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

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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.