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(American Journal of Pathology. 2006;169:314-324.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.051112

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

Purba Biswas^*, Sandra Canosa^*, David Schoenfeld^*, Jonathan Schoenfeld^*, Puyau Li^*, Lydia C. Cheas, Jin Zhang^*, Alfredo Cordova, Bauer Sumpio and Joseph A. Madri^*

From the Departments of Pathology^* and Surgery, Yale University School of Medicine, New Haven, Connecticut; and the Department of Medicine, Brown University School of Medicine, Providence, Rhode Island

Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) regulates a variety of endothelial and immune cell biological responses. PECAM-1-null mice exhibit prolonged and increased permeability after inflammatory insults. We observed that in PECAM-1-null endothelial cells (ECs), ß-catenin remained tyrosine phosphorylated, coinciding with a sustained increase in permeability. Src homology 2 domain containing phosphatase 2 (SHP-2) association with ß-catenin was diminished in PECAM-1-null ECs, suggesting that lack of PECAM-1 inhibits the ability of this adherens junction component to become dephosphorylated, promoting a sustained increase in permeability. ß-Catenin/Glycogen synthase kinase 3 (GSK-3ß) association and ß-catenin serine phosphorylation levels were increased and ß-catenin expression levels were reduced in PECAM-1-null ECs. Glycogen synthase kinase 3 (GSK-3ß) serine phosphorylation (inactivation) was blunted in PECAM-1-null ECs after histamine treatment or shear stress. Our data suggest that PECAM-1 serves as a critical dynamic regulator of endothelial barrier permeability. On stimulation by a vasoactive substance or shear stress, PECAM-1 became tyrosine phosphorylated, enabling recruitment of SHP-2 and tyrosine-phosphorylated ß-catenin to its cytoplasmic domain, facilitating dephosphorylation of ß-catenin, and allowing reconstitution of adherens junctions. In addition, PECAM-1 modulated the levels of ß-catenin by regulating the activity of GSK-3ß, which in turn affected the serine phosphorylation of ß-catenin and its proteosomal degradation, affecting the ability of the cell to reform adherens junctions in a timely fashion.

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