MECHANISMS OF FGF RECEPTOR REGULATION AND SIGNALING

描述（改编自申请人摘要）：成纤维细胞生长因子 FGF（FGF）包含至少18种结构相关多肽的家族，其 在胚胎发育、血管生成和伤口愈合中发挥重要作用。 FGF通过结合并激活一种独特的 受体酪氨酸激酶亚类。哺乳动物FGF受体（FGFR）家族 由四个基因（FGFR 1-FGFR 4）组成。每个FGFR结合一个独特的库， FGF配体。这种结合的特异性由以下差异决定： 细胞外结构域中的一级结构以及选择性剪接。 二聚化对于FGFR活化是必不可少的，然而，单独的FGF不能 诱导受体二聚化和活化，需要肝素样 分子来促进这一过程。研究人员提出了四个具体的 目的是研究FGF和肝素 含硫酸盐蛋白聚糖诱导受体二聚化和活化， 赋予配体结合特异性的结构要求，以及 细胞外结构域的每个亚结构域对调节细胞内蛋白质的作用 配体结合此外，在人类中发现的FGFR突变的影响， 将检查骨骼疾病对配体结合的影响。这些目标将是 通过X射线晶体学研究结合生物化学 使用表达突变FGFR的培养细胞的实验。此外该 FGF，肝素和配体结合结构域的缔合热力学 FGFR将通过等温滴定量热法和BIAcore进行表征 分析.这些研究将增加我们对FGFR信号转导的认识 并为理解FGFR突变的影响提供基础， 在人类骨骼疾病中。由于FGF参与血管生成， 肿瘤发生，预计这些结构和 功能分析将有助于合理设计新型FGF 治疗癌症的拮抗剂，以及提高我们对 其他肝素结合生长因子

DESCRIPTION (Adapted from applicant's abstract): The fibroblast growth factors (FGFs) comprise a family of at least 18 structurally related polypeptides that play important roles in embryonic development, angiogenesis and wound healing. FGFs exert these diverse effects by binding to and activating a distinct subclass of receptor tyrosine kinases. The mammalian FGF receptor (FGFR) family is composed of four genes (FGFR1-FGFR4). Each FGFR binds a unique repertoire of FGF ligands. The specificity of this binding is determined by differences in primary structure in the extracellular domain as well as alternative splicing. Dimerization is essential for FGFR activation, however, FGFs alone are unable to induce receptor dimerization and activation, requiring heparin-like molecules to facilitate this process. The investigator proposes four specific aims to investigate the molecular mechanisms by which FGFs and heparin sulfate-containing proteoglycans induce receptor dimerization and activation, the structural requirements that impart ligand binding specificity, and the contribution of each subdomain of the extracellular domain to regulation of ligand binding. In addition, the effects of FGFR mutations found in human skeletal disorders on ligand binding will be examined. These aims will be accomplished by x-ray crystallographic studies combined with biochemical experiments employing cultured cells expressing mutant FGFRs. In addition, the association thermodynamics of FGFs, heparin and the ligand-binding domains of FGFRs will be characterized by isothermal titration calorimetry and BIAcore analysis. These studies will increase our knowledge of FGFR signal transduction and provide a basis for understanding the effects of FGFR mutations that result in human skeletal disorders. Since FGFs are involved in angiogenesis and tumorigenesis, it is anticipated that the results of these structural and functional analyses will facilitate the rational design of novel FGF antagonists for the treatment of cancer as well as enhance our understanding of other heparin-binding growth factors