A reaction-diffusion model of basic fibroblast growth factor interactions with cell surface receptors.
Basic fibroblast growth factor (FGF-2) is a potent angiogenic growth factor involved in the development of diseases such as cancer, atherosclerosis, and heart and limb ischemia, as well as normal wound healing and tissue development. Despite being one of the most heavily studied angiogenic growth factors, the binding kinetics and signaling pathways of FGF-2 are still incompletely understood. In this study, we address the role of the low-affinity heparan sulfate proteoglycans (HSPGs), the identity of the minimal signaling complex leading to FGF-2 activity, and the importance of FGF-2 dimerization using a mathematical model of FGF-2 diffusion and ligand-receptor binding. Unique model features include the degradation of internalized cell surface species, the binding of a second FGF-2 ligand to a high-affinity FGF receptor (FGFR), and the dimerization of FGF-2 ligands. All experimentally determined reaction rates and diffusivity values are scaled to 37 degrees C. Our model results suggest that FGF-2-induced cellular response is the result of a temporal combination of triads (FGF-2/HSPG/FGFR complexes), double triads (2 FGF-2/HSPG/FGFR complexes), and FGF-2-bound HSPGs (FGF-2/HSPG complexes). Moreover, ligand dimerization is shown to potentially regulate FGF-2 activity by shifting the distribution of signaling complexes from the less stable triads to the more stable double triads.
Filion
Renee J
RJ
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Popel
Aleksander S
AS
D000818:Animals; D041702:BALB 3T3 Cells; D001665:Binding Sites; D003198:Computer Simulation; D004058:Diffusion; D019281:Dimerization; D016222:Fibroblast Growth Factor 2 / Q000737:chemistry* / Q000378:metabolism*; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D046911:Macromolecular Substances; D051379:Mice; D008954:Models, Biological; D008956:Models, Chemical; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013696:Temperature
D019812:Heparan Sulfate Proteoglycans; D046911:Macromolecular Substances; D011956:Receptors, Cell Surface; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2