Extracellular Modulation of Multiprotein Signalling Complexes: Molecular Regulation of FGFR Signalling by Anosmin & Heparan Sulphate Proteoglycans

多蛋白信号传导复合物的细胞外调节：Anosmin 对 FGFR 信号传导的分子调节

基本信息

批准号：
BB/F006616/1
负责人：
Jeremy Turnbull
金额：
$ 40.76万
依托单位：
University of Liverpool
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2008
资助国家：
英国
起止时间：
2008 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FF006616%2F1
关键词：
Extracellular Modulation Multiprotein Signalling Complexes

项目摘要

Defects of a recently discovered protein called anosmin-1, or of a signaling protein called fibroblast growth factor receptor 1 (FGFR1), cause Kallmann's syndrome, an inherited human disorder resulting from abnormal development of neurons involved in smell and hormone-releasing functions. We recently discovered that anosmin-1 functions through interactions with FGFR1 signalling complexes that involve binding to a complex polysaccharide called heparan sulphate (HS), resulting in amplified responses. Our data provide the first evidence for anosmin-1 acting as a specific modulator of FGFR1 signalling and reveal a defined molecular mechanism linking the 2 genetic forms of Kallmans syndrome. In this project we are planning to characterize in more detail the molecular mechanisms of HS-dependent regulation of FGFR signalling by anosmin-1. We will use a variety of molecular, cell and structural biology techniques to examine the functional interactions between these molecules. These studies will provide insights into the regulation of multiprotein complexes involved in receptor signalling processes. The results will extend our understanding of the molecular mechanisms for the normal function of anosmin-1 and HS in FGFR signalling during human nervous system development, as well as in abnormal development in Kallmann's syndrome. This work could help to identify new targets for treating this syndrome, and also underpin the development of novel applications in tissue engineering and nerve regeneration.

最近发现的一种名为 anosmin-1 的蛋白质或一种名为成纤维细胞生长因子受体 1 (FGFR1) 的信号蛋白的缺陷会导致卡尔曼综合症，这是一种遗传性人类疾病，由涉及嗅觉和激素释放功能的神经元发育异常引起。我们最近发现 anosmin-1 通过与 FGFR1 信号复合物相互作用发挥作用，该复合物涉及与一种称为硫酸乙酰肝素 (HS) 的复杂多糖结合，从而导致放大的反应。我们的数据为 anosmin-1 作为 FGFR1 信号传导的特异性调节剂提供了第一个证据，并揭示了连接卡尔曼斯综合征的 2 种遗传形式的明确分子机制。在这个项目中，我们计划更详细地描述 anosmin-1 对 FGFR 信号传导的 HS 依赖性调节的分子机制。我们将使用各种分子、细胞和结构生物学技术来检查这些分子之间的功能相互作用。这些研究将为受体信号传导过程中涉及的多蛋白复合物的调节提供见解。这些结果将加深我们对人类神经系统发育过程中 FGFR 信号传导中 anosmin-1 和 HS 正常功能以及卡尔曼综合征发育异常的分子机制的理解。这项工作有助于确定治疗这种综合征的新靶点，并支持组织工程和神经再生方面新应用的开发。