Jin, Y., Ding, Y., Richards, M. et al. Tyrosine-protein kinase Yes controls endothelial junctional plasticity and barrier integrity by regulating VE-cadherin phosphorylation and endocytosis. Nat Cardiovasc Res 1, 1156–1173 (2022). https://doi.org/10.1038/s44161-022-00172-z
Tyrosine-protein kinase Yes controls endothelial junctional plasticity and barrier integrity by regulating VE-cadherin phosphorylation and endocytosis
|Author:||Jin, Yi1; Ding, Yindi1; Richards, Mark1;|
1Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck, Beijer and SciLifeLab Laboratory, Uppsala, Sweden
2Oulu Centre for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland
3Max Delbrück Center for Molecular Medicine, Berlin, Germany
4DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
5Charité – Universitätsmedizin Berlin, Berlin, Germany
6Molecular Medicine and Gene Therapy, Lund Stem Cell Centre, Lund University, Lund, Sweden
7Institute for Molecular Bioscience, Division of Cell and Developmental Biology, The University of Queensland, Brisbane, Queensland, Australia
8Instituto de Medicina Molecular - João lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
9Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
10Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany
11Centre for Medical Informatics, Usher Institute, The University of Edinburgh, Edinburgh, UK
12The Bayes Centre, The University of Edinburgh, Edinburgh, UK
13Universidade Católica Portuguesa, Católica Medical School, Católica Biomedical Research Centre, Lisbon, Portugal
|Online Access:||PDF Full Text (PDF, 40 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe20231020140766
|Publish Date:|| 2023-10-20
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.
Nature cardiovascular research
|Pages:||1156 - 1173|
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
1182 Biochemistry, cell and molecular biology
This study was supported by the Swedish Research Council (2020-01349), the Knut and Alice Wallenberg foundation (KAW 2020.0057 and KAW 2019.0276), Fondation Leducq Transatlantic Network of Excellence Grant in Neurovascular Disease (17 CVD 03) to L.C.W., H.G., C.A.F. and M.B., Fundação para a Ciência e Tecnologia (PTDC/MED-PAT/31639/2017; CEECIND/04251/2017), European Research Council (679368) to C.A.F., Deutsche Forschungsgemeinschaft (KFO342, P2; CRC1450, B03) to D.V., the Academy of Finland (LE380986) and the Sigrid Jusélius Foundation to L.E.
Full source data for retinal EC distribution analysis is available on Zenodo (https://doi.org/10.5281/zenodo.7229061). Single-cell RNA-sequencing data generated from WT P6 and P10 retinas64 was obtained from the Sequence Read Archive (https://www.ncbi.nlm. nih.gov/sra), accession no. SRP322112. Additional data supporting the findings in this study are included in the main article and associated files.
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