Docking protein FRS2 in FGF signaling

描述（由申请人提供）：成纤维细胞生长因子（FGFs）包括一个大的生长因子家族，在控制胚胎发育、形态发生、伤口愈合和肿瘤血管生成中起重要作用。FGFs通过与硫酸肝素蛋白聚糖协同作用，激活受体酪氨酸激酶（RTK）家族指定的fgf受体1至4 (FGFR1-FGFR4)，介导其多种细胞反应。我们已经确定了一个名为fgfr底物2 （FRS2）的对接蛋白家族，其功能是通过fgfr信号传导的主要介质。目前的应用旨在通过fgfr获得细胞信号传导的详细视图。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。本建议的具体目的是：1。鉴定FGFR1和FGFR2下游依赖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相互作用的机制和生物学意义。4. 确定FRS2在介导fgfl信号的异源调控中的作用。培养转基因小鼠，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信号传导成分进行x射线晶体学研究，对转基因小鼠进行体内研究，并对敲入和敲除小鼠分离的细胞进行fgf信号传导分析。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认识。它还将为理解fgfr信号在正常生物反应和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）中的作用提供一个框架。

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.