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Vol. 19, Issue 5, 1862-1872, May 2008

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Cis-Dimerization Mediates Function of Junctional Adhesion Molecule A

Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA 30322

Submitted September 6, 2007; Revised January 15, 2008; Accepted February 6, 2008
Monitoring Editor: M. Bishr Omary

Junctional adhesion molecule-A (JAM-A) is a transmembrane component of tight junctions that has been proposed to play a role in regulating epithelial cell adhesion and migration, yet mechanistic structure–function studies are lacking. Although biochemical and structural studies indicate that JAM-A forms cis-homodimers, the functional significance of dimerization is unclear. Here, we report the effects of cis-dimerization–defective JAM-A mutants on epithelial cell migration and adhesion. Overexpression of dimerization-defective JAM-A mutants in 293T cells inhibited cell spreading and migration across permeable filters. Similar inhibition was observed with using dimerization-blocking antibodies. Analyses of cells expressing the JAM-A dimerization-defective mutant proteins revealed diminished β1 integrin protein but not mRNA levels. Further analyses of β1 protein localization and expression after disruption of JAM-A dimerization suggested that internalization of β1 integrin precedes degradation. A functional link between JAM-A and β1 integrin was confirmed by restoration of cell migration to control levels after overexpression of β1 integrin in JAM-A dimerization-defective cells. Last, we show that the functional effects of JAM dimerization require its carboxy-terminal postsynaptic density 95/disc-large/zonula occludins-1 binding motif. These results suggest that dimerization of JAM-A regulates cell migration and adhesion through indirect mechanisms involving posttranscriptional control of β1 integrin levels.

Address correspondence to: Charles A. Parkos (cparkos{at}emory.edu)

Abbreviations used: 6163, dimerization-defective JAM-A mutant E61A/K63A; DL1, dimerization-defective JAM-A mutant with deletion of the distal most immunoglobulin-like loop; FA, focal adhesion; JAM-A, junctional adhesion molecule A; QRT-PCR, quantitative real-time reverse transcription-polymerase chain reaction analysis.