Article: article from journal or magazin.
Caveolin-1 opens endothelial cell junctions by targeting catenins.
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
AIMS: A fundamental phenomenon in inflammation is the loss of endothelial barrier function, in which the opening of endothelial cell junctions plays a central role. However, the molecular mechanisms that ultimately open the cell junctions are largely unknown.¦METHODS AND RESULTS: Impedance spectroscopy, biochemistry, and morphology were used to investigate the role of caveolin-1 in the regulation of thrombin-induced opening of cell junctions in cultured human and mouse endothelial cells. Here, we demonstrate that the vascular endothelial (VE) cadherin/catenin complex targets caveolin-1 to endothelial cell junctions. Association of caveolin-1 with VE-cadherin/catenin complexes is essential for the barrier function decrease in response to the pro-inflammatory mediator thrombin, which causes a reorganization of the complex in a rope ladder-like pattern accompanied by a loss of junction-associated actin filaments. Mechanistically, we show that in response to thrombin stimulation the protease-activated receptor 1 (PAR-1) causes phosphorylation of caveolin-1, which increasingly associates with β- and γ-catenin. Consequently, the association of β- and γ-catenin with VE-cadherin is weakened, thus allowing junction reorganization and a decrease in barrier function. Thrombin-induced opening of cell junctions is lost in caveolin-1-knockout endothelial cells and after expression of a Y/F-caveolin-1 mutant but is completely reconstituted after expression of wild-type caveolin-1.¦CONCLUSION: Our results highlight the pivotal role of caveolin-1 in VE-cadherin-mediated cell adhesion via catenins and, in turn, in barrier function regulation.
Animals, Antigens, CD/metabolism, Base Sequence, CHO Cells, Cadherins/metabolism, Catenins/metabolism, Caveolin 1/deficiency, Caveolin 1/genetics, Cell Line, Cricetinae, Cricetulus, DNA Primers/genetics, Endothelial Cells/drug effects, Endothelial Cells/metabolism, Human Umbilical Vein Endothelial Cells, Humans, Intercellular Junctions/drug effects, Intercellular Junctions/metabolism, Mice, Mice, Knockout, Multiprotein Complexes/metabolism, Mutant Proteins/genetics, Mutant Proteins/metabolism, Thrombin/pharmacology
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