Protein kinase C modifications of VE-cadherin, p120, and beta-catenin contribute to endothelial barrier dysregulation induced by thrombin
| Autor: | Konstantoulaki, M., Kouklis, P., Malik, A. B. |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2003 |
| Předmět: |
Thrombin/*pharmacology
Pulmonary Artery/*physiology Cell Membrane/drug effects/physiology Alkaloids Cadherins/*metabolism Antigens CD Humans Cells Cultured beta Catenin Carbazoles/pharmacology Benzophenanthridines Enzyme Inhibitors/pharmacology Endothelium Vascular/cytology/drug effects/*physiology Cytoskeletal Proteins/*metabolism Indoles/pharmacology Phosphoproteins/*metabolism Catenins Mesylates/pharmacology Kinetics Pyrroles/pharmacology Trans-Activators/*metabolism Cell Adhesion/drug effects/physiology Protein Kinase C/*metabolism Phenanthridines/pharmacology Protein Processing Post-Translational Cell Adhesion Molecules/*metabolism |
| Popis: | The adherens junction is a multiprotein complex consisting of the transmembrane vascular endothelial cadherin (VEC) and cytoplasmic catenins (p120, beta-catenin, plakoglobin, alpha-catenin) responsible for the maintenance of endothelial barrier function. Junctional disassembly and modifications in cadherin/catenin complex lead to increased paracellular permeability of the endothelial barrier. However, the mechanisms of junctional disassembly remain unclear. In this study, we used the proinflammatory mediator thrombin to compromise the barrier function and test the hypothesis that phosphorylation-induced alterations of VEC, beta-catenin, and p120 regulate junction disassembly and mediate the increased endothelial permeability response. The study showed that thrombin induced dephosphorylation of VEC, which is coupled to disassembly of cell-cell contacts, but VEC remained in aggregates at the plasma membrane. The cytoplasmic catenins dissociated from the VEC cytoplasmic domain in thin membrane projections formed in interendothelial gaps. We also showed that thrombin induced dephosphorylation of beta-catenin and phosphorylation of p120. Thrombin-induced interendothelial gap formation and increased endothelial permeability were blocked by protein kinase C inhibition using chelerythrine and Go-6976 but not by LY-379196. Chelerythrine also prevented thrombin-induced phosphorylation changes of the cadherin/catenin complex. Thus the present study links posttranslational modifications of VEC, beta-catenin, and p120 to the mechanism of thrombin-induced increase in endothelial permeability. Am J Physiol Lung Cell Mol Physiol |
| Databáze: | OpenAIRE |
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