ArticlePloS one2013
Computational Model of Gab1/2-Dependent VEGFR2 Pathway to Akt Activation.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 43 citations in OpenAlex.
- Vascular endothelial generating factor pathway in ovarian cancer.Journal of ovarian research · 2025Review
- Quantification of surface-localized and total oxytocin receptor in myometrial smooth muscle cells.Heliyon · 2024Article
- Trafficking dynamics of VEGFR1, VEGFR2, and NRP1 in human endothelial cells.PLoS computational biology · 2024Article
- Structural mapping of PEAK pseudokinase interactions identifies 14-3-3 as a molecular switch for PEAK3 signaling.Nature communications · 2023Article
- Targeting SHP2 phosphatase in hematological malignancies.Expert opinion on therapeutic targets · 2022Review
- Strategies to overcome drug resistance using SHP2 inhibitors.Acta pharmaceutica Sinica. B · 2021Review
- ERK and Akt exhibit distinct signaling responses following stimulation by pro-angiogenic factors.Cell communication and signaling : CCS · 2020Article
- Mathematical Model Predicts Effective Strategies to Inhibit VEGF-eNOS Signaling.Journal of clinical medicine · 2020Article
- Short-term cellular memory tunes the signaling responses of the chemokine receptor CXCR4.Science signaling · 2019Article
- Crosstalk in transition: the translocation of Akt.Journal of mathematical biology · 2019Article
- Mechanistic insight into activation of MAPK signaling by pro-angiogenic factors.BMC systems biology · 2018Article
- Computational modeling of synergistic interaction between αVβ3 integrin and VEGFR2 in endothelial cells: Implications for the mechanism of action of angiogenesis-modulating integrin-binding peptides.Journal of theoretical biology · 2018Article
- Computer Simulation of TSP1 Inhibition of VEGF-Akt-eNOS: An Angiogenesis Triple Threat.Frontiers in physiology · 2018Article
- VEGFR1 promotes cell migration and proliferation through PLCγ and PI3K pathways.NPJ systems biology and applications · 2018Article
- Effects of endothelial cell proliferation and migration rates in a computational model of sprouting angiogenesis.Scientific reports · 2016Article
- Gab2 facilitates epithelial-to-mesenchymal transition via the MEK/ERK/MMP signaling in colorectal cancer.Journal of experimental & clinical cancer research : CR · 2016Article
- Site-Specific Phosphorylation of VEGFR2 Is Mediated by Receptor Trafficking: Insights from a Computational Model.PLoS computational biology · 2015Article
- Systems biology of the microvasculature.Integrative biology : quantitative biosciences from nano to macro · 2015Review
- Analytical reduction of combinatorial complexity arising from multiple protein modification sites.Journal of the Royal Society, Interface · 2015Article
- Computational systems biology approaches to anti-angiogenic cancer therapeutics.Drug discovery today · 2015Review
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.