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Journal/Book: J. Biol. Chem.
Published: 2010
Pages: 26628-26640
Volume: 285
Accession no.: 192

Influence of heparin mimetics on the assembly of the FGF – FGFR4 signaling complex

Krishna Saxena, Ulrich Schieborr, Oliver Anderka, Elke Duchardt-Ferner, Bettina Elshorst, Santosh Lakshmi Gande, Julia Janzon, Denis Kudlinzki, Sridhar Sreeramulu, Matthias K. Dreyer, Karl U. Wendt, Corentin Herbert, Philippe Duchaussoy, Marc Bianciotto, Pierre-Alexandre Driguez
Fibroblast growth factor (FGF) signaling regulates mammalian development and metabolism, and its dysregulation is implicated in many inherited and acquired diseases including cancer. Heparan sulfate glycosaminoglycans (HSGAGs) are essential for FGF signaling as they promote FGF-FGF receptor (FGFR) binding and dimerization. In this report we used novel organic synthesis protocols to prepare homogeneously sulfated heparin mimetics (HM) including hexasaccharide (HM6), octasaccharide (HM8) and decasaccharide (HM10), and tested the ability of these HM to support FGF1 and FGF2 signaling through FGFR4. Biological assays show that HM8 is significantly more potent than HM6 while HM10 shows similar potency as HM8 in promoting FGF2-mediated FGFR4 signaling. In contrast, all three HM have comparable activity in promoting FGFR4 signaling. To understand the molecular basis for the differential activities of these HM in promoting FGF1- and FGF2-FGFR4 signaling, we used nuclear magnetic resonance (NMR) spectroscopy, isothermal titration calorimetry (ITC) and size exclusion chromatography (SEC) to characterize binding interactions of FGF1/2 with the isolated Ig-domain 2 (D2) of FGFR4 in the presence of HM, and binary interactions of FGFs and D2 with HMs. Our data confirm the existence of both a secondary FGF1-FGFR4 interaction site and a direct FGFR4-FGFR4 interaction site thus supporting the formation of the symmetric mode of FGF-FGFR dimerization in solution. Moreover, our results show that the observed higher activity of HM8 relative to HM6 in stimulating FGF2-FGFR4 signaling correlates with the higher affinity of HM8 to bind and dimerize FGF2. Notably FGF2-HM8 exhibits pronounced positive binding cooperativity. Based on our findings we propose a refined symmetric FGF-FGFR dimerization model which incorporates the differential ability of HM to dimerize FGFs.
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Prof. Dr. Harald Schwalbe
Institut für Organische Chemie und Chemische Biologie
Johann Wolfgang Goethe Universität
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