Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 28, Issue 1, Pages 30-40Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E16-06-0459
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Funding
- National Institutes of Health [R01AR050501, R01AR048266, F30HL110447, T32GM008367]
- American Heart Association
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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.
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