Docking protein FRS2 in FGF signaling

FGF 信号传导中的对接蛋白 FRS2

• 批准号: 7058290
• 负责人: JOSEPH SCHLESSINGER
• 金额: $ 35.1万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-23 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7058290
• 关键词: DNA replication; X ray crystallography; biological signal transduction; cell growth regulation; cell line; cell migration; cell proliferation; developmental genetics; embryo /fetus; embryogenesis; fibroblast growth factor; gene expression; genetic regulation; genetically modified animals; growth factor receptors; histogenesis; intermolecular interaction; laboratory mouse; mitogen activated protein kinase; phosphorylation; posttranslational modifications; protein isoforms; protein structure function; protein tyrosine kinase; surface plasmon resonance

DESCRIPTION (provided by applicant): Fibroblast growth factors (FGFs) comprise a large family of growth factors that play important roles in the control of embryonic development, morphogenesis, wound healing, and tumor angiogenesis. FGFs mediate their diverse cellular responses by acting in concert with heparin sulfate proteoglycans to activate a family of receptor tyrosine kinases (RTK) designated FGF-receptors 1 to 4 (FGFR1-FGFR4). We have identified a family of docking proteins designated FGFR-substrate 2 (FRS2) that function as major mediators of signaling via FGFRs. The current application seeks to obtain a detailed view on cellular signaling through FGFRs. Our main goal is to determine the biological role and mechanism of action of FRS2 in FGFR signaling in vitro and in vivo. The specific aims of this proposal are to: 1. Identify the FRS2-dependent independent signaling pathways downstream of FGFR1 and FGFR2. 2. Identify the role of Shc in mediating FGF-signaling pathways. 3. Determine the mechanism and biological significance underlying the interaction between FRS2 and MAPK. 4. Determine the role of FRS2 in mediating heterologous control of FGFl-signaling and 5. Develop genetically modified mice to explore the biological role of FRS2 in vivo. The primary means to accomplish these aims are biochemical analysis of cultured cells expressing wild type or mutant proteins, X-ray crystallographic studies of components of FGFR signaling, in vivo studies of genetically modified mice and analysis of FGF-signaling in cells isolated from knock-in and knock-out mice. The information obtained from these studies will enhance our knowledge on intracellular signaling pathways downstream of FGFR and other RTKs. It would also provide a framework for understanding the role of FGFR-signaling in normal biological responses and in diseases caused by dysfunctions in FGFRs such as Crouzon, Apert, Jackson-Weiss syndromes and other skeletal disorders, as well as tumor angiogenesis, and cancer.

描述（由申请人提供）：成纤维细胞生长因子（FGF）包括在控制胚胎发育、形态发生、伤口愈合和肿瘤血管生成中发挥重要作用的生长因子大家族。FGF通过与硫酸肝素蛋白聚糖协同作用以激活命名为FGF受体1至4（FGFR 1-FGFR 4）的受体酪氨酸激酶（RTK）家族来介导其多样的细胞应答。我们已经确定了一个家庭的对接蛋白命名为FGFR-底物2（FRS 2），作为主要介质的信号通过FGFR。本申请寻求获得关于通过FGFR的细胞信号传导的详细视图。我们的主要目标是确定FRS 2在体外和体内FGFR信号传导中的生物学作用和作用机制。这项建议的具体目标是：1.鉴定FGFR 1和FGFR 2下游的FRS 2依赖性独立信号通路。2.确定Shc在介导FGF信号通路中的作用。3.确定FRS 2和MAPK相互作用的机制和生物学意义。4.确定FRS 2在介导FGF 1-信号传导的异源控制中的作用，以及5.开发转基因小鼠，探索FRS 2在体内的生物学作用。实现这些目标的主要手段是表达野生型或突变蛋白的培养细胞的生化分析、FGFR信号传导组分的X射线晶体学研究、遗传修饰小鼠的体内研究和从敲入和敲除小鼠分离的细胞中FGF信号传导的分析。从这些研究中获得的信息将增强我们对FGFR和其他RTK下游细胞内信号传导途径的了解。它还将为理解FGFR信号传导在正常生物反应和FGFR功能障碍引起的疾病（如Crouzon，Apert，Jackson-Weiss综合征和其他骨骼疾病）以及肿瘤血管生成和癌症中的作用提供框架。