Hypoglycosylated E-cadherin promotes the assembly of tight junctions through the recruitment of PP2A to adherens junctions

Exp Cell Res. 2010 Jul 1;316(11):1871-84. doi: 10.1016/j.yexcr.2010.02.008. Epub 2010 Feb 13.

Abstract

Epithelial cell-cell adhesion is controlled by multiprotein complexes that include E-cadherin-mediated adherens junctions (AJs) and ZO-1-containing tight junctions (TJs). Previously, we reported that reduction of E-cadherin N-glycosylation in normal and cancer cells promoted stabilization of AJs through changes in the composition and cytoskeletal association of E-cadherin scaffolds. Here, we show that enhanced interaction of hypoglycosylated E-cadherin-containing AJs with protein phosphatase 2A (PP2A) represents a mechanism for promoting TJ assembly. In MDCK cells, attenuation of cellular N-glycosylation with siRNA to DPAGT1, the first gene in the N-glycosylation pathway, reduced N-glycosylation of surface E-cadherin and resulted in increased recruitment of stabilizing proteins gamma-catenin, alpha-catenin, vinculin and PP2A to AJs. Greater association of PP2A with AJs correlated with diminished binding of PP2A to ZO-1 and claudin-1 and with increased pools of serine-phosphorylated ZO-1 and claudin-1. More ZO-1 was found in complexes with occludin and claudin-1, and this corresponded to enhanced transepithelial resistance (TER), indicating physiological assembly of TJs. Similar maturation of AJs and TJs was detected after transfection of MDCK cells with the hypoglycosylated E-cadherin variant, V13. Our data indicate that E-cadherin N-glycans coordinate the maturity of AJs with the assembly of TJs by affecting the association of PP2A with these junctional complexes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adherens Junctions / metabolism*
  • Animals
  • Cadherins / chemistry*
  • Cadherins / metabolism*
  • Cell Adhesion / physiology
  • Cell Line
  • Claudin-1
  • Dogs
  • Glycosylation
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism
  • Models, Biological
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / metabolism
  • N-Acetylglucosaminyltransferases / antagonists & inhibitors
  • N-Acetylglucosaminyltransferases / genetics
  • Phosphoproteins / chemistry
  • Phosphoproteins / metabolism
  • Protein Binding
  • Protein Phosphatase 2 / metabolism*
  • Protein Stability
  • RNA, Small Interfering / genetics
  • Tight Junctions / metabolism*
  • Zonula Occludens-1 Protein

Substances

  • Cadherins
  • Claudin-1
  • Membrane Proteins
  • Multiprotein Complexes
  • Phosphoproteins
  • RNA, Small Interfering
  • Zonula Occludens-1 Protein
  • N-Acetylglucosaminyltransferases
  • dolichyl-phosphate alpha-N-acetylglucosaminyltransferase
  • Protein Phosphatase 2