p120-catenin regulates VE-cadherin endocytosis and degradation induced by the Kaposi sarcoma-associated ubiquitin ligase K5

• Type of Material: Article
• Authors: Benjamin A. Nanes, Emory University; Cynthia Myers, Emory University; Chantel M. Cadwell, Emory University; Brian S. Robinson, Emory University; Anthony M. Lowery, Albany Medical College; Peter A. Vincent, Albany Medical College; Marina Mosunjac, Emory University; Klaus Frueh, Oregon Health and Science University; Andrew Kowalczyk, Emory University
• Language: English
• Date: 2017-01-01
• Publisher: American Society for Cell Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2017 Nanes et al.
• License: Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1091/mbc.E16-06-0459
• Title of Journal or Parent Work: Molecular Biology of the Cell
• ISSN: 1059-1524
• Volume: 28
• Issue: 1
• Start Page: 30
• End Page: 40
• Grant/Funding Information: This work was supported by grants from the National Institutes of Health (R01AR050501 and R01AR048266 to A.P.K.).; B.A.N. was supported by fellowships from the National Institutes of Health (F30HL110447 and T32GM008367) and the American Heart Association.
• Keywords: DOWN-REGULATION; HERPESVIRUS; Cell Biology; Science & Technology; P120 CATENIN; TYROSINE PHOSPHORYLATION; BETA-CATENIN; VASCULAR-PERMEABILITY; IMAGE-ANALYSIS; CELL-CELL ADHESION; Life Sciences & Biomedicine; ENDOTHELIAL ADHERENS JUNCTIONS; GROWTH-FACTOR
• Research Categories: Biology, Cell; Chemistry, Biochemistry

Abstract

Vascular endothelial (VE)-cadherin undergoes constitutive internalization driven by a unique endocytic motif that also serves as a p120-catenin (p120) binding site. p120 binding masks the motif, stabilizing the cadherin at cell junctions. This mechanism allows constitutive VE-cadherin endocytosis and recycling to contribute to adherens junction dynamics without resulting in junction disassembly. Here we identify an additional motif that drives VE-cadherin endocytosis and pathological junction disassembly associated with the endothelial-derived tumor Kaposi sarcoma. Human herpesvirus 8, which causes Kaposi sarcoma, expresses the March family ubiquitin ligase K5. We report that K5 targets two membrane-proximal VE-cadherin lysine residues for ubiquitination, driving endocytosis and down-regulation of the cadherin. K5-induced VE-cadherin endocytosis does not require the constitutive endocytic motif. However, K5-induced VE-cadherin endocytosis is associated with displacement of p120 from the cadherin, and p120 protects VE-cadherin from K5. Thus multiple context-dependent signals drive VE-cadherin endocytosis, but p120 binding to the cadherin juxtamembrane domain acts as a master regulator guarding cadherin stability.