Afadin controls p120-catenin-ZO-1 interactions leading to endothelial barrier enhancement by oxidized phospholipids.

Abstract

Afadin is a novel regulator of epithelial cell junctions assembly. However, its role in the formation of endothelial cell junctions and the regulation of vascular permeability remains obscure. We previously described protective effects of oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) in the in vitro and in vivo models of lung endothelial barrier dysfunction and acute lung injury, which were mediated by Rac GTPase. This study examined a role of afadin in the OxPAPC-induced enhancement of interactions between adherens junctions and tight junctions as a novel mechanism of endothelial cell (EC) barrier preservation. OxPAPC induced Rap1-dependent afadin accumulation at the cell periphery and Rap1-dependent afadin interaction with adherens junction and tight junction proteins p120-catenin and ZO-1, respectively. Afadin knockdown using siRNA or ectopic expression of afadin mutant lacking Rap1 GTPase binding domain suppressed OxPAPC-induced EC barrier enhancement and abolished barrier protective effects of OxPAPC against thrombin-induced EC permeability. Afadin knockdown also abolished protective effects of OxPAPC against ventilator-induced lung injury in vivo. These results demonstrate for the first time a critical role of afadin in the regulation of vascular barrier function in vitro and in vivo via coordination of adherens junction-tight junction interactions.

• Authors: Anna A Birukova, Panfeng Fu, Tinghuai Wu, Oleksii Dubrovskyi, Nicolene Sarich, Valery Poroyko, Konstantin G Birukov
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 227 Issue 5 Pg. 1883-90 (May 2012) ISSN: 1097-4652 [Electronic] United States
• PMID: 21732359 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Wiley Periodicals, Inc.

Chemical References

• Catenins
• Membrane Proteins
• Microfilament Proteins
• Phospholipids
• Phosphoproteins
• TJP1 protein, human
• Tjp1 protein, mouse
• Zonula Occludens-1 Protein
• afadin
• rap1 GTP-Binding Proteins
• Delta Catenin

Topics

• Adherens Junctions (metabolism)
• Animals
• Catenins (metabolism)
• Cell Adhesion (physiology)
• Cell Line
• Cells, Cultured
• Cytoskeleton (metabolism)
• Endothelium (metabolism)
• Humans
• Lung (anatomy & histology, metabolism)
• Male
• Membrane Proteins (metabolism)
• Mice
• Mice, Inbred C57BL
• Microfilament Proteins (metabolism)
• Phospholipids (chemistry, metabolism)
• Phosphoproteins (metabolism)
• Tight Junctions (metabolism)
• Zonula Occludens-1 Protein
• rap1 GTP-Binding Proteins (genetics, metabolism)
• Delta Catenin