Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 19, Issue 5, Pages 1862-1872Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E07-09-0869
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Funding
- National Institutes of Health [R01-DK72564, R01-DK61379, R01-DK 79392, DK-53202, DK-55679, DK-59888]
- National Institutes of Health Digestive Disease Research Center [DK-64399]
- Crohn's and Colitis Foundation of America
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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 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. 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 beta 1 integrin levels.
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