Docking protein FRS2 in FGF signaling

FGF 信号传导中的对接蛋白 FRS2

• 批准号: 6812979
• 负责人: JOSEPH SCHLESSINGER
• 金额: $ 35.62万
• 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/6812979
• 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）包含一大类生长因子，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。 FGF 通过与硫酸肝素蛋白聚糖协同作用来激活受体酪氨酸激酶 (RTK) 家族（称为 FGF 受体 1 至 4 (FGFR1-FGFR4)），从而介导多种细胞反应。我们已经鉴定了一个名为 FGFR-底物 2 (FRS2) 的对接蛋白家族，它们作为 FGFR 信号传导的主要介质发挥作用。当前的申请旨在通过 FGFR 获得有关细胞信号传导的详细信息。我们的主要目标是确定 FRS2 在体外和体内 FGFR 信号传导中的生物学作用和作用机制。该提案的具体目标是： 1. 确定 FGFR1 和 FGFR2 下游依赖于 FRS2 的独立信号通路。 2. 确定 Shc 在介导 FGF 信号通路中的作用。 3. 确定FRS2和MAPK之间相互作用的机制和生物学意义。 4.确定FRS2在介导FGF1信号传导的异源控制中的作用，以及5.培育转基因小鼠以探索FRS2在体内的生物学作用。实现这些目标的主要手段是对表达野生型或突变蛋白的培养细胞进行生化分析、对FGFR信号成分进行X射线晶体学研究、对转基因小鼠进行体内研究以及对从敲入和敲除小鼠中分离的细胞中的FGF信号进行分析。从这些研究中获得的信息将增强我们对 FGFR 和其他 RTK 下游细胞内信号通路的了解。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（如克鲁宗、阿珀特、杰克逊-韦斯综合征和其他骨骼疾病，以及肿瘤血管生成和癌症）中的作用提供一个框架。