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

Autor: Jin Y; Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck, Beijer and SciLifeLab Laboratory, Uppsala, Sweden., Ding Y; Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck, Beijer and SciLifeLab Laboratory, Uppsala, Sweden., Richards M; Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck, Beijer and SciLifeLab Laboratory, Uppsala, Sweden., Kaakinen M; Oulu Centre for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland., Giese W; Max Delbrück Center for Molecular Medicine, Berlin, Germany.; DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany., Baumann E; Max Delbrück Center for Molecular Medicine, Berlin, Germany.; Charité - Universitatsmedizin Berlin, Berlin, Germany., Szymborska A; Max Delbrück Center for Molecular Medicine, Berlin, Germany.; DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany., Rosa A; Max Delbrück Center for Molecular Medicine, Berlin, Germany.; DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany., Nordling S; Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck, Beijer and SciLifeLab Laboratory, Uppsala, Sweden., Schimmel L; Institute for Molecular Bioscience, Division of Cell and Developmental Biology, The University of Queensland, Brisbane QLD, Australia., Akmeriç EB; Max Delbrück Center for Molecular Medicine, Berlin, Germany.; Charité - Universitatsmedizin Berlin, Berlin, Germany., Pena A; Instituto de Medicina Molecular - Joao lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Portugal., Nwadozi E; Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck, Beijer and SciLifeLab Laboratory, Uppsala, Sweden., Jamalpour M; Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden., Holstein K; Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany., Sáinz-Jaspeado M; Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck, Beijer and SciLifeLab Laboratory, Uppsala, Sweden., Bernabeu MO; Centre for Medical Informatics, Usher Institute, The University of Edinburgh, UK.; The Bayes Centre, The University of Edinburgh, UK., Welsh M; Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden., Gordon E; Institute for Molecular Bioscience, Division of Cell and Developmental Biology, The University of Queensland, Brisbane QLD, Australia., Franco CA; Instituto de Medicina Molecular - Joao lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Portugal.; Universidade Católica Portuguesa, Católica Medical School, Católica Biomedical Research Centre, Portugal., Vestweber D; Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany., Eklund L; Oulu Centre for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland., Gerhardt H; Max Delbrück Center for Molecular Medicine, Berlin, Germany.; DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany.; Charité - Universitatsmedizin Berlin, Berlin, Germany., Claesson-Welsh L; Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck, Beijer and SciLifeLab Laboratory, Uppsala, Sweden.
Jazyk: angličtina
Zdroj: Nature cardiovascular research [Nat Cardiovasc Res] 2022 Dec 07; Vol. 1 (12), pp. 1156-1173.
DOI: 10.1038/s44161-022-00172-z
Abstrakt: 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.
Competing Interests: Competing Interest Statement The authors declare no competing interests.
Databáze: MEDLINE
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