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Author Notes:

Address correspondence to: Charles A. Parkos (cparkos@emory.edu)

We thank Susan Voss for tissue culture expertise and assistance.

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Research Funding:

This study was supported by National Institutes of Health grants R01-DK72564, R01-DK61379, and R01-DK 79392 (to C.A.P.); DK-53202, DK-55679, and DK-59888 (to A.N.), DK-64399 (National Institutes of Health Digestive Disease Research Center tissue culture and morphology grant), and the Crohn's and Colitis Foundation of America (career development award to A.I.I.).

Cis-Dimerization Mediates Function of Junctional Adhesion Molecule A

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Journal Title:

Molecular Biology of the Cell

Volume:

Volume 19, Number 5

Publisher:

, Pages 1862-1872

Type of Work:

Article | Final Publisher PDF

Abstract:

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.

Copyright information:

© 2008 by The American Society for Cell Biology

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