Computational model of VEGFR2 pathway to ERK activation and modulation through receptor trafficking

WH Tan, AS Popel, F Mac Gabhann - Cellular signalling, 2013 - Elsevier
Cellular signalling, 2013Elsevier
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 …
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.
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