title: p120-catenin regulates VE-cadherin endocytosis and degradation induced by the Kaposi sarcoma-associated ubiquitin ligase K5.
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.
authors: Graduate Program in Biochemistry, Cell, and Developmental Biology, Emory University School of Medicine, Atlanta, GA 30322.|Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322.
authors: Benjamin A
authors: BA
authors: Nanes
authors: Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322.
authors: Cynthia M
authors: CM
authors: Grimsley-Myers
authors: Graduate Program in Biochemistry, Cell, and Developmental Biology, Emory University School of Medicine, Atlanta, GA 30322.|Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322.
authors: Chantel M
authors: CM
authors: Cadwell
authors: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322.
authors: Brian S
authors: BS
authors: Robinson
authors: Center for Cardiovascular Sciences, Albany Medical College, Albany, NY 12208.
authors: Anthony M
authors: AM
authors: Lowery
authors: Center for Cardiovascular Sciences, Albany Medical College, Albany, NY 12208.
authors: Peter A
authors: PA
authors: Vincent
authors: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322.
authors: Marina
authors: M
authors: Mosunjac
authors: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006.
authors: Klaus
authors: K
authors: Früh
authors: Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322 akowalc@emory.edu.|Department of Dermatology, and, Emory University School of Medicine, Atlanta, GA 30322.|Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322.
authors: Andrew P
authors: AP
authors: Kowalczyk
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D001665:Binding Sites; D015820:Cadherins / Q000378:metabolism; D051177:Catenins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D015536:Down-Regulation; D004705:Endocytosis; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism* / Q000502:physiology; D008025:Ligases; D010750:Phosphoproteins / Q000378:metabolism; D061251:Primary Cell Culture; D011485:Protein Binding; D059748:Proteolysis; D012514:Sarcoma, Kaposi; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination; D000095002:Delta Catenin; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D051177:Catenins; D017874:Immediate-Early Proteins; D008025:Ligases; D010750:Phosphoproteins; D025801:Ubiquitin; D000095002:Delta Catenin; D000099152:Cadherin 5; C405867:K5 protein, Human herpesvirus 8; C000722347:CTNND1 protein, human