Mechanisms of FGF Receptor Regulation and Signaling

描述（由申请人提供）：成纤维细胞生长因子（FGFs）通过结合和激活FGF受体酪氨酸激酶（fgfr），在发育中的胚胎和成人中发挥着无处不在的作用。fgfr是一种单通道跨膜受体，由细胞外配体结合区和含有保守酪氨酸激酶结构域的细胞质区组成。FGF- fgfr结合特异性对于FGF信号的调节至关重要，由FGF和fgfr之间的一级序列差异决定。同样，活化的FGFR对细胞内靶标的特异性识别和酪氨酸磷酸化是FGF信号传导的一个基本步骤，并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FGF信号是广泛的人类病理状况的原因，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，并为在分子水平上彻底理解FGF信号提供了强大的动力。这项建议的具体目标是：

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.