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p120-catenin regulates leukocyte transmigration through an effect on VE-cadherin phosphorylation
P. Alcaide, G. Newton, S. Auerbach, , T.N. Mayadas, D.E. Golan, P. Yacono, P. Vincent, A. Kowalczyk, F.W. Luscinskas
Published in
PMID: 18641366
Volume: 112
Issue: 7
Pages: 2770 - 2779
Vascular endothelial-cadherin (VE-cad) is localized to adherens junctions at endothelial cell borders and forms a complex with α-, β-, γ-, and p120-catenins (p120). We previously showed that the VE-cad complex disassociates to form shortlived "gaps" during leukocyte transendothelial migration (TEM); however, whether these gaps are required for leukocyte TEM is not clear. Recently p120 has been shown to control VE-cad surface expression through endocytosis. We hypothesized that p120 regulates VE-cad surface expression, which would in turn have functional consequences for leukocyte transmigration. Here we show that endothelial cells transduced with an adenovirus expressing p120GFP fusion protein significantly increase VE-cad expression. Moreover, endothelial junctions with high p120GFP expression largely prevent VE-cad gap formation and neutrophil leukocyte TEM; if TEM occurs, the length of time required is prolonged. We find no evidence that VE-cad endocytosis plays a role in VE-cad gap formation and instead show that this process is regulated by changes in VE-cad phosphorylation. In fact, a nonphosphorylatable VE-cad mutant prevented TEM. In summary, our studies provide compelling evidence that VE-cad gap formation is required for leukocyte transmigration and identify p120 as a critical intracellular mediator of this process through its regulation of VE-cad expression at junctions. © 2008 by The American Society of Hematology.
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