Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 24, Issue 18, Pages 2849-2860Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E13-06-0298
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Funding
- National Institutes of Health [DK061379, DK072564, DK079392, DK59888, DK55679, DK064399, R37AI38296, P30CA68485, P60DK20593, R01AI76983]
- Crohn's and Colitis Foundation of America Career Development Award
- Deutsche Forschungsgemeinschaft [KFO274]
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Intestinal barrier function is regulated by epithelial tight junctions (TJs), structures that control paracellular permeability. Junctional adhesion molecule-A (JAM-A) is a TJ-associated protein that regulates barrier; however, mechanisms linking JAM-A to epithelial permeability are poorly understood. Here we report that JAM-A associates directly with ZO-2 and indirectly with afadin, and this complex, along with PDZ-GEF1, activates the small GTPase Rap2c. Supporting a functional link, small interfering RNA-mediated down-regulation of the foregoing regulatory proteins results in enhanced permeability similar to that observed after JAM-A loss. JAM-A-deficient mice and cultured epithelial cells demonstrate enhanced paracellular permeability to large molecules, revealing a potential role of JAM-A in controlling perijunctional actin cytoskeleton in addition to its previously reported role in regulating claudin proteins and small-molecule permeability. Further experiments suggest that JAM-A does not regulate actin turnover but modulates activity of RhoA and phosphorylation of nonmuscle myosin, both implicated in actomyosin contraction. These results suggest that JAM-A regulates epithelial permeability via association with ZO-2, afadin, and PDZ-GEF1 to activate Rap2c and control contraction of the apical cytoskeleton.
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