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Mechanisms of fibroblast growth factor (FGF) and FGF receptor autoinhibition.

机译：成纤维细胞生长因子（FGF）和FGF受体自身抑制的机制。

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摘要

The fibroblast growth factor (FGF) signaling system is a ubiquitous cellular sensor of local environmental changes and mediator of cell-to-cell communication with broad roles in development and in the adulthood. A concerted interplay of three essential components, including FGFs, their high-affinity partners---FGF receptors (FGFRs), and highly sulfated polysaccharides---heparin/heparan sulfate (HS) proteoglycans (HSPGs), mediates FGF signaling resulting in the functional versatility of developmental and physiological processes. The multitude of biological effects of FGFs and the many signaling pathways activated by this family of ligands imply that FGF signaling must be tightly regulated regarding timing, duration and spread of the signal. In fact, spatial and temporal expression of FGFs, FGFRs and HSPGs, together with tissue-specific dependent alternative splicing, are the major determinants of FGF binding specificity, duration and the extent of signaling. The regulation is further achieved by both positive and negative feedback loops in the extracellular space and within the cell. Indeed loss of these autoinhibitory mechanisms is often the culprit of human pathologies. Herein, I describe two novel autoregulatory mechanisms by which FGFs and FGFRs can maintain and modulate the delicate balance necessary for proper FGF signaling. Specifically, I show that homodimerization of FGF9 and FGF20 autoinhibits signaling activity of these ligands by suppressing both receptor binding and HS-dependent diffusion in the extracellular matrix (ECM). Also I address the role of the acid box (AB) linker region in FGFR3c autoinhibition. I show that the alternatively spliced AB of FGFR3c plays a focal role in FGFR autoinhibition (1) by blocking the heparin-binding site (HBS) of FGFR in cis; (2) by occluding the HBS of the ligand in trans and (3) by generating futile/signaling-incompetent FGF/FGFR complexes.
机译：成纤维细胞生长因子（FGF）信号系统是一种普遍存在的局部环境变化的细胞传感器，是细胞间通讯的介质，在发育和成年期起着广泛的作用。 FGF，其高亲和性伴侣-FGF受体（FGFR）和高度硫酸化的多糖--肝素/硫酸乙酰肝素（HS）蛋白聚糖（HSPG）等三个基本成分的相互作用相互作用介导FGF信号转导发育和生理过程的功能多样性。 FGF的多种生物学效应以及被该配体家族激活的许多信号传导途径都暗示着必须在信号的时间，持续时间和传播方面严格控制FGF信号传导。实际上，FGF，FGFR和HSPG的时空表达以及组织特异性依赖的选择性剪接是FGF结合特异性，持续时间和信号传导程度的主要决定因素。通过细胞外空间和细胞内的正反馈回路和负反馈回路进一步实现调节。确实，这些自抑制机制的丧失通常是人类病理的罪魁祸首。在这里，我描述了两种新颖的自动调节机制，通过这些机制，FGF和FGFR可以维持和调节适当FGF信号传导所必需的微妙平衡。具体而言，我表明FGF9和FGF20的同源二聚化通过抑制细胞外基质（ECM）中的受体结合和HS依赖性扩散，自动抑制这些配体的信号传导活性。我也解决了酸性框（AB）接头区域在FGFR3c自抑制中的作用。我表明，FGFR3c的另一种剪接的AB在FGFR自抑制中起着焦点作用（1）通过在顺式中阻断FGFR的肝素结合位点（HBS）； （2）通过反式封闭配体的HBS，（3）通过生成无用/无信号的FGF / FGFR复合物。

著录项

  • 作者

    Kalinina, Juliya.;

  • 作者单位

    New York University.;

  • 授予单位 New York University.;
  • 学科 Biology Molecular.;Biology Cell.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 196 p.
  • 总页数 196
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

  • 入库时间 2022-08-17 11:38:26

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