Ankyrin-G Inhibits Endocytosis of Cadherin Dimers

• Type of Material: Article
• Authors: Chantel M. Cadwell, Emory University; Paul M. Jenkins, Duke University; Vann Bennett, Duke University; Andrew Kowalczyk, Emory University
• Language: English
• Date: 2016-01-08
• Publisher: American Society for Biochemistry and Molecular Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1074/jbc.M115.648386
• Title of Journal or Parent Work: Journal of Biological Chemistry
• ISSN: 0021-9258
• Volume: 291
• Issue: 2
• Start Page: 691
• End Page: 704
• Grant/Funding Information: This work was supported by National Institutes of Health Grants RO1AR050501 and RO1AR048266 (to A. P.K.).
• Keywords: INTERNALIZATION; MICROVASCULAR ENDOTHELIAL-CELLS; P120-CATENIN; ADHERENS JUNCTIONS; ADHESION; EPITHELIAL-CELLS; Science & Technology; Life Sciences & Biomedicine; Biochemistry & Molecular Biology; ALPHA-CATENIN; VASCULAR-PERMEABILITY; P120 CATENIN; VE-CADHERIN
• Research Categories: Health Sciences, Oncology; Biology, Cell; Chemistry, Biochemistry

Abstract

Dynamic regulation of endothelial cell adhesion is central to vascular development and maintenance. Furthermore, altered endothelial adhesion is implicated in numerous diseases. Therefore, normal vascular patterning and maintenance require tight regulation of endothelial cell adhesion dynamics. However, the mechanisms that control junctional plasticity are not fully understood. Vascular endothelial cadherin (VE-cadherin) is an adhesive protein found in adherens junctions of endothelial cells. VE-cadherin mediates adhesion through trans interactions formed by its extracellular domain. Trans binding is followed by cis interactions that laterally cluster the cadherin in junctions. VE-cadherin is linked to the actin cytoskeleton through cytoplasmic interactions with β- and α-catenin, which serve to increase adhesive strength. Furthermore, p120-catenin binds to the cytoplasmic tail of cadherin and stabilizes it at the plasma membrane. Here we report that induced cis dimerization of VE-cadherin inhibits endocytosis independent of both p120 binding and trans interactions. However, we find that ankyrin-G, a protein that links membrane proteins to the spectrin- actin cytoskeleton, associates with VE-cadherin and inhibits its endocytosis. Ankyrin-G inhibits VE-cadherin endocytosis independent of p120 binding. We propose a model in which ankyrin-G associates with and inhibits the endocytosis of VEcadherin cis dimers. Our findings support a novel mechanism for regulation of VE-cadherin endocytosis through ankyrin association with cadherin engaged in lateral interactions.