Expression of junctional adhesion molecule-A prevents spontaneous and random motility

J Cell Sci. 2005 Feb 1;118(Pt 3):623-32. doi: 10.1242/jcs.01661. Epub 2005 Jan 18.

Abstract

Junctional adhesion molecule-A (JAM-A) is a cell-surface glycoprotein that localizes to intercellular junctions and associates with intracellular proteins via PSD95-Dlg-ZO1-binding residues. To define the functional consequences of JAM-A expression, we have produced endothelial cells from JAM-A-deficient mice. We report here that the absence of JAM-A enhanced spontaneous and random motility. In turn, the enhanced motility of JAM-A-negative cells was abrogated either on transfection of exogenous JAM-A or on treatment with inhibitors of glycogen synthase kinase-3beta (GSK-3beta). In addition, in JAM-A-positive cells, motility was enhanced on inactivation of protein kinase Czeta (PKCzeta), which is an inhibitor of GSK-3beta. Although these findings suggested that JAM-A might inhibit GSK-3beta, we found that expression per se of JAM-A did not change the levels of inactive GSK-3beta. Thus, JAM-A expression may regulate effectors of motility that are also downstream of the PKCzeta/GSK-3beta axis. In support of this view, we found that JAM-A absence increased the number of actin-containing protrusions, reduced the stability of microtubules and impaired the formation of focal adhesions. Notably, all the functional consequences of JAM-A absence were reversed either on treatment with GSK-3beta inhibitors or on transfection of full-length JAM-A, but not on transfection of a JAM-A deletion mutant devoid of the PSD95-Dlg-ZO1-binding residues. Thus, by regulating cytoskeletal and adhesive structures, JAM-A expression prevents cell motility, probably in a PSD95-Dlg-ZO1-dependent manner.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism
  • Cell Adhesion Molecules / physiology*
  • Cell Communication / physiology
  • Cell Line, Transformed
  • Cell Movement / drug effects
  • Cell Movement / physiology*
  • Cell Surface Extensions / metabolism
  • Endothelial Cells / cytology*
  • Endothelial Cells / metabolism
  • Enzyme Inhibitors / pharmacology
  • Focal Adhesions / metabolism
  • Gene Expression
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Indoles / pharmacology
  • Lithium / pharmacology
  • Maleimides / pharmacology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Microtubules / metabolism
  • Phosphorylation / drug effects
  • Protein Kinase C / antagonists & inhibitors
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Receptors, Cell Surface / physiology*

Substances

  • Cell Adhesion Molecules
  • Enzyme Inhibitors
  • F11r protein, mouse
  • Indoles
  • Maleimides
  • Membrane Proteins
  • Receptors, Cell Surface
  • SB 216763
  • Lithium
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • protein kinase C zeta
  • Protein Kinase C
  • Glycogen Synthase Kinase 3