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Context‐Specific Regulation of VEGF Receptor Signaling

Our objective is to build an integrated model of ligand‐receptor interactions, receptor trafficking, and site‐specific phosphorylation of vascular endothelial growth factor (VEGF) receptors; the model can account for the effects of altered ligand presentation and perturbations to receptor trafficking and regulatory proteins. We develop and validate computational models that include VEGF, VEGFR homo‐ and heterodimers, and the coreceptor Neuropilin‐1 (NRP1) presented in cis (expressed in same cell as VEGFRs) or trans (expressed on adjacent cells). Our simulations demonstrate distinct cellular localization of VEGFR2 phosphorylated on tyrosines 1175 and 1214, leading to proliferation and migration/branching, respectively. We show that altered VEGFR2 trafficking due to VEGF immobilization (e.g. to the extracellular matrix) is sufficient to mechanistically explain all available data on VEGFR2 phosphorylation after stimulation with immobilized VEGF, suggesting that the receptors do not undergo different conformational changes in response to matrix‐bound VEGF. Our model simulations incorporate regulation of VEGFR2 trafficking and site‐specific phosphorylation by NRP1. We also describe the mechanism behind prolonged activation of signaling downstream of VEGFR2 when NRP1 is presented in trans. Using this model, we identify perturbations of VEGFR2 trafficking, interactions with and presentation of Neuropilin‐1, and changes in expression or activity of phosphatases acting on VEGFR2 as key levers that alter how VEGF binding to VEGFR2 results in different coordinated patterns of multiple downstream signaling pathways.