Systematic approaches to reveal novel regulatory functions of tyrosine phosphorylation

揭示酪氨酸磷酸化新调节功能的系统方法

• 批准号: 10456652
• 负责人: Kristen M Naegle
• 金额: $ 38.01万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10456652
• 关键词: Address; Biochemical; Cell Signaling Process; Cell physiology; Cells; Cues; Decision Making; Diabetes Mellitus; Disease; Growth; Human; In Vitro; Inflammation; Location; Malignant Neoplasms; Mediating; Outcome; Phenotype; Phosphorylation; Physiological; Proteome; Role; Signal Transduction; Site; Specificity; Tertiary Protein Structure; Testing; Tyrosine; Tyrosine Phosphorylation; Work; base; extracellular; falls; improved; new therapeutic target; novel

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.

项目摘要 许多细胞信号网络依赖酪氨酸磷酸化将细胞外提示转化为细胞表型 结果。酪氨酸磷酸化（PTYR）对多种细胞过程很重要，并且通常在 疾病。 PTYR的鉴定已经爆炸性增长，现在已知存在46,000个PTYR站点 在人类蛋白质组中，我们仅了解这些站点中一小部分的功能。这项工作fo- 在磷酸化的独特酪氨酸现象上的插座 - ptyr的25％落在蛋白质结构域内， PTYR介导的信号网络中心。我们建议探索蛋白质域是保守的事实 在结构和功能上，通过关注酪氨酸磷酸化，这在do- 电源。基本前提是PTYR在特定结构位置内的功能效应 域将在所有共享的域上具有相同的效果。这个项目将特别解决小说 酪氨酸对其互动伙伴的多种类型领域的特定城市的可能性 磷酸化发生在域内。通过集成的计算和实验性来启用这项工作 可以：确定保守的酪氨酸磷酸化，根据 构成域功能中酪氨酸，使用物理证据了解其参与细胞 信号传导过程，并系统地测试PTYR对域功能的影响，并在细胞信号净 - 作品。重点关注细胞信号中的两个重要相互作用域，这项工作可能会揭示新的范式 涉及PTYR介导的信号传导，这对我们对细胞信号的基本理解和 可以帮助确定各种疾病的新治疗靶标。