p120-catenin binding masks an endocytic signal conserved in classical cadherins.
p120-catenin (p120) binds to the cytoplasmic tails of classical cadherins and inhibits cadherin endocytosis. Although p120 regulation of cadherin internalization is thought to be important for adhesive junction dynamics, the mechanism by which p120 modulates cadherin endocytosis is unknown. In this paper, we identify a dual-function motif in classical cadherins consisting of three highly conserved acidic residues that alternately serve as a p120-binding interface and an endocytic signal. Mutation of this motif resulted in a cadherin variant that was both p120 uncoupled and resistant to endocytosis. In endothelial cells, in which dynamic changes in adhesion are important components of angiogenesis and inflammation, a vascular endothelial cadherin (VE-cadherin) mutant defective in endocytosis assembled normally into cell-cell junctions but potently suppressed cell migration in response to vascular endothelial growth factor. These results reveal the mechanistic basis by which p120 stabilizes cadherins and demonstrate that VE-cadherin endocytosis is crucial for endothelial cell migration in response to an angiogenic growth factor.
Graduate Program in Biochemistry, Cell, and Developmental Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Benjamin A
BA
Nanes
Christine
C
Chiasson-MacKenzie
Anthony M
AM
Lowery
Noboru
N
Ishiyama
Victor
V
Faundez
Mitsuhiko
M
Ikura
Peter A
PA
Vincent
Andrew P
AP
Kowalczyk
D022005:Adherens Junctions / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D019556:COS Cells; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D051177:Catenins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D002450:Cell Communication; D045744:Cell Line, Tumor; D002465:Cell Movement; D002522:Chlorocebus aethiops; D004705:Endocytosis; D042783:Endothelial Cells; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation; D009154:Mutation; D018919:Neovascularization, Physiologic; D011485:Protein Binding; D042442:Vascular Endothelial Growth Factors; D000095002:Delta Catenin; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D051177:Catenins; D042442:Vascular Endothelial Growth Factors; D000095002:Delta Catenin; D000099152:Cadherin 5