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Papers In Press, published online ahead of print May 28, 2002
School of Biosciences, University of Birmingham, Birmingham, W. Midlands B15 2TT
Corresponding Author: j.e.turnbull{at}bham.ac.uk
Heparan sulfate (HS) regulates the kinetics of FGF2-stimulated intracellular signaling and differentially activates cell proliferation of cells expressing different FGFRs. Evidence suggests that HS interacts with both FGFs and FGFRs to form active ternary signaling complexes. Here we compare the interactions of two FGFRs with HS. We show that the ectodomains of FGFR1 IIIc and FGFR2 IIIc exhibit specific interactions with different characteristics for both heparin and porcine mucosal HS. These glycans are both known to activate FGF signaling via these receptors. FGFR2 interacts with a higher apparent affinity than FGFR1 despite both involving 6-O-, 2-O- and N-sulfates. FGFR1 and FGFR2 bind heparin with mean association rate constants of 1.9 x 105 and of 2.1 x 106 M-1s-1, respectively, and dissociation rate constants of 1.2 x 10-2 and of 2.7 x 10-2 s-1, respectively. These produced calculated affinities of 65 and 13 nM, respectively. Hence, FGFR1 and FGFR2 bind to heparin chains with markedly different kinetics and affinities. We propose a mechanistic model where the kinetic parameters of the HS/FGFR interaction are a key element regulating the formation of ternary complexes and the resulting FGF signaling outcomes.
J. Biol. Chem, 10.1074/jbc.M111754200
Submitted on December 10, 2001
Revised on May 24, 2002
Accepted on May 28, 2002
Fibroblast growth factor receptors 1 and 2 interact differently with heparin/heparan sulfate: implications for dynamic assembly of a ternary signaling complex
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