Homophilic Interaction of Junctional Adhesion Molecule

Bazzoni, Gianfranco; Martínez-Estrada, Ofelia M.; Mueller, Francis; Nelboeck, Peter; Schmid, Georg; Bartfai, Tamás; Dejana, Elisabetta; Brockhaus, Manfred

doi:10.1074/jbc.m003946200

Cited by 140 publications

(150 citation statements)

References 30 publications

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“…After transfection into Madin-Darby canine kidney (MDCK) II cells, JAM proteins are enriched at cell-cell borders of transfected cells and not at borders of transfected and nontransfected cells, suggesting JAMs engage in homophilic adhesive interactions (16,186). At least for JAM-1, homophilic adhesion appears to involve JAM-1 cis-dimerization and trans-interaction of the NH 2 -terminal domains with JAM-1 dimers on the adjacent cell (19,46,130). What follows is a description of each JAM member and a determination as to whether it might play a role in neutrophil emigration in the lung.…”

Section: B Jamsmentioning

confidence: 99%

Unique Structural Features That Influence Neutrophil Emigration Into the Lung

Burns

Smith²,

Walker³

2003

Physiological Reviews

269

273

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Neutrophil emigration in the lung differs substantially from that in systemic vascular beds where extravasation occurs primarily through postcapillary venules. Migration into the alveolus occurs directly from alveolar capillaries and appears to progress through a sequence of steps uniquely influenced by the cellular anatomy and organization of the alveolar wall. The cascade of adhesive and stimulatory events so critical to the extravasation of neutrophils from postcapillary venules in many tissues is not evident in this setting. Compelling evidence exists for unique cascades of biophysical, adhesive, stimulatory, and guidance factors that arrest neutrophils in the alveolar capillary bed and direct their movement through the endothelium, interstitial space, and alveolar epithelium. A prominent path accessible to the neutrophil appears to be determined by the structural interactions of endothelial cells, interstitial fibroblasts, as well as type I and type II alveolar epithelial cells.

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Section: B Jamsmentioning

confidence: 99%

Unique Structural Features That Influence Neutrophil Emigration Into the Lung

Burns

Smith²,

Walker³

2003

Physiological Reviews

269

273

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“…4 Compete for Binding to JAM1-Experiments were conducted to determine whether inhibitory antibodies J3F.1 and J10.4 bind to a common region of JAM1. Competition assays were performed in which binding of biotinylated J10.4 to immobilized JAM1 was measured in the presence of antibodies J3F.1, J10.4, 1H2A9, control IgG1, or no antibody.…”

Section: Differing Effects Of Jam1 Antibodies On Barrier Recovery-mentioning

confidence: 99%

“…The crystal structure of JAM1 predicts that it forms stable homodimers (16,17). Cross-linking experiments suggest that JAM1 forms homodimers in solution and on the surface of transfected CHO cells (4). Other studies suggest that heterotypic interactions are important for JAM1 function.…”

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confidence: 99%

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Involvement of the Junctional Adhesion Molecule-1 (JAM1) Homodimer Interface in Regulation of Epithelial Barrier Function

Mandell

McCall

Parkos

2004

Journal of Biological Chemistry

113

120

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Junctional adhesion molecule-1 (JAM1) is a tight junction-associated immunoglobulin superfamily protein implicated in the regulation of tight junctions and leukocyte transmigration. The structural basis for the function of JAM1 has yet to be determined. Here we provide evidence that JAM1 homodimer formation is important for its function in epithelial cells. Experiments were conducted to determine the effects of a panel of JAM1 monoclonal antibodies on epithelial barrier recovery after transient disruption by calcium switch. Two monoclonal antibodies were observed to inhibit barrier recovery in contrast to another monoclonal antibody that had no effect. Epitope mapping by phage display revealed that both inhibitory antibodies bind to a region of JAM1 located within the N-terminal Ig-like loop (residues 111-123). Competition experiments with synthetic peptides and site-directed mutagenesis confirmed the location of this epitope. Analysis of the crystal structure of JAM1 revealed that this epitope includes residues within the putative homodimer interface, and one of the two inhibitory antibodies was then shown to block JAM1 homodimer formation in vitro. Finally, mutations within the homodimer interface were shown to prevent enrichment of JAM1 at points of cell contact, presumably by interference with homophilic interactions. These findings suggest that homodimer formation may be important for localization of JAM1 at tight junctions and for regulation of epithelial barrier function.A crucial function of epithelial cells is in the maintenance of a selective barrier separating the external from internal environments. It is well known that tight junctions (TJs) 1 play an important role in the maintenance and regulation of these barriers. Located at the apical-most part of the lateral epithelial cell membrane, TJs regulate paracellular diffusion of ions and small molecules across epithelial barriers. In addition, TJs serve as a fence between the apical and basolateral domains of polarized cells and facilitate bi-directional signal transduction between the intracellular and extracellular environments. TJs are composed of both transmembrane and cytoplasmic structural elements. Transmembrane protein members include occludins, claudins, coxsackie adenovirus receptors, and junctional adhesion molecules (JAMs). Knowledge of how these various proteins contribute to TJ function is continually evolving.JAM1 is an immunoglobulin superfamily protein that localizes to TJs of epithelial and endothelial cells (1) as well as to the surface of leukocytes (2). Evidence suggests a role for JAM1 in TJ assembly (3). Exogenous expression of JAM1 in CHO cells has been shown to promote localization of ZO-1 and occludin at points of cell contact (4). Monoclonal antibodies to JAM1 have been shown to inhibit reassembly of TJs and block recovery of transepithelial resistance to ion flux (3). Similar effects on epithelial barrier function were observed with recombinant soluble JAM1 consisting of the extracellular domain fused to IgG Fc (5). In add...

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“…Robust evidence has been provided for a key role of JAM-A in leukocyte transmigration (5) and inflammatory extravasation (7). Inhibition of transmigration with the mAb BV11 that specifically recognizes JAM-A homodimers implicated homophilic interactions involved in this process (8). In contrast, transmigration of human leukocytes has been shown to involve heterophilic interactions of JAM-A with its integrin receptor LFA-1 (3).…”

mentioning

confidence: 99%

The Functional Interaction of the β2 Integrin Lymphocyte Function-Associated Antigen-1 with Junctional Adhesion Molecule-A Is Mediated by the I Domain

Fraemohs

Koenen

Ostermann

et al. 2004

The Journal of Immunology

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Binding of the β2 integrin LFA-1 (αLβ2) to junctional adhesion molecule-A (JAM-A) has been shown to enhance leukocyte adhesion and transendothelial migration. This is mediated by the membrane-proximal Ig-like domain 2 of JAM-A; however, the location of the JAM-A binding site in LFA-1 has not been identified. We have deleted the I domain in the αL subunit of LFA-1 and expressed this αL mutant in αl-deficient Jurkat J-β2.7 cells to demonstrate that the I domain of LFA-1 is crucial for their adhesion to immobilized JAM-A. This was substantiated by blocking the stimulated adhesion of wild-type Jurkat T cells or monocytic Mono Mac 6 cells to JAM-A using the I domain-directed mAb TS1/22 or the small molecule antagonist BIRT 377, which stabilizes the low-affinity conformation of the I domain. The immobilized LFA-1 I domain locked in the open high-affinity conformation was sufficient to support binding of transfected Chinese hamster ovary cells expressing JAM-A. Solid-phase binding assays confirmed a direct interaction of recombinant JAM-A with the immobilized locked-open I domain. These data provide the first evidence that the I domain of LFA-1 contains a functional binding site for JAM-A.

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Homophilic Interaction of Junctional Adhesion Molecule

Cited by 140 publications

References 30 publications

Unique Structural Features That Influence Neutrophil Emigration Into the Lung

Unique Structural Features That Influence Neutrophil Emigration Into the Lung

Involvement of the Junctional Adhesion Molecule-1 (JAM1) Homodimer Interface in Regulation of Epithelial Barrier Function

The Functional Interaction of the β2 Integrin Lymphocyte Function-Associated Antigen-1 with Junctional Adhesion Molecule-A Is Mediated by the I Domain

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