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

Wan Hua Tan, Aleksander S Popel, Feilim Mac Gabhann

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2496-2510
Number of pages15
JournalCellular Signalling
Volume25
Issue number12
DOIs
Publication statusPublished - Dec 2013

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Keywords

  • Angiogenesis
  • Endothelial signaling
  • Mathematical model
  • Receptor tyrosine kinase
  • Systems biology
  • Trafficking

ASJC Scopus subject areas

  • Cell Biology

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