PECAM-1 affects GSK-3beta-mediated beta-catenin phosphorylation and degradation.
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), beta-catenin remained tyrosine phosphorylated, coinciding with a sustained increase in permeability. Src homology 2 domain containing phosphatase 2 (SHP-2) association with beta-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. beta-Catenin/Glycogen synthase kinase 3 (GSK-3beta) association and beta-catenin serine phosphorylation levels were increased and beta-catenin expression levels were reduced in PECAM-1-null ECs. Glycogen synthase kinase 3 (GSK-3beta) 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 beta-catenin to its cytoplasmic domain, facilitating dephosphorylation of beta-catenin, and allowing reconstitution of adherens junctions. In addition, PECAM-1 modulated the levels of beta-catenin by regulating the activity of GSK-3beta, which in turn affected the serine phosphorylation of beta-catenin and its proteosomal degradation, affecting the ability of the cell to reform adherens junctions in a timely fashion.
Biswas
Purba
P
Department of Pathology, Yale University School of Medicine, 310 Cedar St., Lauder Hall, Rm. L115, New Haven, CT 06520, USA.
Canosa
Sandra
S
Schoenfeld
David
D
Schoenfeld
Jonathan
J
Li
Puyau
P
Cheas
Lydia C
LC
Zhang
Jin
J
Cordova
Alfredo
A
Sumpio
Bauer
B
Madri
Joseph A
JA
D000818:Animals; D015153:Blotting, Western; D002199:Capillary Permeability / Q000502:physiology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006632:Histamine / Q000494:pharmacology; D018494:Histamine Agents / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000187:drug effects / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011968:Receptors, Histamine / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism*
D018494:Histamine Agents; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011968:Receptors, Histamine; D051176:beta Catenin; D006632:Histamine; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3