FGF-2/fibroblast growth factor receptor/heparin-like glycosaminoglycan interactions: a compensation model for FGF-2 signaling.
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
R
Harvard Medical School, Boston, Massachusetts 02115, USA.
Venkataraman
G
G
Berry
D
D
Godavarti
R
R
Sasisekharan
R
R
D001665:Binding Sites; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D008956:Models, Chemical; D016297:Mutagenesis, Site-Directed; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D015398:Signal Transduction
D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; D006493:Heparin; C496348:FGFR1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1