Fibroblast growth factor receptors 1 and 2 interact differently with heparin/heparan sulfate. Implications for dynamic assembly of a ternary signaling complex

Heparan sulfate (HS) regulates the kinetics of fibroblast growth factor 2 (FGF2)-stimulated intracellular signaling and differentially activates cell proliferation of cells expressing different FGF receptors (FGFRs). Evidence suggests that HS interacts with both FGFs and FGFRs to form active ternary...

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Bibliographic Details
Published in:The Journal of biological chemistry 2002-08, Vol.277 (32), p.28554
Main Authors: Powell, Andrew K, Fernig, David G, Turnbull, Jeremy E
Format: Article
Language:English
Subjects:
Animals
Binding, Competitive
Biotinylation
Cattle
Dose-Response Relationship, Drug
Electrophoresis, Polyacrylamide Gel
Enzyme-Linked Immunosorbent Assay
Fibroblast Growth Factors - metabolism
Glycosaminoglycans - metabolism
Heparin - metabolism
Heparitin Sulfate - metabolism
Kinetics
Lung - metabolism
Models, Biological
Protein Binding
Protein Structure, Tertiary
Receptor Protein-Tyrosine Kinases - metabolism
Receptor, Fibroblast Growth Factor, Type 1
Receptor, Fibroblast Growth Factor, Type 2
Receptors, Fibroblast Growth Factor - metabolism
Signal Transduction
Swine
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Summary:Heparan sulfate (HS) regulates the kinetics of fibroblast growth factor 2 (FGF2)-stimulated intracellular signaling and differentially activates cell proliferation of cells expressing different FGF receptors (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 10(5) and 2.1 x 10(6) m(-1)s(-1), respectively, and dissociation rate constants of 1.2 x 10(-2) and 2.7 x 10(-2) s(-1), respectively. These produced calculated affinities of 63 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.
ISSN:0021-9258
DOI:10.1074/jbc.M111754200