There is mounting evidence that cell surface receptor organization plays an important role in cell signaling. Little is known about the spatiotemporal organization of the receptor tyrosine kinase VEGFR2 (Vascular Endothelial Growth Factor Receptor 2) and its interaction partners in endothelial cells. Using quantitative single-molecule imaging and analysis, we found that VEGFR2 exhibits motion and interaction heterogeneity in its resting state, such that the sequence of steps leading to VEGFR2 activation by VEGF depends on the state of VEGFR2 at rest. Thus, there is not one model, but rather multiple co-existing models, of VEGFR2 activation by VEGF. In addition, we found that VEGFR2 exhibits localization heterogeneity in its resting state, with a subset of VEGFR2 molecules in the vicinity of focal adhesions. Novel conditional colocalization analysis revealed that this localization increases the chance of VEGFR2 to encounter its downstream effector TSAd, which in turn mediates signaling that regulates focal adhesion turnover upon VEGFR2 activation. These results suggest that the balance between the different signaling pathways downstream of VEGFR2 is partly regulated by its spatial organization. The links revealed by our studies between the spatiotemporal organization of VEGFR2 and its signaling are likely generalizable to other receptor tyrosine kinases, as the receptors of this family share many common features.

Quantitative analysis of receptor organization and signaling on the endothelial cell surface

ACS Spring 2022

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