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, 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.
Xiao
Kanyan
K
Department of Dermatology, Emory University, Atlanta, GA 30322, USA.
Garner
Jennifer
J
Buckley
Kathleen M
KM
Vincent
Peter A
PA
Chiasson
Christine M
CM
Dejana
Elisabetta
E
Faundez
Victor
V
Kowalczyk
Andrew P
AP
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD; D015820:Cadherins / Q000502:physiology*; D051177:Catenins; D015815:Cell Adhesion Molecules / Q000502:physiology*; D002478:Cells, Cultured; D002966:Clathrin / Q000502:physiology*; D004705:Endocytosis / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000502:physiology*; D014168:Transferrin / Q000378:metabolism; D000095002:Delta Catenin; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D051177:Catenins; D015815:Cell Adhesion Molecules; D002966:Clathrin; D010750:Phosphoproteins; D014168:Transferrin; D000095002:Delta Catenin; D000099152:Cadherin 5; C000722347:CTNND1 protein, human