JAM-A associates with ZO-2, afadin, and PDZ-GEF1 to activate Rap2c and regulate epithelial barrier function.

Monteiro AC, Sumagin R, Rankin CR, Leoni G, Mina MJ, Reiter DM, Stehle T, Dermody TS, Schaefer SA, Hall RA, Nusrat A, Parkos CA
Mol Biol Cell. 2013 24 (18): 2849-60

PMID: 23885123 · PMCID: PMC3771947 · DOI:10.1091/mbc.E13-06-0298

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.

MeSH Terms (25)

Animals Capsid Proteins Cell Adhesion Molecules Cell Line Cell Membrane Permeability Cell Polarity Cytoskeleton Down-Regulation Endocytosis Epithelial Cells Guanine Nucleotide Exchange Factors Humans Mice Microfilament Proteins Models, Biological Molecular Weight Nerve Tissue Proteins Protein Binding Protein Transport rap1 GTP-Binding Proteins ras Proteins Receptors, Cell Surface rhoA GTP-Binding Protein Tight Junctions Zonula Occludens-2 Protein

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