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化为细胞表型信号。 成果。酪氨酸磷酸化（pTyr）对于不同的细胞过程是重要的，并且通常涉及 疾病对pTyr的鉴定呈爆炸性增长，目前已知存在46，000个pTyr位点 在人类蛋白质组中，我们只了解这些位点中一小部分的功能。这项工作是为了- 这是一种独特的酪氨酸磷酸化现象，25%的pTyr位于蛋白质结构域内， pTyr介导的信号网络的中心。我们建议利用蛋白质结构域保守的事实 在结构上和功能上，通过关注在DO中结构保守的酪氨酸磷酸化， 电源。基本前提是，pTyr在特定结构位置内的功能效应， 域将有相同的效果在所有域共享它。这个项目将专门解决小说 多种类型的结构域的相互作用伙伴的特异性受酪氨酸调节的可能性 磷酸化发生在结构域内。这项工作是通过集成的计算和实验 方法，这可以：确定保守的酪氨酸磷酸化，假设的作用基础上的作用， 保守酪氨酸结构域功能，使用生理学证据来了解其参与细胞 信号转导过程，并系统地测试pTyr对体外和细胞信号转导网络内结构域功能的影响， 工程.聚焦于细胞信号传导中的两个重要的相互作用域，这项工作将可能揭示新的范式 涉及pTyr介导的信号传导，这在我们对细胞信号传导的基本理解中具有广泛的意义， 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.