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MBC in Press, published online ahead of print January 28, 2009
Mol. Biol. Cell 10.1091/mbc.E08-10-1014

A more recent version of this article appeared on April 1, 2009
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Submitted on October 9, 2008
Revised on January 2, 2009
Accepted on January 22, 2009

Junctional Adhesion Molecule A (JAM-A) Interacts with Afadin and PDZ-GEF2 to Activate Rap1A, Regulate {beta}1 Integrin Levels, and Enhance Cell Migration

Eric A. Severson, Winston Y. Lee, Christopher T. Capaldo, Asma Nusrat, and Charles A. Parkos

Epithelial Pathobiology Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322

Monitoring Editor: Benjamin Margolis

Junctional adhesion molecule-A (JAM-A) is a transmembrane tight junction protein that has been shown to regulate barrier function and cell migration through incompletely understood mechanisms. We have previously demonstrated that JAM-A regulates cell migration by dimerization of the membrane-distal immunoglobulin-like loop and a C-terminal PDZ binding motif. Disruption of dimerization resulted in decreased epithelial cell migration secondary to diminished levels of {beta}1 integrin and active Rap1. Here we report that JAM-A is physically and functionally associated with the PDZ domain containing molecules Afadin and PDZ-GEF2, but not ZO-1, in epithelial cells and these interactions mediate outside-in signaling events. Both Afadin and PDZ-GEF2 colocalized and coimmunoprecipitated with JAM-A. Furthermore, association of PDZ-GEF2 with Afadin was dependent on the expression of JAM-A. Loss of JAM-A, Afadin or PDZ-GEF2, but not ZO-1 or PDZ-GEF1, similarly decreased cellular levels of activated Rap1, {beta}1 integrin protein and epithelial cell migration. The functional effects observed were secondary to decreased levels of Rap1A since knockdown of Rap1A, but not Rap1B, resulted in decreased {beta}1 integrin levels and reduced cell migration. These findings suggest that JAM-A dimerization facilitates formation of a complex with Afadin and PDZ-GEF2 that activates Rap1A, which regulates {beta}1 integrin levels and cell migration.

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




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Arterioscler Thromb Vasc Biol, August 1, 2009; 29(8): 1200 - 1206.
[Abstract] [Full Text] [PDF]


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