title: Computational model of VEGFR2 pathway to ERK activation and modulation through receptor trafficking.
abstract: Vascular Endothelial Growth Factor (VEGF) signal transduction is central to angiogenesis in development and in pathological conditions such as cancer, retinopathy and ischemic diseases. We constructed and validated a computational model of VEGFR2 trafficking and signaling, to study the role of receptor trafficking kinetics in modulating ERK phosphorylation in VEGF-stimulated endothelial cells. Trafficking parameters were optimized and validated against four previously published in vitro experiments. Based on these parameters, model simulations demonstrated interesting behaviors that may be highly relevant to understanding VEGF signaling in endothelial cells. First, at moderate VEGF doses, VEGFR2 phosphorylation and ERK phosphorylation are related in a log-linear fashion, with a stable duration of ERK activation; but with higher VEGF stimulation, phosphoERK becomes saturated, and its duration increases. Second, a large endosomal fraction of VEGFR2 makes the ERK activation reaction network less sensitive to perturbations in VEGF dosage. Third, extracellular-matrix-bound VEGF binds and activates VEGFR2, but by internalizing at a slower rate, matrix-bound VEGF-induced intracellular ERK phosphorylation is predicted to be greater in magnitude and more sustained, in agreement with experimental evidence. Fourth, different endothelial cell types appear to have different trafficking rates, which result in different levels of endosomal receptor localization and different ERK response profiles.
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University School of Medicine, 720 Rutland Ave., Baltimore, MD 21205, USA.
authors.forename: Wan Hua
authors.initials: WH
authors.lastname: Tan
authors.forename: Aleksander S
authors.initials: AS
authors.lastname: Popel
authors.forename: Feilim
authors.initials: F
authors.lastname: Mac Gabhann
mesh_terms: D003198:Computer Simulation; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D018919:Neovascularization, Physiologic; D021381:Protein Transport; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Angiogenesis; Endothelial signaling; Mathematical model; Receptor tyrosine kinase; Systems biology; Trafficking