Article

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

University of Milan, Milano, Lombardy, Italy
Molecular Biology of the Cell (Impact Factor: 4.47). 12/2005; 16(11):5141-51. DOI: 10.1091/mbc.E05-05-0440
Source: PubMed

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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    • "We have previously shown that both BMPRI and BMPRII undergo clathrin-mediated endocytosis, but caveolin-dependent internalization was only observed for BMPRII (Hartung et al., 2006). It has been reported that VEcadherin is internalized via clathrin-coated pits by a p120-catenin- dependent mechanism (Xiao et al., 2005). Besides, VE-cadherin recruits caveolin-1 to endothelial cell junctions and phosphorylated caveolin-1 weakens VE-cadherin–catenin interactions and thus regulates endothelial barrier function (Kronstein et al., 2012). "
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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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    • "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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