  The binding of basic fibroblast growth factor (FGF-2) to its cell surface
receptor (CSR) and subsequent signal transduction is known to be enhanced by
Heparan Sulfate Proteoglycans (HSPGs). HSPGs bind FGF-2 with low affinity and
likely impact CSR-mediated signaling via stabilization of FGF-2-CSR complexes
via association with both the ligand and the receptor. What is unknown is
whether HSPG associates with CSR in the absence of FGF-2. In this paper, we
determine conditions by which pre-association would impact CSR-FGF-2-HSPG triad
formation assuming diffusion-limited surface reactions. Using mean-field rate
equations, we show that (i) when [HSPG] is much higher than [CSR], the presence
of pre-formed complexes does not affect the steady state of FGF-2 binding, and
(ii) when the concentrations are comparable, the presence of pre-formed
complexes substantially increases the steady state concentration of FGF-2 bound
to CSR. These findings are supported by explicit cellular automaton
simulations, which justify the mean-field treatment. We discuss the advantages
of such a two-receptor system compared to a single receptor model, when the
parameters are comparable. Further, we speculate that the observed high
concentration of HSPG in intact cells ([HSPG] ~ 100[CSR]) provides a way to
ensure that the binding levels of FGF-2 to its signaling receptor remains high,
irrespective of the presence of pre-formed CSR-HSPG complexes on the cell
surface, while allowing the cell to finely tune the response to FGF-2 via
down-regulation of the signaling receptor.
