R. Padera et al., FGF-2/fibroblast growth factor receptor/heparin-like glycosaminoglycan interactions: a compensation model for FGF-2 signaling, FASEB J, 13(13), 1999, pp. 1677-1687
Heparin-like glycosaminoglycans (HLGAGs) play a central role in the biologi
cal activity and signaling behavior of basic fibroblast growth factor (FGF-
P), Recent studies, however, indicate that FGF-2 may be able to signal in t
he absence of HLGAG, raising the question of the nature of the role of HLGA
G 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 valid
ated with F32 cell proliferation data using wild-type FGF-S, heparin bindin
g 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-m
ediated cellular response is a function of both FGF-2 and HLGAG concentrati
ons 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-S molecules show that reduction in heparin bind
ing interactions and primary receptor site binding interactions can also be
compensated for in the same manner. These results suggest a molecular mech
anism 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/fibro
blast growth factor receptor/heparin-like glycosaminoglycan interactions: a
compensation model for FGF-2 signaling.