Mechanisms of FGF Receptor Regulation and Signaling

说明(申请人提供)：成纤维细胞生长因子(FGFs)通过结合和激活成纤维细胞生长因子受体酪氨酸激酶(FGFRs)，在发育中的胚胎和成人中发挥其普遍的作用。FGFRs是一种单程跨膜受体，由一个胞外配体结合区和一个含有保守酪氨酸激酶结构域的胞内区组成。FGFFR结合的特异性是调节FGFs信号的关键，它是由FGFs和FGFRs之间的初级序列差异决定的。同样，激活的FGFR对细胞内靶点的特异性识别和酪氨酸磷酸化是成纤维细胞生长因子信号传递的基本步骤，决定了哪些特定的下游通路被激活，从而决定了随后的细胞反应。异常的成纤维细胞生长因子信号与多种人类病理疾病有关，包括骨骼综合征、嗅觉综合征、磷酸盐消耗障碍和癌症。这些疾病的多样性反映了FGFs在人类生物学中所发挥的广泛而重要的功能，并为在分子水平上深入了解FGFs信号转导机制提供了强大的推动力。这项建议的具体目标是： I.建立成纤维细胞生长因子-FGFR结合特异性/混杂的模式，并确定其结构基础。 II.阐明FGFR胞外区自抑制的结构基础。 阐明FGFR与细胞内信号分子相互作用的结构基础。IV.阐明在人类骨骼综合征和癌症中，FGFR激酶结构域突变导致FGFRs结构性激活的结构基础。 实现这些目标的主要手段将是X射线结晶学，再加上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成纤维细胞生长因子信号转导的了解，并将使我们了解致病的成纤维细胞生长因子和成纤维细胞生长因子受体突变的影响。更广泛地说，这些研究将有助于合理设计新型的成纤维细胞生长因子信号拮抗剂用于治疗各种病理疾病，并将加深我们对整个受体酪氨酸激酶超家族信号的理解。

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.