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MBC in Press, published online ahead of print February 13, 2008
Mol. Biol. Cell 10.1091/mbc.E07-09-0869

A more recent version of this article appeared on May 1, 2008
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Submitted on September 6, 2007
Revised on January 15, 2008
Accepted on February 6, 2008

Cis-dimerization Mediates Function of Junctional Adhesion Molecule A

Eric A. Severson, Liangyong Jiang, Andrei I. Ivanov, Kenneth J. Mandell, Asma Nusrat, and Charles A. Parkos

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

Monitoring Editor: M. Bishr Omary

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. While 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 {beta}1 integrin protein but not mRNA levels. Further analyses of {beta}1 protein localization and expression after disruption of JAM-A dimerization suggested that internalization of {beta}1 integrin precedes degradation. A functional link between JAM-A and {beta}1 integrin was confirmed by restoration of cell migration to control levels after overexpression of {beta}1 integrin in JAM-A dimerization-defective cells. Lastly, we show that the functional effects of JAM dimerization require its carboxy-terminal PDZ binding motif. These results suggest that dimerization of JAM-A regulates cell migration and adhesion through indirect mechanisms involving post-transcriptional control of {beta}1 integrin levels.

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






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