RESEARCH ARTICLE Site-Specific Phosphorylation of VEGFR2 Is Mediated by Receptor Trafficking: Insights from a Computational Model

Matrix-binding isoforms and non-matrix-binding isoforms of vascular endothelial growth fac-tor (VEGF) are both capable of stimulating vascular remodeling, but the resulting blood ves-sel networks are structurally and functionally different. Here, we develop and validate a computational model of the binding of soluble and immobilized ligands to VEGF receptor 2 (VEGFR2), the endosomal trafficking of VEGFR2, and site-specific VEGFR2 tyrosine phos-phorylation to study differences in induced signaling between these VEGF isoforms. In cap-turing essential features of VEGFR2 signaling and trafficking, our model suggests that VEGFR2 trafficking parameters are largely consistent across multiple endothelial cell lines. Simulations demonstrate distinct localization of VEGFR2 phosphorylated on Y1175 and Y1214. This is the first model to clearly show that differences in site-specific VEGFR2 acti-vation when stimulated with immobilized VEGF compared to soluble VEGF can be ac-counted for by altered trafficking of VEGFR2 without an intrinsic difference in receptor activation. The model predicts that Neuropilin-1 can induce differences in the surface-to-in-ternal distribution of VEGFR2. Simulations also show that ligated VEGFR2 and phosphory