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JAM4, a junctional cell adhesion molecule interacting with a tight junction protein, MAGI-1.

ABSTRACT: MAGI-1 is a membrane-associated guanylate kinase protein at tight junctions in epithelial cells. It interacts with various molecules and functions as a scaffold protein at cell junctions. We report here a novel MAGI-1-binding protein that we named junctional adhesion molecule 4 (JAM4). JAM4 belongs to an immunoglobulin protein family. JAM4 was colocalized with ZO-1 in kidney glomeruli and in intestinal epithelial cells. Biochemical in vitro studies revealed that JAM4 bound to MAGI-1 but not to ZO-1, whereas JAM1 did not bind to MAGI-1. JAM4 and MAGI-1 interacted with each other and formed clusters in COS-7 cells when coexpressed. JAM4 mediated calcium-independent homophilic adhesion and was accumulated at cell-cell contacts when expressed in L cells. MAGI-1, ZO-1, and occludin were recruited to JAM4-based cell contacts. JAM4 also reduced the permeability of CHO cell monolayers. MAGI-1 strengthened JAM4-mediated cell adhesion in L cells and sealing effects in CHO cells. These findings suggest that JAM4 together with MAGI-1 provides an adhesion machinery at tight junctions, which may regulate the permeability of kidney glomerulus and small intestinal epithelial cells.

SUBMITTER: Hirabayashi S

PROVIDER: S-EPMC156145 | biostudies-literature | 2003 Jun

REPOSITORIES: biostudies-literature

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JAM4, a junctional cell adhesion molecule interacting with a tight junction protein, MAGI-1.

Hirabayashi Susumu S Tajima Makiko M Yao Ikuko I Nishimura Wataru W Mori Hiroki H Hata Yutaka Y

Molecular and cellular biology 20030601 12

MAGI-1 is a membrane-associated guanylate kinase protein at tight junctions in epithelial cells. It interacts with various molecules and functions as a scaffold protein at cell junctions. We report here a novel MAGI-1-binding protein that we named junctional adhesion molecule 4 (JAM4). JAM4 belongs to an immunoglobulin protein family. JAM4 was colocalized with ZO-1 in kidney glomeruli and in intestinal epithelial cells. Biochemical in vitro studies revealed that JAM4 bound to MAGI-1 but not to Z ...[more]

PMID: 12773569

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Project description:OBJECTIVE:EZH2 is an epigenetic regulator that mediates H3K27 trimethylation (H3K27me3) and modulates DNA methylation. The aim of this study was to characterize the role of EZH2 in CD4+ T cells in the pathogenesis of systemic lupus erythematosus. METHODS:EZH2 expression levels were determined in CD4+ T cells isolated from lupus patients and healthy controls. The epigenetic effects of EZH2 overexpression in CD4+ T cells were evaluated using a genome-wide DNA methylation approach. Gene expression profiles and microRNAs (miRNAs) were assessed by quantitative polymerase chain reaction, while protein expression was examined by Western blotting. A cell adhesion assay was used to assess adhesion of CD4+ T cells to human microvascular endothelial cells. RESULTS:EZH2 and H3K27me3 levels were increased in CD4+ T cells from lupus patients compared to healthy controls. T cell production of EZH2 was down-regulated in the presence of miR-26a and miR-101, and levels of both miRNAs were reduced in lupus CD4+ T cells. Overexpression of EZH2 induced in CD4+ T cells resulted in significant DNA methylation changes. Genes involved in leukocyte adhesion and migration, including F11R (which encodes junctional adhesion molecule A [JAM-A]), became hypomethylated in CD4+ T cells when EZH2 was overexpressed. Overexpression of EZH2 resulted in increases in JAM-A expression and CD4+ T cell adhesion. Preincubation of EZH2-transfected CD4+ T cells with neutralizing antibodies against JAM-A significantly blunted cell adhesion. Similarly, CD4+ T cells from lupus patients overexpressed JAM-A and adhered significantly more to endothelial cells than to T cells from healthy controls. Blocking JAM-A or EZH2 significantly reduced the capacity of lupus CD4+ T cells to adhere to endothelial cells. CONCLUSION:The results of this study identify a novel role of EZH2 in T cell adhesion mediated by epigenetic remodeling and up-regulation of JAM-A. Blockade of EZH2 or JAM-A might have therapeutic potential by acting to reduce T cell adhesion, migration, and extravasation in patients with lupus.

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JAM4, a junctional cell adhesion molecule interacting with a tight junction protein, MAGI-1.

Publications

JAM4, a junctional cell adhesion molecule interacting with a tight junction protein, MAGI-1.

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