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

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.

An immunologist's guide to CD31 function in T-cells

“…2). In fact, by inducing dephosphorylation of b-catenin and enhancing anchorage of the vascular endothelial (VE)-cadherin complex, CD31 might contribute to the stabilization of endothelial adherens junctions (Biswas et al, 2006). Importantly, this role represents a further molecular mechanism for the enhanced extravasation of T-cells that has been observed following induction of EAE in CD31-deficient mice (Graesser et al, 2002).…”

The role of cytoskeleton in the regulation of vascular endothelial barrier function

“…Such recruitment allows for β-catenin dephosphorylation, ensuring reconstitution of adherence junctions [Biswas et al, 2006]. Besides, PECAM modulates the level of β-catenin by controlling glycogene synthase kinase β (GSKβ) activity and the rate of β-catenin degradation [Biswas et al, 2006]. Indeed, PECAM-1-null mice exhibit prolonged and increased permeability after inflammatory insults, proving unequivocally that PECAM plays positive role in maintaining barrier function [Graesser et al, 2002].…”

“…When found within adherence junctions, it acts to recruit β-and γ-catenins to cell contacts in phosphorylation-dependent manner [Biswas et al, 2005;Biswas et al, 2006]. Such recruitment allows for β-catenin dephosphorylation, ensuring reconstitution of adherence junctions [Biswas et al, 2006]. Besides, PECAM modulates the level of β-catenin by controlling glycogene synthase kinase β (GSKβ) activity and the rate of β-catenin degradation [Biswas et al, 2006].…”

“…One of them, PECAM, is thought to provide adhesion and serve as scaffolding molecule in several signaling pathways. When found within adherence junctions, it acts to recruit β-and γ-catenins to cell contacts in phosphorylation-dependent manner [Biswas et al, 2005;Biswas et al, 2006]. Such recruitment allows for β-catenin dephosphorylation, ensuring reconstitution of adherence junctions [Biswas et al, 2006].…”

Nrf2 as an Endothelial Mechanosensitive Transcription Factor

“…In this context, platelet EC adhesion molecule-1, a mechanosensitive membrane protein that is upregulated during inflammation, 87 may mediate not only NOX2-derived superoxide generation in response to disturbed FSS 88 but also glycogen synthase kinase-3β activation 89 leading to enhanced EC oxidative stress because of diminished Nrf2 activity. BTB and CNC homology 1 (Bach-1) is a Nrf2-regulated transcriptional repressor of a subset of ARE-regulated genes such as HO-1 39 and thus antagonizes the activator function of Nrf2.…”