title: Ankyrin-G Inhibits Endocytosis of Cadherin Dimers.
abstract: Dynamic regulation of endothelial cell adhesion is central to vascular development and maintenance. Furthermore, altered endothelial adhesion is implicated in numerous diseases. Therefore, normal vascular patterning and maintenance require tight regulation of endothelial cell adhesion dynamics. However, the mechanisms that control junctional plasticity are not fully understood. Vascular endothelial cadherin (VE-cadherin) is an adhesive protein found in adherens junctions of endothelial cells. VE-cadherin mediates adhesion through trans interactions formed by its extracellular domain. Trans binding is followed by cis interactions that laterally cluster the cadherin in junctions. VE-cadherin is linked to the actin cytoskeleton through cytoplasmic interactions with β- and α-catenin, which serve to increase adhesive strength. Furthermore, p120-catenin binds to the cytoplasmic tail of cadherin and stabilizes it at the plasma membrane. Here we report that induced cis dimerization of VE-cadherin inhibits endocytosis independent of both p120 binding and trans interactions. However, we find that ankyrin-G, a protein that links membrane proteins to the spectrin-actin cytoskeleton, associates with VE-cadherin and inhibits its endocytosis. Ankyrin-G inhibits VE-cadherin endocytosis independent of p120 binding. We propose a model in which ankyrin-G associates with and inhibits the endocytosis of VE-cadherin cis dimers. Our findings support a novel mechanism for regulation of VE-cadherin endocytosis through ankyrin association with cadherin engaged in lateral interactions.
authors.affiliation: From the Biochemistry, Cell, and Developmental Biology Graduate Program.
authors.forename: Chantel M
authors.initials: CM
authors.lastname: Cadwell
authors.affiliation: the Howard Hughes Medical Institute, Department of Biochemistry, Cell Biology, and Neurobiology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Jenkins
authors.affiliation: the Howard Hughes Medical Institute, Department of Biochemistry, Cell Biology, and Neurobiology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Vann
authors.initials: V
authors.lastname: Bennett
authors.affiliation: Department of Cell Biology, Department of Dermatology, and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322 and akowalc@emory.edu.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Kowalczyk
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D017487:Ankyrins / Q000378:metabolism*; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051177:Catenins / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D017124:Conserved Sequence; D004705:Endocytosis; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D055503:Protein Multimerization; D021381:Protein Transport; D014364:Tryptophan / Q000235:genetics; D000095002:Delta Catenin; D000099152:Cadherin 5
chemical_list: D017487:Ankyrins; D015703:Antigens, CD; D015820:Cadherins; D051177:Catenins; D050505:Mutant Proteins; D014364:Tryptophan; D000095002:Delta Catenin; D000099152:Cadherin 5; C490613:ANK3 protein, human
keywords: adaptor protein; adherens junction; adhesion; cadherin; endocytosis; endothelial cell