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

Please see the Main Proposal from Liverpool Ref No : G505503

Defects of either anosmin-1 or fibroblast growth factor receptor 1 (FGFR1) underlie hereditary Kallmann's syndrome (KS), a human disorder of olfactory and gonadotropin- releasing hormone-1 (GnRH-1) neuronal ontogeny. We recently discovered a functional interaction between anosmin-1 and the multiprotein FGFR1/FGF2/heparan sulphate (HS) complex where anosmin-1 acts as an isoform-specific co-ligand enhancing FGFR1 signalling activity. Here we propose to further characterise the nature of anosmin-1 interaction with the FGF/HS/FGFR1 complex in order to develop an understanding of the molecular mechanisms of anosmin-1 action on FGFR1 signalling. We will: (1) map the binding sites of anosmin-1 with its interacting partners and determine the HS specificity necessary for these interactions (2) determine the FGFR/FGF subtype specificities in anosmin-1-mediated signalling (3) evaluate the functional and structural impacts of loss-of- function mutations in anosmin-1 and FGFR1 which confer KS phenotype (4) identify the HSPG core protein involved in anosmin-1/FGFR1 signalling and examine the possible cooperative signalling pathways (5) develop studies on the structural basis of anosmin-1 function in FGFR1 activation by CD spectroscopy and crystallographic structure determination of anosmin-1 and its complexes These studies will extend our understanding of the molecular mechanisms of normal function of anosmin-1 and HS in FGFR signalling during both normal and abnormal human nervous system development. Overall, this will provide novel insights of fundamental significance on multiprotein complexes involved in regulation of cell surface receptor signalling processes.