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Xiao, K. et al. p120-catenin regulates clathrin-dependent endocytosis of VE-cadherin. Mol. Biol. Cell 16, 5141-5151

Department of Dermatology, Emory University, Atlanta, GA 30322, USA.
Molecular Biology of the Cell (Impact Factor: 4.55). 12/2005; 16(11):5141-51. DOI: 10.1091/mbc.E05-05-0440
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ABSTRACT 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.

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    • "In endothelial cells, TNFα induces hyperpermeability in part by tyrosine phosphorylation of VE-cadherin (Y658) followed by its internalization and degradation.[10] [11] Tyrosine phosphorylation of VE-cadherin interrupts its association with p120-catenin, an association that is barrier protective in that p120-catenin promotes VEcadherin retention at the plasma membrane.[12] It has been established that TNFα induces activation of the Src-family kinase Fyn which targets VE-cadherin and mediates its internalization in human lung endothelia.[10] "
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    Biochemical and Biophysical Research Communications 11/2014; · 2.28 Impact Factor
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    • "In endothelial cells, TNFa induces hyperpermeability in part by tyrosine phosphorylation of VE-cadherin (Y658) followed by its internalization and degradation [10] [11]. Tyrosine phosphorylation of VE-cadherin interrupts its association with p120-catenin, an association that is barrier protective in that p120-catenin promotes VE-cadherin retention at the plasma membrane [12]. It has been established that TNFa induces activation of the Src-family kinase Fyn which targets VE-cadherin and mediates its internalization in human lung endothelia [10]. "
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    • "Previous studies have suggested that the expression of cadherin at the plasma membrane and AJs is determined by endocytosis [10] and that the clathrin-mediated endocytosis pathway is generally accepted to be responsible for the internalization of VE-cad and the regulation of hyperpermeability [12], [13]. For example, vascular endothelial growth factor (VEGF)-induced vascular hyperpermeability and the internalization of VE-cad is clathrin-mediated [14]. "
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