P120-catenin regulates VE-cadherin endocytosis and degradation induced by the Kaposi sarcoma- Associated ubiquitin ligase K5

Benjamin A. Nanes, Cynthia M. Grimsley-Myers, Chantel M. Cadwell, Brian S. Robinson, Anthony M. Lowery, Peter A. Vincentd, Marina Mosunjac, Klaus Früh, Andrew P. Kowalczyk

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)30-40
Number of pages11
JournalMolecular biology of the cell
Volume28
Issue number1
DOIs
StatePublished - Jan 1 2017

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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