构域是保守的这一事实 在结构和功能上都是通过关注酪氨酸磷酸化，它在结构上是保守的，在DO-1中。 电源。基本前提是ptyr在特定的fic结构位置内的功能效应 域将在共享它的所有域之间产生相同的效果。这个项目将专门解决这部小说的问题 其相互作用伙伴的多种类型的域的特定fi城市受酪氨酸调节的可能性 结构域内发生的磷酸化。这项工作是通过集成计算和实验来实现的 方法，其中可以：识别保守的酪氨酸磷酸化，基于角色的假设效应 保守结构域功能的酪氨酸，利用生理学证据来理解其参与细胞 信号传递过程，并系统地测试pTyr在体外和细胞信号网络内对结构域功能的影响。 行得通。聚焦于细胞信号中两个重要的相互作用领域，这项工作可能会揭示新的范式 涉及pTyr介导的信号转导，这对我们对细胞信号和 可以帮助确定广泛疾病的新治疗靶点。

Project Summary Many cell signaling networks rely on tyrosine phosphorylation to convert extracellular cues into cell phenotypic outcomes. Tyrosine phosphorylation (pTyr) is important to diverse cellular processes and is often implicated in disease. There has been explosive growth in the identification of pTyr, with 46,000 pTyr sites now known to exist in the human proteome and we understand the function of only a small percentage of these sites. This work fo- cuses on a uniquely tyrosine phenomenon of phosphorylation – 25% of pTyr fall within protein domains, which are central to pTyr-mediated signaling networks. We propose to exploit the fact that protein domains are conserved both structurally and functionally by focusing on tyrosine phosphorylation that is structurally conserved within do- mains. The fundamental premise is that the functional effect of pTyr within a specific structural location within a domain will have the same effect across all domains that share it. This project will specifically address the novel possibility that the specificity of multiple types of domains for their interacting partners is regulated by tyrosine phosphorylation occurring within the domain. This work is enabled by integrated computational and experimental approaches, which can: identify conserved tyrosine phosphorylation, hypothesize effects based on the role of that conserved tyrosine within domain function, use physiological evidence to understand its involvement in cell signaling processes, and systematically test pTyr effects on domain function in vitro and within cell signaling net- works. Focusing on two important interaction domains in cell signaling, this work will likely reveal new paradigms involving pTyr-mediated signaling, which has broad implications in our basic understanding of cell signaling and could help identify new therapeutic targets across a broad range of diseases.