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* Harvard Medical School, Boston, Massachusetts 02115, USA;
Harvard-MIT Division of Health Sciences and Technology,
Division of Bioengineering and Environmental Health, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
1Correspondence: MIT, 77 Massachusetts Ave., Building 16–561, Cambridge, MA 02139, USA. E-mail: ramnat{at}mit.edu
Heparin-like glycosaminoglycans (HLGAGs) play a central role in the biological activity and signaling behavior of basic fibroblast growth factor (FGF-2). Recent studies, however, indicate that FGF-2 may be able to signal in the absence of HLGAG, raising the question of the nature of the role of HLGAG in FGF-2 signaling. In this study, we present a conceptual framework for FGF-2 signaling and derive a simple model from it that describes signaling via both HLGAG-independent and HLGAG-dependent pathways. The model is validated with F32 cell proliferation data using wild-type FGF-2, heparin binding mutants (K26A, K119A/R120A, K125A), and receptor binding mutants (Y103A, Y111A/W114A). In addition, this model can predict the cellular response of FGF-2 and its mutants as a function of FGF-2 and HLGAG concentration based on experimentally determined thermodynamic parameters. We show that FGF-2-mediated cellular response is a function of both FGF-2 and HLGAG concentrations and that a reduction of one of the components can be compensated for by an increase in the other to achieve the same measure of cellular response. Analysis of the mutant FGF-2 molecules show that reduction in heparin binding interactions and primary receptor site binding interactions can also be compensated for in the same manner. These results suggest a molecular mechanism that could be used by cells in physiological systems to modulate the FGF-2-mediated cellular response by controlling HLGAG expression.—Padera, R., Venkataraman, G., Berry, D., Godavarti, R., Sasisekharan, R. FGF-2/fibroblast growth factor receptor/heparin-like glycosaminoglycan interactions: a compensation model for FGF-2 signaling.
Key Words: FGF receptor • thermodynamic parameters • extracellular matrix
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