Mechanisms of FGF Receptor Regulation and Signaling

描述（由申请人提供）：成纤维细胞生长因子（FGF）通过结合和激活 FGF 受体酪氨酸激酶（FGFR），在发育中的胚胎以及成人中发挥普遍作用。 FGFR 是单程跨膜受体，由胞外配体结合区和含有保守酪氨酸激酶结构域的胞质区组成。 FGF-FGFR 结合特异性对于 FGF 信号传导的调节至关重要，并且由 FGF 和 FGFR 之间的一级序列差异决定。同样，激活的 FGFR 对细胞内靶标的特异性识别和酪氨酸磷酸化是 FGF 信号转导的基本步骤，决定了哪些特定的下游途径被激活，从而决定了随后发生的细胞反应。异常的 FGF 信号传导导致多种人类病理状况，包括骨骼综合征、嗅觉综合征、磷酸盐消耗性疾病和癌症。这些疾病的多样性反映了 FGF 在人类生物学中发挥的多功能和重要功能，并为在分子水平上全面了解 FGF 信号传导提供了强大的动力。该提案的具体目标是： I. 建立 FGF-FGFR 结合特异性/混杂性的模式并确定其结构基础。 二.阐明 FGFR 胞外区自抑制的结构基础。 三．阐明 FGFR 与细胞内信号分子相互作用的结构基础。四．阐明 FGFR 激酶结构域突变导致人类骨骼综合征和癌症中 FGFR 组成型激活的结构基础。 实现这些目标的主要手段是 X 射线晶体学，结合表面等离子体共振和稳态动力学分析。从这些研究中获得的基本结构和生化信息将增强我们对 FGF 信号传导的了解，并使我们能够了解致病性 FGF 和 FGFR 突变的影响。从更广泛的角度来看，这些研究将有助于合理设计新型 FGF 信号传导拮抗剂，用于治疗各种病理状况，还将增强我们对整个受体酪氨酸激酶超家族信号传导的理解。

DESCRIPTION (provided by applicant): Fibroblast growth factors (FGFs) execute their ubiquitous roles in the developing embryo, as well as in the adult, by binding and activating FGF receptor tyrosine kinases (FGFRs). FGFRs are single pass transmembrane receptors composed of an extracellular ligand binding region and a cytoplasmic region harboring the conserved tyrosine kinase domain. FGF-FGFR binding specificity is essential for the regulation of FGF signaling and is determined by primary sequence differences among FGFs and FGFRs. Similarly, specific recognition and tyrosine phosphorylation of intracellular targets by the activated FGFR is a fundamental step in FGF signaling and determines which specific downstream pathways are activated and, hence, what cellular response ensues. Aberrant FGF signaling is responsible for a wide spectrum of human pathological conditions including skeletal syndromes, olfactory syndromes, phosphate wasting disorders and cancer. The diversity of these diseases reflects the versatile and vital functions that FGFs play in human biology and provides a strong impetus for a thorough understanding of FGF signaling at the molecular level. The specific aims of this proposal are: I. Establish the pattern of, and determine the structural basis for, FGF-FGFR binding specificity/promiscuity. II. Elucidate the structural basis for autoinhibition in the extracellular region of FGFR. III. Elucidate the structural basis by which FGFR interacts with intracellular signaling molecules. IV. Elucidate the structural basis by which FGFR kinase domain mutations result in constitutive activation of FGFRs in human skeletal syndromes and cancer. The primary means to accomplish these aims will be X-ray crystallography, coupled with surface plasmon resonance and steady-state kinetic analysis. The fundamental structural and biochemical information obtained from these studies will enhance our knowledge of FGF signaling and will allow us to understand the effects of pathogenic FGF and FGFR mutations. In broader terms, these studies will facilitate the rational design of novel antagonists of FGF signaling for use in treatment of a variety of pathological conditions and will also enhance our understanding of signaling of the entire receptor tyrosine kinase superfamily.