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Molecular and Cellular Biology, September 2009, p. 4663-4678, Vol. 29, No. 17
0270-7306/09/$08.00+0     doi:10.1128/MCB.01780-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Homodimerization Controls the Fibroblast Growth Factor 9 Subfamily's Receptor Binding and Heparan Sulfate-Dependent Diffusion in the Extracellular Matrix ^,

Juliya Kalinina,¹ Sara A. Byron,² Helen P. Makarenkova,^3,4 Shaun K. Olsen,^1,|| Anna V. Eliseenkova,¹ William J. Larochelle,^5, Mohanraj Dhanabal,^5, Steven Blais,¹ David M. Ornitz,⁷ Loren A. Day,⁶ Thomas A. Neubert,¹ Pamela M. Pollock,² and Moosa Mohammadi^1*

Department of Pharmacology of New York University School of Medicine, 550 First Avenue, New York, New York 10016,¹ Cancer and Cell Biology Division of Translational Genomics Research Institute, Phoenix, Arizona 85004,² Department of Neurobiology of Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, California 92037,³ Neurosciences Institute, 10640 John Jay Hopkins Drive, San Diego, California 92121,⁴ CuraGen Corporation, Branford, Connecticut 06405,⁵ Public Health Research Institute of University of Medicine and Dentistry of New Jersey, 225 Warren Street, Newark, New Jersey 07103,⁶ Department of Developmental Biology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110⁷

Received 20 November 2008/ Returned for modification 19 January 2009/ Accepted 8 June 2009

Uncontrolled fibroblast growth factor (FGF) signaling can lead to human diseases, necessitating multiple layers of self-regulatory control mechanisms to keep its activity in check. Herein, we demonstrate that FGF9 and FGF20 ligands undergo a reversible homodimerization, occluding their key receptor binding sites. To test the role of dimerization in ligand autoinhibition, we introduced structure-based mutations into the dimer interfaces of FGF9 and FGF20. The mutations weakened the ability of the ligands to dimerize, effectively increasing the concentrations of monomeric ligands capable of binding and activating their cognate FGF receptor in vitro and in living cells. Interestingly, the monomeric ligands exhibit reduced heparin binding, resulting in their increased radii of heparan sulfate-dependent diffusion and biologic action, as evidenced by the wider dilation area of ex vivo lung cultures in response to implanted mutant FGF9-loaded beads. Hence, our data demonstrate that homodimerization autoregulates FGF9 and FGF20's receptor binding and concentration gradients in the extracellular matrix. Our study is the first to implicate ligand dimerization as an autoregulatory mechanism for growth factor bioactivity and sets the stage for engineering modified FGF9 subfamily ligands, with desired activity for use in both basic and translational research.

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* Corresponding author. Mailing address: Department of Pharmacology, New York University School of Medicine, 550 First Avenue, New York, NY 10016. Phone: (212) 263-2907. Fax: (212) 263-7133. E-mail: moosa.mohammadi{at}nyumc.org

Published ahead of print on 29 June 2009.

Supplemental material for this article may be found at http://mcb.asm.org/.

^|| Present address: Department of Structural Biology, Sloan-Kettering Institute, New York, NY 10065.

Present address: 454 Life Sciences Corporation, 1 Commercial St., Branford, CT 06405.

Present address: Serono Inc., One Technology Place, Rockland, MA 02370.

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Molecular and Cellular Biology, September 2009, p. 4663-4678, Vol. 29, No. 17
0270-7306/09/$08.00+0     doi:10.1128/MCB.01780-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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