PKCα Activation of p120-Catenin Serine 879 Phospho-Switch Disassembles VE-Cadherin Junctions and Disrupts Vascular Integrity

• Published in: Circulation research Vol. 111; no. 6; pp. 739 - 749
• Main Authors: Vandenbroucke St Amant, Emily, Tauseef, Mohammad, Vogel, Stephen M, Gao, Xiao-Pei, Mehta, Dolly, Komarova, Yulia A, Malik, Asrar B
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 31.08.2012; Lippincott Williams & Wilkins
• Subjects: Adherens Junctions - drug effects; Adherens Junctions - metabolism; Animals; Antigens, CD - metabolism; Biological and medical sciences; Cadherins - metabolism; Capillary Permeability - drug effects; Capillary Permeability - physiology; Catenins - genetics; Catenins - metabolism; Cells, Cultured; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Fundamental and applied biological sciences. Psychology; Humans; Immunoblotting; In Vitro Techniques; Lipopolysaccharides - pharmacology; Lung - blood supply; Lung - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microvessels - metabolism; Microvessels - physiology; Mutation; Phosphorylation; Protein Binding - drug effects; Protein Kinase C-alpha - genetics; Protein Kinase C-alpha - metabolism; Receptor, PAR-1 - metabolism; RNA Interference; Serine - genetics; Serine - metabolism; Thrombin - pharmacology; Vertebrates: cardiovascular system; Serine; Activation; Inflammation; Permeability; Cadherin; intercellular junctions; Endothelium; Signal transduction; Vertebrata; Mammalia; Aminoacid; Junction; Circulatory system; vascular permeability; Catenin
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.112.269654

RATIONALE:Adherens junctions (AJs) are the primary intercellular junctions in microvessels responsible for endothelial barrier function. Homophilic adhesion of vascular endothelial (VE) cadherin forms AJs, which are stabilized by binding of p120-catenin (p120). p120 dissociation from VE-cadherin results in loss of VE-cadherin homotypic interaction and AJ disassembly; however, the signaling mechanisms regulating p120 dissociation from VE-cadherin are not understood. OBJECTIVE:To address the mechanism of protein kinase C (PKC)-α function in increasing endothelial permeability, we determined the role of PKCα phosphorylation of p120 in mediating disruption of AJ integrity. METHODS AND RESULTS:We showed that PKCα phosphorylation of p120 at serine (S)879 in response to thrombin or lipopolysaccharide challenge reduced p120 binding affinity for VE-cadherin and mediated AJ disassembly secondary to VE-cadherin internalization. In studies in mouse lung vessels, expression of the phosphodeficient S879A-p120 mutant prevented the increase in vascular permeability induced by activation of the thrombin receptor PAR-1. CONCLUSIONS:PKCα phosphorylation of p120 at S879 is a critical phospho-switch mediating disassociation of p120 from VE-cadherin that results in AJ disassembly. Therefore, blocking PKCα-mediated p120 phosphorylation represents a novel targeted anti-inflammatory strategy to prevent disruption of vascular endothelial barrier function.