PECAM-1 affects GSK-3beta-mediated beta-catenin phosphorylation and degradation

Am J Pathol. 2006 Jul;169(1):314-24. doi: 10.2353/ajpath.2006.051112.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Blotting, Western
  • Capillary Permeability / physiology*
  • Cells, Cultured
  • Endothelial Cells / metabolism*
  • Fluorescent Antibody Technique
  • Glycogen Synthase Kinase 3 / metabolism*
  • Glycogen Synthase Kinase 3 beta
  • Histamine / pharmacology
  • Histamine Agents / pharmacology
  • Humans
  • Mice
  • Models, Biological
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Platelet Endothelial Cell Adhesion Molecule-1 / drug effects
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Histamine / drug effects
  • Receptors, Histamine / metabolism
  • Signal Transduction / physiology*
  • beta Catenin / metabolism*

Substances

  • Histamine Agents
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Receptors, Histamine
  • beta Catenin
  • Histamine
  • Phosphatidylinositol 3-Kinases
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3