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

Lead Research Organisation: University of Liverpool
Department Name: Sch of Biological Sciences

Abstract

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.

Technical Summary

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.

Publications

10 25 50
 
Description New understading of signalling pathway regulation by extracelluar complexes of proteins with proteoglycans
Exploitation Route Further research
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Hosting visit to Liverpool University by local ARUK funding supporters 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Supporters
Results and Impact Contact was invaluable in informing supporters directly about research activities supported in Liverpool by their fund raising efforts

Funding supporters were able to gain insights into new potential treatments for AD, and how their funding is used for research.
Year(s) Of Engagement Activity 2013
 
Description Media releases on research findings 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact University press releases on the novel Alzheimer drug hits we discovered, along with developments in synthetic chemistry of our sugars, and applications in nerve repair and cancer therapeutics

International press coverage, radio interviews (Radio City Liverpool), and TV news (BBC NW Tonight).
Year(s) Of Engagement Activity 2006,2007,2008,2012,2013
 
Description Outreach to Business Community 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Health professionals
Results and Impact Article in magazine Research Intelligence by UoL Business Gateway,(see website link "Sweet Smell of Success" http://www.liv.ac.uk/researchintelligence/issue30/alzheimers.html)

Dissemination of information to business community
Year(s) Of Engagement Activity 2007
URL http://www.liv.ac.uk/researchintelligence/issue30/alzheimers.html
 
Description Public Lecture to Garston Rotary Club 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Lecture to Garston Rotary Club

Contributing the Public Understanding of Science
Year(s) Of Engagement Activity 2008
 
Description Public lecture to Liverpool Soroptimists Club 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Talk sparked many questions and discussion of AD and potential new drugs and diagnostics

Contribution to Public Understanding of Science
Year(s) Of Engagement Activity 2014
 
Description RCUK/BBSRC event: Lifelong Health: Bioscience of Ageing (at Westminster) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Poster highlighting discovery of new class of drugs for AD at the RCUK/BBSRC event: 2007 Lifelong Health: Bioscience of Ageing (at Westminster)

Dissemination of information on research success to MPs and policymakers
Year(s) Of Engagement Activity 2007
 
Description Supporting ARUK fund raising publicity with major London donor 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Supporters
Results and Impact Supporters engaged directly with researcher undertaking research activity.

As above
Year(s) Of Engagement Activity 2013
 
Description Visit to Coleg Cambria, Wrexham. Meet the Scientist & Careers Talk. February 2019. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Visit to Coleg Cambria, Wrexham. Meet the Scientist & Careers Talk. February 2019.
Year(s) Of Engagement Activity 2019