Ligand-induced coupling versus receptor pre-association: cellular automaton simulations of FGF-2 binding.
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.
Gopalakrishnan
Manoj
M
Department of Physics, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061-0435, USA. manoj@owl.phys.vt.edu
Forsten-Williams
Kimberly
K
Täuber
Uwe C
UC
D002468:Cell Physiological Phenomena; D003198:Computer Simulation; D019281:Dimerization; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D011485:Protein Binding; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D019812:Heparan Sulfate Proteoglycans; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2