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

作者：Yi Jin, Yindi Ding, Mark Richards, Mika Kaakinen, Wolfgang Giese, Elisabeth Baumann, Anna Szymborska, André Rosa, Sofia Nordling, Lilian Schimmel, Emir Bora Akmeriç, Andreia Pena, Emmanuel Nwadozi, Maria Jamalpour, Katrin Holstein, Miguel Sáinz‐Jaspeado, Miguel O. Bernabéu, Michael Welsh, Emma Gordon, Cláudio A. Franco, Dietmar Vestweber, Lauri Eklund, Holger Gerhardt, Lena Claesson‐Welsh · 发表于：Nature Cardiovascular Research · 年份：2022 · DOI：10.1038/s44161-022-00172-z · 被引用次数：56 · 研究领域：Hippo pathway signaling and YAP/TAZ、Barrier Structure and Function Studies、Caveolin-1 and cellular processes

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.