Mechanisms of outside-in signaling at the tight junction by junctional adhesion molecule A

Junctional adhesion molecule A (JAM-A) is a tight junction-associated, PDZ binding domain containing transmembrane protein that forms cis-homodimers in endothelial and epithelial cells. In vivo, the function of JAM-A in colonic mucosa has been examined using JAM-A knockout mice, which have increased intestinal permeability, inflammation and cellular proliferation compared to wild-type controls. In vitro studies have revealed that downregulation of JAM-A leads to altered cell migration secondary to diminished levels of beta1 integrin on the cell surface. Similar findings have been observed after transfection of epithelial cells with mutant JAM-A, which is defective in dimerization or lacks the PDZ binding domain. The dominant-negative effects of these mutant JAM-A proteins are most likely secondary to the inability of mutant JAM-A to form signaling complexes, the lack of which results in decreases in active or GTP-bound Rap1. This review highlights findings that support a hypothetical model for JAM-A mediated outside-in signaling. In this model, JAM-A dimerization is required for close cytoplasmic apposition of complexes containing specific PDZ domain-containing scaffold proteins that activate signaling molecules to serve as effectors for the regulation of cellular functions. The possibility of interactions of JAM-A cis-dimers between cells in trans is also discussed.