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Bves modulates tight junction associated signaling.

ABSTRACT: Blood vessel epicardial substance (Bves) is a transmembrane adhesion protein that regulates tight junction (TJ) formation in a variety of epithelia. The role of TJs within epithelium extends beyond the mechanical properties. They have been shown to play a direct role in regulation of RhoA and ZONAB/DbpA, a y-box transcription factor. We hypothesize that Bves can modulate RhoA activation and ZONAB/DbpA activity through its regulatory effect on TJ formation. Immortalized human corneal epithelial (HCE) cells were stably transfected with Flag-tagged full length chicken Bves (w-Bves) or C-terminus truncated Bves (t-Bves). We found that stably transfected w-Bves and t-Bves were interacting with endogenous human Bves. However, interaction with t-Bves appeared to disrupt cell membrane localization of endogenous Bves and interaction with ZO-1. w-Bves cells exhibited increased TJ function reflected by increased trans-epithelial electrical resistance, while t-Bves cells lost TJ protein immunolocalization at cell-cell contacts and exhibited decreased trans-epithelial electrical resistance. In parental HCE and w-Bves cells ZONAB/DbpA and GEF-H1 were seen at cell borders in the same pattern as ZO-1. However, expression of t-Bves led to decreased membrane localization of both ZONAB/DbpA and GEF-H1. t-Bves cells had increased RhoA activity, as indicated by a significant 30% increase in FRET activity compared to parental HCE cells. ZONAB/DbpA transcriptional activity, assessed using a luciferase reporter probe, was increased in t-Bves cells. These studies demonstrate that Bves expression and localization can regulate RhoA and ZONAB/DbpA activity.

SUBMITTER: Russ PK

PROVIDER: S-EPMC3024319 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Bves modulates tight junction associated signaling.

Russ Patricia K PK Pino Christopher J CJ Williams Christopher S CS Bader David M DM Haselton Frederick R FR Chang Min S MS

PloS one 20110120 1

Blood vessel epicardial substance (Bves) is a transmembrane adhesion protein that regulates tight junction (TJ) formation in a variety of epithelia. The role of TJs within epithelium extends beyond the mechanical properties. They have been shown to play a direct role in regulation of RhoA and ZONAB/DbpA, a y-box transcription factor. We hypothesize that Bves can modulate RhoA activation and ZONAB/DbpA activity through its regulatory effect on TJ formation. Immortalized human corneal epithelial ( ...[more]

PMID: 21283798

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Project description:Defective barrier function is a predisposing factor in inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Although TGFβ signaling defects have been associated with IBD and CAC, few studies have examined the relationship between TGFβ and intestinal barrier function. Here, we examine the role of TGFβ signaling via SMAD4 in modulation of colon barrier function. The Smad4 gene was conditionally deleted in the intestines of adult mice and intestinal permeability assessed using an in vivo 4 kDa FITC-Dextran (FD4) permeability assay. Mouse colon was isolated for gene expression (RNA-sequencing), Western blot, and immunofluorescence analysis. In vitro colon organoid culture was utilized to assess junction-related gene expression by qPCR and transepithelial resistance (TER). In silico analyses of human IBD and colon cancer databases were performed. Mice lacking intestinal expression of Smad4 demonstrate increased colonic permeability to FD4 without gross mucosal damage. mRNA/protein expression analyses demonstrate significant increases in Cldn2/Claudin 2 and Cldn8/Claudin 8, and decreases in Cldn3, Cldn4, and Cldn7/Claudin 7 with intestinal SMAD4 loss in vivo without changes in Claudin protein localization. TGFβ1/BMP2 treatment of polarized SMAD4+ colonoids increases TER. Cldn2, Cldn4, Cldn7, and Cldn8 are regulated by canonical TGFβ signaling, and TGFβ-dependent regulation of these genes is dependent on nascent RNA transcription (Cldn2, Cldn4, Cldn8) but not nascent protein translation (Cldn4, Cldn8). Human IBD/colon cancer specimens demonstrate decreased SMAD4, CLDN4, CLDN7, and CLDN8 and increased CLDN2 compared with healthy controls. Canonical TGFβ signaling modulates the expression of tight junction proteins and barrier function in mouse colon.NEW & NOTEWORTHY We demonstrate that canonical TGFβ family signaling modulates the expression of critical tight junction proteins in colon epithelial cells, and that expression of these tight junction proteins is associated with maintenance of colon epithelial barrier function in mice.

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Bves modulates tight junction associated signaling.

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Bves modulates tight junction associated signaling.

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