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: 10029062
• 负责人: Kristen M Naegle
• 金额: $ 36.01万
• 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/10029062
• 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; Structure; 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.

项目总结