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Ligand-induced Coupling versus Receptor Pre-association: Cellular automaton simulations of FGF-2 binding | Manoj Gopalakrishnan
; Kimberly Forsten-Williams
; Uwe C. Tauber
; | Date: |
18 Aug 2003 | Journal: | J. Theor. Biol. 227(2) 239-251 (2004) | Subject: | Statistical Mechanics; Soft Condensed Matter; Biological Physics; Subcellular Processes | cond-mat.stat-mech cond-mat.soft physics.bio-ph q-bio.SC | 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. | Source: | arXiv, cond-mat/0308348 | Services: | Forum | Review | PDF | Favorites |
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