Unique Role of Junctional Adhesion Molecule-A in Maintaining Mucosal Homeostasis in Inflammatory Bowel Disease

Vetrano, Stefania; Rescigno, María; Rosaria, Maria; Correale, Carmen; Rumio, Cristiano; Doni, Andrea; Fantini, Massimo; Sturm, Andreas; Borroni, Elena Monica; Repici, Alessandro; Locati, Massimo; Malesci, Alberto; Dejana, Elisabetta; Danese, Silvio

doi:10.1053/j.gastro.2008.04.002

Cited by 219 publications

(209 citation statements)

References 34 publications

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“…Because epithelial cell migration is necessary for maintenance of epithelial barrier function and the repair, loss of JAM-A would thus be expected to adversely affect recovery after mucosal injury. Indeed, our results are consistent with a key role of JAM-A in mucosal injury/repair in vivo as JAM-A knockout mice have increased disease severity in a chemically induced mouse model of colitis (Laukoetter et al, 2007;Vetrano et al, 2008). In particular, there was significantly increased colonic mucosal injury and inflammation in JAM-A-deficient animals, compared with wild-type controls.…”

Section: Discussionsupporting

confidence: 89%

Junctional Adhesion Molecule A Interacts with Afadin and PDZ-GEF2 to Activate Rap1A, Regulate β1 Integrin Levels, and Enhance Cell Migration

Severson

Lee

Capaldo

et al. 2009

MBoC

160

166

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Junctional adhesion molecule-A (JAM-A) is a transmembrane tight junction protein that has been shown to regulate barrier function and cell migration through incompletely understood mechanisms. We have previously demonstrated that JAM-A regulates cell migration by dimerization of the membrane-distal immunoglobulin-like loop and a C-terminal postsynaptic density 95/disc-large/zona occludens (PDZ) binding motif. Disruption of dimerization resulted in decreased epithelial cell migration secondary to diminished levels of ␤1 integrin and active Rap1. Here, we report that JAM-A is physically and functionally associated with the PDZ domain-containing molecules Afadin and PDZ-guanine nucleotide exchange factor (GEF) 2, but not zonula occludens (ZO)-1, in epithelial cells, and these interactions mediate outside-in signaling events. Both Afadin and PDZ-GEF2 colocalized and coimmunoprecipitated with JAM-A. Furthermore, association of PDZ-GEF2 with Afadin was dependent on the expression of JAM-A. Loss of JAM-A, Afadin, or PDZ-GEF2, but not ZO-1 or PDZ-GEF1, similarly decreased cellular levels of activated Rap1, ␤1 integrin protein, and epithelial cell migration. The functional effects observed were secondary to decreased levels of Rap1A because knockdown of Rap1A, but not Rap1B, resulted in decreased ␤1 integrin levels and reduced cell migration. These findings suggest that JAM-A dimerization facilitates formation of a complex with Afadin and PDZ-GEF2 that activates Rap1A, which regulates ␤1 integrin levels and cell migration.

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Section: Discussionsupporting

confidence: 89%

Junctional Adhesion Molecule A Interacts with Afadin and PDZ-GEF2 to Activate Rap1A, Regulate β1 Integrin Levels, and Enhance Cell Migration

Severson

Lee

Capaldo

et al. 2009

MBoC

160

166

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“…We found that low-PC mice had altered or reduced expression of ZO-1, JAM-A, and claudin-3, three tight junction proteins required for intestinal barrier function. Most notable was the down-regulation of JAM-A, a molecule that we recently identified as a crucial mediator of intestinal barrier permeability (11,21). In addition, consistent with the in vivo findings, aPC had a strong effect on tight junctions in vitro; its presence was able to inhibit the altered expression of ZO-1 and JAM-A induced by TNF-α.…”

Section: Discussionsupporting

confidence: 82%

“…To investigate whether intestinal epithelium expresses components of the PC system, we performed confocal microscopy using specific antibodies to PC, EPCR, PAR-1, and TM, and an antibody for pan-cytokeratin, a specific epithelial marker, on sections of colon obtained from 16 healthy individuals (Fig. 1A) (11). PC, EPCR, and PAR-1, but not TM, were expressed by ECs in the intestine, as indicated by colocalization with pan-cytokeratin (Fig.…”

Section: Resultsmentioning

confidence: 99%

Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation

Vetrano

Ploplis

Sala

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The protein C (PC) pathway is a well-characterized coagulation system. Endothelial PC receptors and thrombomodulin mediate the conversion of PC to its activated form, a potent anticoagulant and anti-inflammatory molecule. Here we show that the PC pathway is expressed on intestinal epithelial cells. The epithelial expression of PC and endothelial PC receptor is down-regulated In patients with inflammatory bowel disease. PC −/− /PC(Tg) mice, expressing only 3% of WT PC, developed spontaneous intestinal inflammation and were prone to severe experimental colitis. These mice also demonstrated spontaneous elevated production of inflammatory cytokines and increased intestinal permeability. Structural analysis of epithelial tight junction molecules revealed that lack of PC leads to decreased JAM-A and claudin-3 expression and an altered pattern of ZO-1 expression. In vitro, treatment of epithelial cells with activated PC led to protection of tight junction disruption induced by TNF-α, and in vivo, topical treatment with activated PC led to mucosal healing and amelioration of colitis. Taken together, these findings demonstrate that the PC pathway is a unique system involved in controlling intestinal homeostasis and inflammation by regulating epithelial barrier function.

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“…100 Although the exposure of epithelial monolayers to inflammatory cytokines also results in apoptosis, a surprising finding has been that the disruption in barrier function during inflammation can occur secondary to altered tight junctions and even in the absence of apoptosis. 101,102 These observations raise important questions regarding other pathophysiological consequences secondary to loss of tight junction molecules under inflammatory conditions.…”

Section: Effects Of Inflammation On Epithelial Cell Functionmentioning

confidence: 99%

“…For example, as observed in Figure 5A, expression of the tight junctioneassociated molecule JAM-A is diminished after epithelial exposure to inflammatory cytokines, which has also been reported in the colonic mucosa of individuals with IBD. 101 JAM-A represents a well-studied protein in the JAM family and, with abundant structural, biochemical, and functional data, there has been an opportunity to better understand the functional biology of this protein under normal and reduced expression conditions, as seen during inflammation.…”

Section: Effects Of Inflammation On Epithelial Cell Functionmentioning

confidence: 99%

Neutrophil-Epithelial Interactions

Parkos

2016

The American Journal of Pathology

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Unique Role of Junctional Adhesion Molecule-A in Maintaining Mucosal Homeostasis in Inflammatory Bowel Disease

Cited by 219 publications

References 34 publications

Junctional Adhesion Molecule A Interacts with Afadin and PDZ-GEF2 to Activate Rap1A, Regulate β1 Integrin Levels, and Enhance Cell Migration

Junctional Adhesion Molecule A Interacts with Afadin and PDZ-GEF2 to Activate Rap1A, Regulate β1 Integrin Levels, and Enhance Cell Migration

Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation

Neutrophil-Epithelial Interactions

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