PECAM-1 Affects GSK-3-Mediated -Catenin Phosphorylation and Degradation

Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) regulates a variety of endothelial and im-mune cell biological responses. PECAM-1-null miceexhibit prolonged and increased permeability afterinflammatory insults. We observed that in PECAM-1-null endothelial cells (ECs), -catenin remained ty-rosine phosphorylated, coinciding with a sustainedincrease in permeability. Src homology 2 domaincontaining phosphatase 2 (SHP-2) association with -catenin was diminished in PECAM-1-null ECs, sug-gesting that lack of PECAM-1 inhibits the ability of thisadherens junction component to become dephospho-rylated, promoting a sustained increase in permeabil-ity. -Catenin/Glycogen synthase kinase 3 (GSK-3 )associationand -cateninserinephosphorylationlev-els were increased and -catenin expression levelswere reduced in PECAM-1-null ECs. Glycogen syn-thase kinase 3 (GSK-3 ) serine phosphorylation (in-activation) was blunted in PECAM-1-null ECs after his-tamine treatment or shear stress. Our data suggestthat PECAM-1 serves as a critical dynamic regulator ofendothelial barrier permeability. On stimulation by avasoactive substance or shear stress, PECAM-1 be-came tyrosine phosphorylated, enabling recruitmentof SHP-2 and tyrosine-phosphorylated -catenin to itscytoplasmic domain, facilitating dephosphorylationof -catenin, and allowing reconstitution of adherensjunctions. In addition, PECAM-1 modulated the levelsof -catenin by regulating the activity of GSK-3 ,which in turn affected the serine phosphorylation of -catenin and its proteosomal degradation, affectingthe ability of the cell to reform adherens junctions ina timely fashion.