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Tyrosine-protein kinase Yes controls endothelial junctional plasticity and barrier integrity by regulating VE-cadherin phosphorylation and endocytosis

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Item Type:Article
Title:Tyrosine-protein kinase Yes controls endothelial junctional plasticity and barrier integrity by regulating VE-cadherin phosphorylation and endocytosis
Creators Name:Jin, Y. and Ding, Y. and Richards, M. and Kaakinen, M. and Giese, W. and Baumann, E. and Szymborska, A. and Rosa, A. and Nordling, S. and Schimmel, L. and Akmeriç, E.B. and Pena, A. and Nwadozi, E. and Jamalpour, M. and Holstein, K. and Sáinz-Jaspeado, M. and Bernabeu, M.O. and Welsh, M. and Gordon, E. and Franco, C.A. and Vestweber, D. and Eklund, L. and Gerhardt, H. and Claesson-Welsh, L.
Abstract:Vascular endothelial (VE)-cadherin in endothelial adherens junctions is an essential component of the vascular barrier, critical for tissue homeostasis and implicated in diseases such as cancer and retinopathies. Inhibitors of Src cytoplasmic tyrosine kinase have been applied to suppress VE-cadherin tyrosine phosphorylation and prevent excessive leakage, edema and high interstitial pressure. Here we show that the Src-related Yes tyrosine kinase, rather than Src, is localized at endothelial cell (EC) junctions where it becomes activated in a flow-dependent manner. EC-specific Yes1 deletion suppresses VE-cadherin phosphorylation and arrests VE-cadherin at EC junctions. This is accompanied by loss of EC collective migration and exaggerated agonist-induced macromolecular leakage. Overexpression of Yes1 causes ectopic VE-cadherin phosphorylation, while vascular leakage is unaffected. In contrast, in EC-specific Src deficiency, VE-cadherin internalization is maintained and leakage is suppressed. In conclusion, Yes-mediated phosphorylation regulates constitutive VE-cadherin turnover, thereby maintaining endothelial junction plasticity and vascular integrity.
Keywords:Angiogenesis, Cadherins, Phosphorylation, Animals, Mice
Source:Nature Cardiovascular Research
ISSN:2731-0590
Publisher:Springer Nature
Volume:1
Page Range:1156–1173
Date:December 2022
Official Publication:https://doi.org/10.1038/s44161-022-00172-z

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