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

Monteiro, Ana Carolina; Sumagin, Ronen; Rankin, Carl R.; Leoni, Giovanna; Mina, Michael J.; Reiter, Dirk M.; Stehle, Thilo; Dermody, Terence S.; Schaefer, Stacy A.; Hall, Randy A.; Nusrat, Asma; Parkos, Charles A.

doi:10.1091/mbc.e13-06-0298

Cited by 119 publications

(129 citation statements)

References 60 publications

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“…111,112 Indeed, JAM-A deficiency is associated with increased permeability to large molecules (40-kDa dextran). 66 These findings highlight how an inflammatory microenvironment can have indirect and potent effects on epithelial homeostasis.…”

Section: Neutrophil-epithelial Interactionsmentioning

confidence: 96%

“…106 It is now appreciated that dimerization of JAM at cell-cell contacts results in PDZ-mediated concentration of critical scaffold and signaling molecules, including afadin and guanine nucleotide exchange factors, such as PDZ-GEF2, to activate the small GTPase Rap1 that regulate b1 integrin expression and cell migration. 66,108 Indeed, altered disease progression observed in certain types of cancer has also been linked to cellular levels of JAM-A and b1 integrin. 109,110 Signaling pathways downstream of JAM-A that regulate barrier, migration, and proliferation are summarized in Figure 5B.…”

Section: Neutrophil-epithelial Interactionsmentioning

confidence: 99%

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Neutrophil-Epithelial Interactions

Parkos

2016

The American Journal of Pathology

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Section: Neutrophil-epithelial Interactionsmentioning

confidence: 96%

Section: Neutrophil-epithelial Interactionsmentioning

confidence: 99%

Neutrophil-Epithelial Interactions

Parkos

2016

The American Journal of Pathology

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“…JAM‐A regulates apical actomyosin contraction, and deficiencies lead to enhanced MLC2 phosphorylation 36. However, unlike in mice with JAM‐A deficiency 35, CerS2 null mice did not show increased epithelial proliferation and formation of large lymphoid aggregates.…”

Section: Discussionmentioning

confidence: 90%

“…Mucin dysfunction 33, 34 and JAM‐A deficiency 35, 36 have been shown to cause increased intestinal permeability, especially under basal conditions, with an enhanced susceptibility to experimental colitis. Thus, we evaluated mucin production in CerS2 null mice.…”

Section: Resultsmentioning

confidence: 99%

Ablation of ceramide synthase 2 exacerbates dextran sodium sulphate‐induced colitis in mice due to increased intestinal permeability

Kim

Volpert

Shin

et al. 2017

J Cellular Molecular Medi

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Ceramides mediate crucial cellular processes including cell death and inflammation and have recently been implicated in inflammatory bowel disease. Ceramides consist of a sphingoid long‐chain base to which fatty acids of various length can be attached. We now investigate the effect of alerting the ceramide acyl chain length on a mouse model of colitis. Ceramide synthase (CerS) 2 null mice, which lack very‐long acyl chain ceramides with concomitant increase of long chain bases and C16‐ceramides, were more susceptible to dextran sodium sulphate‐induced colitis, and their survival rate was markedly decreased compared with that of wild‐type littermates. Using mixed bone‐marrow chimeric mice, we showed that the host environment is primarily responsible for intestinal barrier dysfunction and increased intestinal permeability. In the colon of CerS2 null mice, the expression of junctional adhesion molecule‐A was markedly decreased and the phosphorylation of myosin light chain 2 was increased. In vitro experiments using Caco‐2 cells also confirmed an important role of CerS2 in maintaining epithelial barrier function; CerS2‐knockdown via CRISPR‐Cas9 technology impaired barrier function. In vivo myriocin administration, which normalized long‐chain bases and C16‐ceramides of the colon of CerS2 null mice, increased intestinal permeability as measured by serum FITC‐dextran levels, indicating that altered SLs including deficiency of very‐long‐chain ceramides are critical for epithelial barrier function. In conclusion, deficiency of CerS2 influences intestinal barrier function and the severity of experimental colitis and may represent a potential mechanism for inflammatory bowel disease pathogenesis.

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“…Afadin is an actin-binding protein associated with nectin and cadherin-based adherens junctions, as well as tight junctions (Yamamoto et al, 1997;Ooshio et al, 2010;Mandai et al, 1997;Indra et al, 2014;Choi et al, 2016;Monteiro et al, 2013). Afadin was a high-ranking hit in our EphA2 BioID screen (2D, #3; 3D, #13).…”

Section: Epha2 and Afadin Interact In Keratinocytesmentioning

confidence: 99%

EphA2 proteomics in human keratinocytes reveals a novel association with afadin and epidermal tight junctions

White

Ventrella

Kaplan

et al. 2016

Journal of Cell Science

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EphA2 is a receptor tyrosine kinase that helps to maintain epidermal tissue homeostasis. A proximity-dependent biotin identification (BioID) approach was used to identify proteins in close proximity to EphA2 within primary human keratinocytes and three-dimensional (3D) reconstituted human epidermis (RHE) cultures to map a putative protein interaction network for this membrane receptor that exhibits a polarized distribution in stratified epithelia. Although a subset of known EphA2 interactors were identified in the BioID screen, >97% were uniquely detected in keratinocytes with over 50% of these vicinal proteins only present in 3D human epidermal culture. Afadin (AFDN), a cytoskeletal and junction-associated protein, was present in 2D and 3D keratinocyte cultures, and validated as a so-far-unknown EphA2-interacting protein. Loss of EphA2 protein disrupted the subcellular distribution of afadin and occludin in differentiated keratinocytes, leading to impairment of tight junctions. Collectively, these studies illustrate the use of the BioID approach in order to map receptor interaction networks in 3D human epithelial cultures, and reveal a positive regulatory role for EphA2 in the organization of afadin and epidermal tight junctions.

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

Abstract: Intestinal barrier function is regulated by epithelial tight junctions, structures that control paracellular permeability. JAM-A regulates epithelial permeability through association with ZO-2, afadin, and PDZ-GEF1 to activate Rap2c and control contraction of the apical cytoskeleton.

Cited by 119 publications

References 60 publications

Neutrophil-Epithelial Interactions

Neutrophil-Epithelial Interactions

Ablation of ceramide synthase 2 exacerbates dextran sodium sulphate‐induced colitis in mice due to increased intestinal permeability

EphA2 proteomics in human keratinocytes reveals a novel association with afadin and epidermal tight junctions

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