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Vol. 16, Issue 11, 5141-5151, November 2005
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* Department of Dermatology, Emory University, Atlanta, GA 30322;
|| Department of Cell Biology, Emory University, Atlanta, GA 30322;
FIRC Institute of Molecular Oncology, Department of Biomolecular and Biotechnological Sciences, University of Milan, Milan 20139, Italy;
Graduate Program in Biochemistry, Cell, and Developmental Biology, Emory University, Atlanta, GA 30322; and
The Center for Cardiovascular Sciences, Albany Medical College, Albany, NY 12208
Submitted May 19, 2005;
Revised July 11, 2005;
Accepted August 15, 2005
Monitoring Editor: M. Bishr Omary
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.
Abbreviations used: IL-2R, interleukin 2 receptor; MEC, microvascular endothelial cell; p120: p120-catenin.
Address correspondence to: Andrew P. Kowalczyk (akowalc{at}emory.edu).
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