Ligand-induced Coupling versus Receptor Pre-association: Cellular automaton simulations of FGF-2 binding

TL;DR

This study uses cellular automaton simulations and mean-field equations to explore how pre-association of HSPGs with cell surface receptors influences FGF-2 binding, revealing conditions that enhance or do not affect ligand-receptor complex formation.

Contribution

It demonstrates, through simulations and equations, how receptor pre-association impacts FGF-2 binding dynamics and provides insights into cellular regulation mechanisms.

Findings

Pre-formed complexes do not affect FGF-2 binding when HSPG is abundant.

Comparable concentrations of HSPG and CSR increase FGF-2 binding with pre-association.

High HSPG levels ensure sustained FGF-2 signaling regardless of pre-association.

Abstract

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.