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.
Severson
Eric A
EA
Epithelial Pathobiology Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Parkos
Charles A
CA
D000818:Animals; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000737:chemistry / Q000378:metabolism; D008954:Models, Biological; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D019108:Tight Junctions / Q000737:chemistry / Q000378:metabolism*; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
D015815:Cell Adhesion Molecules; C407243:F11R protein, human; C498686:F11r protein, mouse; D007136:Immunoglobulins; D008840:Microfilament Proteins; D011956:Receptors, Cell Surface; C108835:afadin; D020827:rap1 GTP-Binding Proteins