Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

Mol. Cell. Biol. 25 (2): 671-684

Copyright © 2005 by the American Society for Microbiology. All rights reserved.

Analysis of Mutations in Fibroblast Growth Factor (FGF) and a Pathogenic Mutation in FGF Receptor (FGFR) Provides Direct Evidence for the Symmetric Two-End Model for FGFR Dimerization

Omar A. Ibrahimi,1,{dagger} Brian K. Yeh,1,{dagger} Anna V. Eliseenkova,1 Fuming Zhang,2 Shaun K. Olsen,1 Makoto Igarashi,3 Stuart A. Aaronson,3 Robert J. Linhardt,2, and Moosa Mohammadi1*

Department of Pharmacology, New York University School of Medicine,1 Department of Oncological Sciences, Mount Sinai School of Medicine, New York,3 Department of Chemistry, Biology, and Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, New York2

Received for publication 31 May 2004. Revision received 28 June 2004. Accepted for publication 4 October 2004.

Abstract: Two competing models for fibroblast growth factor (FGF) receptor (FGFR) dimerization have recently emerged based on ternary FGF-FGFR-heparin crystal structures. In the symmetric two-end model, heparin promotes dimerization of two FGF-FGFR complexes by stabilizing bivalent interactions of the ligand and receptor through primary and secondary sites and by stabilizing direct receptor-receptor contacts. In the asymmetric model, there are no protein-protein contacts between the two FGF-FGFR complexes, which are bridged solely by heparin. To identify the correct mode of FGFR dimerization, we abolished interactions at the secondary ligand-receptor interaction site, which are observed only in the symmetric two-end model, using site-directed mutagenesis. Cellular studies and real-time binding assays, as well as matrix-assisted laser desorption ionization-time of flight analysis, demonstrate that loss of secondary ligand-receptor interactions results in diminished FGFR activation due to decreased dimerization without affecting FGF-FGFR binding. Additionally, structural and biochemical analysis of an activating FGFR2 mutation resulting in Pfeiffer syndrome confirms the physiological significance of receptor-receptor contacts in the symmetric two-end model and provides a novel mechanism for FGFR gain of function in human skeletal disorders. Taken together, the data validate the symmetric two-end model of FGFR dimerization and argue against the asymmetric model of FGFR dimerization.

* Corresponding author. Mailing address: Department of Pharmacology, New York University School of Medicine, New York, NY 10016. Phone: (212) 263-2907. Fax: (212) 263-7133. E-mail: mohammad{at}saturn.med.nyu.edu.

{dagger} O.A.I. and B.K.Y. contributed equally to this paper.

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Plasticity in Interactions of Fibroblast Growth Factor 1 (FGF1) N Terminus with FGF Receptors Underlies Promiscuity of FGF1.
A. Beenken, A. V. Eliseenkova, O. A. Ibrahimi, S. K. Olsen, and M. Mohammadi (2012)
J. Biol. Chem. 287, 3067-3078
   Abstract »    Full Text »    PDF »
Influence of Heparin Mimetics on Assembly of the FGF{middle dot}FGFR4 Signaling Complex.
K. Saxena, U. Schieborr, O. Anderka, E. Duchardt-Ferner, B. Elshorst, S. L. Gande, J. Janzon, D. Kudlinzki, S. Sreeramulu, M. K. Dreyer, et al. (2010)
J. Biol. Chem. 285, 26628-26640
   Abstract »    Full Text »    PDF »
Extended N-Sulfated Domains Reside at the Nonreducing End of Heparan Sulfate Chains.
G. O. Staples, X. Shi, and J. Zaia (2010)
J. Biol. Chem. 285, 18336-18343
   Abstract »    Full Text »    PDF »
Differential Interactions of FGFs with Heparan Sulfate Control Gradient Formation and Branching Morphogenesis.
H. P. Makarenkova, M. P. Hoffman, A. Beenken, A. V. Eliseenkova, R. Meech, C. Tsau, V. N. Patel, R. A. Lang, and M. Mohammadi (2009)
Science Signaling 2, ra55
   Abstract »    Full Text »    PDF »
Mosquito Heparan Sulfate and Its Potential Role in Malaria Infection and Transmission.
P. Sinnis, A. Coppi, T. Toida, H. Toyoda, A. Kinoshita-Toyoda, J. Xie, M. M. Kemp, and R. J. Linhardt (2007)
J. Biol. Chem. 282, 25376-25384
   Abstract »    Full Text »    PDF »
FGF-10 and its receptor exhibit bidirectional paracrine targeting to urothelial and smooth muscle cells in the lower urinary tract.
D. Zhang, J. Kosman, N. Carmean, R. Grady, and J. A. Bassuk (2006)
Am J Physiol Renal Physiol 291, F481-F494
   Abstract »    Full Text »    PDF »
Suppressors of cytokine signaling (SOCS) 1 and SOCS3 interact with and modulate fibroblast growth factor receptor signaling.
T. Ben-Zvi, A. Yayon, A. Gertler, and E. Monsonego-Ornan (2006)
J. Cell Sci. 119, 380-387
   Abstract »    Full Text »    PDF »
Cooperative Dimerization of Fibroblast Growth Factor 1 (FGF1) upon a Single Heparin Saccharide May Drive the Formation of 2:2:1 FGF1{middle dot}FGFR2c{middle dot}Heparin Ternary Complexes.
C. J. Robinson, N. J. Harmer, S. J. Goodger, T. L. Blundell, and J. T. Gallagher (2005)
J. Biol. Chem. 280, 42274-42282
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882