p120-Catenin regulates clathrin-dependent endocytosis of VE-cadherin

VE-cadherin is an adhesion molecule critical to vascular barrier function and angiogenesis. VE-cadherin expression levels are regulated by p120 catenin, which prevents lysosomal degradation of cadherins by unknown mechanisms. To test whether the VE-cadherin cytoplasmic domain mediates endocytosis, a...

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Bibliographic Details
Published in:Molecular biology of the cell 2005-11, Vol.16 (11), p.5141-5151
Main Authors: Xiao, Kanyan, Garner, Jennifer, Buckley, Kathleen M, Vincent, Peter A, Chiasson, Christine M, Dejana, Elisabetta, Faundez, Victor, Kowalczyk, Andrew P
Format: Article
Language:English
Subjects:
Adolescent
Adult
Aged
Aged, 80 and over
Antigens, CD
Cadherins - physiology
Catenins
Cell Adhesion Molecules - physiology
Cells, Cultured
Clathrin - physiology
Endocytosis - drug effects
Endocytosis - physiology
Humans
Male
Middle Aged
Phosphoproteins - physiology
Transferrin - metabolism
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Summary:VE-cadherin is an adhesion molecule critical to vascular barrier function and angiogenesis. VE-cadherin expression levels are regulated by p120 catenin, which prevents lysosomal degradation of cadherins by unknown mechanisms. To test whether the VE-cadherin cytoplasmic domain mediates endocytosis, and to elucidate the nature of the endocytic machinery involved, the VE-cadherin tail was fused to the interleukin (IL)-2 receptor (IL-2R) extracellular domain. Internalization assays demonstrated that the VE-cadherin tail dramatically increased endocytosis of the IL-2R in a clathrin-dependent manner. Interestingly, p120 inhibited VE-cadherin endocytosis via a mechanism that required direct interactions between p120 and the VE-cadherin cytoplasmic tail. However, p120 did not inhibit transferrin internalization, demonstrating that p120 selectively regulates cadherin internalization rather than globally inhibiting clathrin-dependent endocytosis. Finally, cell surface labeling experiments in cells expressing green fluorescent protein-tagged p120 indicated that the VE-cadherin-p120 complex dissociates upon internalization. These results support a model in which the VE-cadherin tail mediates interactions with clathrin-dependent endocytic machinery, and this endocytic processing is inhibited by p120 binding to the cadherin tail. These findings suggest a novel mechanism by which a cytoplasmic binding partner for a transmembrane receptor can serve as a selective plasma membrane retention signal, thereby modulating the availability of the protein for endo-lysosomal processing.
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.E05-05-0440