This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ibrahimi, O. A.
Right arrow Articles by Mohammadi, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ibrahimi, O. A.
Right arrow Articles by Mohammadi, M.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, January 2005, p. 671-684, Vol. 25, No. 2
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.2.671-684.2005
Copyright © 2005, 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 31 May 2004/ Returned for modification 28 June 2004/ Accepted 4 October 2004

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.

Molecular and Cellular Biology, January 2005, p. 671-684, Vol. 25, No. 2
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.2.671-684.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Makarenkova, H. P., Hoffman, M. P., Beenken, A., Eliseenkova, A. V., Meech, R., Tsau, C., Patel, V. N., Lang, R. A., Mohammadi, M. (2009). Differential Interactions of FGFs with Heparan Sulfate Control Gradient Formation and Branching Morphogenesis. Sci Signal 2: ra55-ra55 [Abstract] [Full Text]  
  • Sinnis, P., Coppi, A., Toida, T., Toyoda, H., Kinoshita-Toyoda, A., Xie, J., Kemp, M. M., Linhardt, R. J. (2007). Mosquito Heparan Sulfate and Its Potential Role in Malaria Infection and Transmission. J. Biol. Chem. 282: 25376-25384 [Abstract] [Full Text]  
  • Zhang, D., Kosman, J., Carmean, N., Grady, R., Bassuk, J. A. (2006). FGF-10 and its receptor exhibit bidirectional paracrine targeting to urothelial and smooth muscle cells in the lower urinary tract. Am. J. Physiol. Renal Physiol. 291: F481-F494 [Abstract] [Full Text]  
  • Ben-Zvi, T., Yayon, A., Gertler, A., Monsonego-Ornan, E. (2006). Suppressors of cytokine signaling (SOCS) 1 and SOCS3 interact with and modulate fibroblast growth factor receptor signaling. J. Cell Sci. 119: 380-387 [Abstract] [Full Text]  
  • Robinson, C. J., Harmer, N. J., Goodger, S. J., Blundell, T. L., Gallagher, J. T. (2005). 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. J. Biol. Chem. 280: 42274-42282 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»