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Originally published In Press as doi:10.1074/jbc.M111754200 on May 28, 2002

J. Biol. Chem., Vol. 277, Issue 32, 28554-28563, August 9, 2002
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Fibroblast Growth Factor Receptors 1 and 2 Interact Differently with Heparin/Heparan Sulfate
IMPLICATIONS FOR DYNAMIC ASSEMBLY OF A TERNARY SIGNALING COMPLEX*

Andrew K. Powell, David G. FernigDagger §, and Jeremy E. Turnbull

From the School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT and Dagger  School of Biological Sciences, Life Sciences Building, University of Liverpool, Crown Street, Liverpool, L69 7ZB, United Kingdom

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 × 105 and 2.1 × 106 M-1s-1, respectively, and dissociation rate constants of 1.2 × 10-2 and 2.7 × 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.

* This work was funded by a Medical Research Council (MRC) United Kingdom Senior Research Fellowship (to J. E. T.) and an MRC Ph.D. studentship (to A. K. P.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Acknowledges the support of the Cancer and Polio Research Fund, the North West Cancer Research Fund, and the Biotechnology and Biological Sciences Research Council.

To whom correspondence should be addressed. Tel.: 44-121-414-7527; Fax: 44-870-1210-564; E-mail: j.e.turnbull@bham.ac.uk.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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