Heterogeneity in VEGF Receptor-2 Mobility and Organization on the Endothelial Cell Surface Leads to Diverse Models of Activation by VEGF

• Published in: Cell reports (Cambridge) 2020-09, Vol.32 (13), p.108187-108187, Article 108187
• Main Authors: da Rocha-Azevedo, Bruno, Lee, Sungsoo, Dasgupta, Aparajita, Vega, Anthony R., de Oliveira, Luciana R., Kim, Tae, Kittisopikul, Mark, Malik, Zachariah A., Jaqaman, Khuloud
• Format: Article
• Language: English
• Subjects: angiogenesis; computational analysis; multi-scale; nanoscale; particle tracking; quantitative microscopy; single-molecule imaging; spatiotemporal; stochastic; VEGFR
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108187

The dynamic nanoscale organization of cell surface receptors plays an important role in signaling. We determine this organization and its relation to activation of VEGF receptor-2 (VEGFR-2), a critical receptor tyrosine kinase in endothelial cells (ECs), by combining single-molecule imaging of endogenous VEGFR-2 in live ECs with multiscale computational analysis. We find that surface VEGFR-2 can be mobile or exhibit restricted mobility and be monomeric or non-monomeric, with a complex interplay between the two. This basal heterogeneity results in heterogeneity in the sequence of steps leading to VEGFR-2 activation by VEGF. Specifically, we find that VEGF can bind to monomeric and non-monomeric VEGFR-2 and that, when binding to monomeric VEGFR-2, its effect on dimerization depends on the mobility of VEGFR-2. Our study highlights the dynamic and heterogeneous nature of cell surface receptor organization and the need for multiscale, single-molecule-based analysis to determine its relationship to receptor activation and signaling. [Display omitted] •VEGFR-2 exhibits motion and interaction heterogeneity on endothelial cell surface•The steps of VEGFR-2 activation by VEGF depend on the basal state of VEGFR-2•VEGF binds VEGFR-2 monomers and non-monomers on endothelial cell surface•The effect of VEGF on VEGFR-2 dimerization varies by mobility of VEGFR-2 monomers da Rocha-Azevedo et al. show that VEGFR-2 exhibits mobility and interaction heterogeneity on the endothelial cell surface. The sequence of steps leading to VEGFR-2 activation by VEGF depends on the basal state of VEGFR-2. Thus, there is not one model but multiple co-existing models of VEGFR-2 activation by VEGF.