• Circulation research · Aug 2012

    PKCα activation of p120-catenin serine 879 phospho-switch disassembles VE-cadherin junctions and disrupts vascular integrity.

    • Emily Vandenbroucke St Amant, Mohammad Tauseef, Stephen M Vogel, Xiao-Pei Gao, Dolly Mehta, Yulia A Komarova, and Asrar B Malik.
    • Department of Pharmacology, Center for Lung and Vascular Biology, University of Illinois College of Medicine, 835 S Wolcott Ave, M/C 86, Chicago, IL 60612, USA.
    • Circ. Res. 2012 Aug 31; 111 (6): 739-49.

    RationaleAdherens 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.ObjectiveTo 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 ResultsWe 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.ConclusionsPKCα 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.

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