p120-catenin regulates VE-cadherin endocytosis and degradation induced by the Kaposi sarcoma–associated ubiquitin ligase K5
| Autor: | Brian S. Robinson, Chantel M. Cadwell, Klaus Früh, Marina Mosunjac, Peter A. Vincent, Cynthia M. Grimsley-Myers, Anthony M. Lowery, Benjamin A. Nanes, Andrew P. Kowalczyk |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Delta Catenin animal structures Endocytic cycle Primary Cell Culture Down-Regulation Endocytosis Immediate-Early Proteins Adherens junction Ligases 03 medical and health sciences Ubiquitin Antigens CD Humans Molecular Biology Sarcoma Kaposi Binding Sites 030102 biochemistry & molecular biology biology Cadherin Cell Membrane Ubiquitination Endothelial Cells Catenins Cell Biology Articles Adherens Junctions Cadherins Phosphoproteins 3. Good health Ubiquitin ligase Cell biology 030104 developmental biology Cell Biology of Disease Catenin embryonic structures Proteolysis biology.protein VE-cadherin Protein Binding |
| Zdroj: | Molecular Biology of the Cell |
| ISSN: | 1939-4586 1059-1524 |
| Popis: | Endocytosis of VE-cadherin in response to the Kaposi sarcoma E3 ubiquitin ligase K5 is dependent on two membrane-proximal lysine residues but independent of a constitutive endocytosis motif. p120-catenin blocks endocytosis mediated by both motifs, demonstrating that p120 is a master regulator of multiple context-dependent endocytic signals. 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. |
| Databáze: | OpenAIRE |
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