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Cis-dimerization mediates function of junctional adhesion molecule A.

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 beta1 integrin protein but not mRNA levels. Further analyses of beta1 protein localization and expression after disruption of JAM-A dimerization suggested that internalization of beta1 integrin precedes degradation. A functional link between JAM-A and beta1 integrin was confirmed by restoration of cell migration to control levels after overexpression of beta1 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 beta1 integrin levels.

SUBMITTER: Severson EA

PROVIDER: S-EPMC2366836 | biostudies-other | 2008 May

REPOSITORIES: biostudies-other

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Cis-dimerization mediates function of junctional adhesion molecule A.

Severson Eric A EA Jiang Liangyong L Ivanov Andrei I AI Mandell Kenneth J KJ Nusrat Asma A Parkos Charles A CA

Molecular biology of the cell 20080213 5

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. Overexpr ...[more]

PMID: 18272784

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Dataset Information

Cis-dimerization mediates function of junctional adhesion molecule A.

Publications

Cis-dimerization mediates function of junctional adhesion molecule A.

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