SFEBES2008 Poster Presentations Cytokines and growth factors (7 abstracts)
Extracellular matrix protein anosmin-1 modulates FGFR1/FGF2/heparin complex formation
Youli Hu 1 , Soo-Hyun Kim 1 , Scott Guimond 2 , Ruby Quartey-Papafio 3 , Steven Cadman 1 , Paul Travers 3 , Erhard Hoheneste 4 , Jeremy Turnbull 2 & Pierre Bouloux 1
1Royal Free and University College Medical School, London, UK; 2University of Liverpool, Liverpool, UK; 3Royal Free Hospital, London, UK; 4Imperial College London, London, UK.
Introduction: Fibroblast growth factor (FGF) signalling involved in many physiological and pathophysiological processes requires the complex formation of FGF receptor, FGF and heparan sulphate, which is regulated by multiple extracellular inputs. FGFR1 as KAL-2 gene and anosmin-1, an extracellular matrix protein encoded by KAL-1 gene are associated with Kallmann syndrome characterised by anosmia and hypogonadotropic hypogonadism. Anosmin-1 induces neurite outgrowth and cytoskeletal rearrangement in human embryonic GnRH olfactory neuroblast through FGFR1 signalling and enhances proliferation of BaF3 cells expressing FGFR1 in the presence of exogenous FGF2 and heparin.
Aims: To investigate molecular mechanism as to how anosmin-1 affects FGFR1/FGF2/heparin complex formation.
Methods: Surface plasmon resonance was performed by coupling anosmin-1 and its analogues onto the sensor surface with the single injection of soluble FGFR1 ectodomain or sequential injection of FGFR1, FGF2, heparin and desulphated heparin.
Results: Anosmin-1 directly binds to FGFR1 with a Kd around 7×10−9 M, but fails to bind FGF2. The first FnIII domain of anosmin-1 and FGFR1 ectodomain without the first immunoglobulin-like domain and acid box are sufficient for their interaction. The anosmin-1/FGFR1 complex can bind to FGF2, but not to the FGF2/heparin complex. Alternatively, anosmin-1 and heparin complex can bind to FGFR1/FGF2 complex, but not FGFR1 alone. This quaternary complex formation depends on the length of heparin but not the specific sulphation pattern.
Conclusion: Anosmin-1 may perform dual activities with respect to FGFR1/FGF2/heparin complex formation dependent on the molecules in this complex that anosmin-1 first encounters. Prior binding of anosmin-1 to heparin will help FGFR1/FGF2/heparin complex formation and may overcome the requirement for the specific sulphation. On the other hand, anosmin-1 may exert an inhibitory effect on the complex formation when anosmin-1 first binds to FGFR1.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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