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. However, no detailed mass-action models of VEGF receptor signaling have been developed. We constructed and validated the first computational model of VEGFR2 trafficking and signaling, to study the opposing roles of Gab1 and Gab2 in regulation of Akt phosphorylation in VEGF-stimulated endothelial cells. Trafficking parameters were optimized against 5 previously published in vitro experiments, and the model was validated against six independent published datasets. The model showed agreement at several key nodes, involving scaffolding proteins Gab1, Gab2 and their complexes with Shp2. VEGFR2 recruitment of Gab1 is greater in magnitude, slower, and more sustained than that of Gab2. As Gab2 binds VEGFR2 complexes more transiently than Gab1, VEGFR2 complexes can recycle and continue to participate in other signaling pathways. Correspondingly, the simulation results show a log-linear relationship between a decrease in Akt phosphorylation and Gab1 knockdown while a linear relationship was observed between an increase in Akt phosphorylation and Gab2 knockdown. Global sensitivity analysis demonstrated the importance of initial-concentration ratios of antagonistic molecular species (Gab1/Gab2 and PI3K/Shp2) in determining Akt phosphorylation profiles. It also showed that kinetic parameters responsible for transient Gab2 binding affect the system at specific nodes. This model can be expanded to study multiple signaling contexts and receptor crosstalk and can form a basis for investigation of therapeutic approaches, such as tyrosine kinase inhibitors (TKIs), overexpression of key signaling proteins or knockdown experiments.
Highlights
Vascular Endothelial Growth Factor (VEGF) signal transduction in angiogenesis is a biologically significant process both for physiological development and for pathological conditions such as cancer, ocular diseases [1,2,3] and ischemic diseases [4]
Model Parameterization and Validation To understand the VEGF-induced impact of Gab1 and Gab2 on Akt phosphorylation, we developed a mass-action model to capture the signaling dynamics of key molecular species in the network
To test the validity of this selected parameter set, we employed the four remaining datasets used in Figure 2A–F (Chabot et al for phosphorylated VEGFR2 [35]; Schneeweis et al, Bruns et al and Zhang et al for phosphorylated Akt [37,38,39]), plus two additional time-course experimental datasets of intermediate signaling molecules (Laramee et al for Gab1 measurements and Caron et al for Gab2 measurements [22,23])
Summary
Vascular Endothelial Growth Factor (VEGF) signal transduction in angiogenesis is a biologically significant process both for physiological development and for pathological conditions such as cancer, ocular diseases [1,2,3] and ischemic diseases [4]. Approved antiangiogenic drugs have shown promise in the treatment of cancer and age-related macular degeneration. VEGF acts by binding to and activating receptor tyrosine kinases (VEGFRs) on cell surfaces. The multiple signaling pathways downstream of VEGF activation of VEGFRs are dynamic and heavily coupled; crosstalk interactions between them influence cell phenotypes. Computational models have the potential to describe, explain and predict VEGF signal transduction under various conditions, including quiescence, disease and drug interventions
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