TY - JOUR
T1 - Computational model of VEGFR2 pathway to ERK activation and modulation through receptor trafficking
AU - Tan, Wan Hua
AU - Popel, Aleksander S.
AU - Mac Gabhann, Feilim
N1 - Funding Information:
This work was supported by the National Institutes of Health (NIH) grants R01 HL101200 , R01 CA138264 , and U54 CA143868 (ASP) and R00 HL093219 (FMG). The authors thank David Noren and Dr. Gang Liu for useful discussions and critical comments.
PY - 2013/12
Y1 - 2013/12
N2 - 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.
AB - 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.
KW - Angiogenesis
KW - Endothelial signaling
KW - Mathematical model
KW - Receptor tyrosine kinase
KW - Systems biology
KW - Trafficking
UR - http://www.scopus.com/inward/record.url?scp=84884306439&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84884306439&partnerID=8YFLogxK
U2 - 10.1016/j.cellsig.2013.08.015
DO - 10.1016/j.cellsig.2013.08.015
M3 - Article
C2 - 23993967
AN - SCOPUS:84884306439
SN - 0898-6568
VL - 25
SP - 2496
EP - 2510
JO - Cellular Signalling
JF - Cellular Signalling
IS - 12
ER -