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

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journal contribution
posted on 15.11.2013, 00:00 by Emily Vandenbroucke St Amant, Mohammad Tauseef, Stephen M. Vogel, Xiao-Pei Gao, Dolly Mehta, Yulia Komarova, Asrar B. Malik
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 S879 in response to thrombin or LPS 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.

Funding

This work was supported by National Institutes of Health grants R01 HL 45638 and P01 HL 60678 to A.B.M, R01 HL103922 to Y. K, RO1 HL71794 to D.M. and by grant 10PRE4210048 from the American Heart Association Midwest affiliate to E.V.

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Publisher Statement

Post print version of article may differ from published version. The definitive version is available through American Heart Association at DOI: 10.1161/CIRCRESAHA.112.269654

Publisher

American Heart Association

Language

en_US

issn

1524-4571

Issue date

01/08/2012

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