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

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征，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异常发育引起。我们最近发现，anosmin-1的功能是通过与FGFR1信号复合物的相互作用来实现的，这种作用涉及到与一种名为硫酸乙酰肝素(HS)的复杂多糖的结合，从而导致放大的反应。我们的数据为anosmin-1作为FGFR1信号的特异性调节器提供了第一个证据，并揭示了一个明确的分子机制，将两种遗传形式的Kallmann综合征联系起来。在这个项目中，我们计划更详细地描述anosmin-1对依赖HS的FGFR信号调节的分子机制。我们将使用各种分子、细胞和结构生物学技术来研究这些分子之间的功能相互作用。这些研究将为参与受体信号传递过程的多蛋白复合体的调节提供洞察力。这一结果将扩大我们对Anosmin-1和HS在人类神经系统发育过程中FGFR信号转导中正常功能的分子机制以及在Kallmann综合征异常发育中的分子机制的理解。这项工作有助于确定治疗这种综合征的新靶点，也为组织工程和神经再生领域的新应用开发奠定了基础。

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.