Association of the zonula adherens with mRNAs
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE86986 | GEO | 2017/08/25
SECONDARY ACCESSION(S): PRJNA343129
REPOSITORIES: GEO
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Project description:The Adherens Junction protein p120-catenin is implicated in the regulation of cadherin stability, cell migration and inflammatory responses in mammalian epithelial tissues. How these events are coordinated to promote wound repair is not understood. We show that p120-catenin regulates the intrinsic migratory properties or primary mouse keratinocytes, but also influences the migratory behavior of neighboring cells by secreted signals. These events are rooted in the ability of p120-catenin to regulate RhoA-GTPase activity, which leads to a two-tiered control of cell migration. One restrains cell motility via increase of actin stress fibers, reduction in integrin turnover, and an increase in focal adhesions robustness. The other is coupled to the secretion of inflammatory cytokines including Interleukin-24, which causally enhances randomized cell movements. Taken together, our results indicate that p120-RhoA-GTPase-mediated signaling can differentially regulate the migratory behavior of epidermal cells, which has potential implications for chronic wound responses and cancer.
2016-12-31 | GSE55019 | GEO
Project description:Endothelial barrier integrity is ensured by the stability of the adherens junction (AJ) complexes comprised of VE-cadherin as well as accessory proteins such as β-catenin and p120-catenin. Disruption of the endothelial barrier due to disassembly of AJs results in tissue edema and the influx of inflammatory cells. Using three-dimensional structured illumination microscopy (3D- SIM), we found that the mitochondrial protein Mitofusin-2 (Mfn2) co-localizes at the plasma membrane with VE-cadherin and β-catenin in endothelial cells during homeostasis. Upon inflammatory stimulation, Mfn2 is sulfenylated, the Mfn2/β-catenin complex disassociates from the AJs and translocates into the nucleus where Mfn2 negatively regulates the transcriptional activity of β-catenin. Endothelial-specific deletion of Mfn2 resulted in inflammatory injury, indicating an anti-inflammatory role of Mfn2 in vivo. Our results suggest that Mfn2 acts in a non- canonical manner to suppress the inflammatory response by stabilizing cell-cell adherens junctions and by binding to the transcriptional activator β-catenin.
2023-04-18 | GSE148987 | GEO
Project description:Background: Negative-pressure wound therapy has become widely available in modern chronic wound cares. Accelerated keratinocyte (HaCaT cell) movements and decreased E-cadherin expressions induced by the applied negative pressure gradient of 125 mmHg (NP) have been reported in previous studies. However, the molecular mechanism for E-cadherin regulations under NP remains unexplored. We highlighted the signal transduction involved in NP-induced E-cadherin regulation for keratinocytes in the study. Results: Microarray results showed that catenin 1 (CTNND1) gene, the gene encoding the p120-catenin (p120ctn) in cell-cell junctions, was significantly (p = 0.0005) upregulated in HaCaT cells under NP for 12 hours in comparison with those at ambient pressure (AP). Cell fractionations and immunoblotting data showed that NP increased p120ctn phosphorylation, and resulted in p120ctn translocation from the plasma membrane to the cytoplasm. Fluorescent stains suggested that NP diminished the co-localization of p120ctn and E-cadherin on the plasma membrane. Similar phenomenon was also observed in the cells with overexpressed p120ctn at NP. Interestingly, overexpression of dN- p120ctn, a deletion mutant of p120ctn without the N-terminal phosphorylation sites, restored the adherens junctions (AJ) at NP. Knockdown of p120ctn with lentiviral small hairpin RNA not only diminished E-cadherin expressions but also accelerated cell movement at AP. Conclusions: Phosphorylation of p120ctn is endowed to respond rapidly to NP and contributes to the AJ disassembly. This NP-induced E-cadherin downregulation can possibly accelerate wound-healing process. Conclusions: Phosphorylation of p120ctn is endowed to respond rapidly to NP and contributes to the AJ disassembly. This NP-induced E-cadherin downregulation can possibly accelerate wound-healing process. HaCaT cells under negative pressure (NP) gradient of 125 mmHg for 12 hours in comparison with those at ambient pressure (AP) were tested for RNA extraction and hybridization on Affymetrix microarrays. The experiments have been biological replicated three times. The differential expression gene between NP and AP were selected and validated with qPCR method.
2015-12-31 | E-GEOD-70512 | biostudies-arrayexpress
Project description:Background: Negative-pressure wound therapy has become widely available in modern chronic wound cares. Accelerated keratinocyte (HaCaT cell) movements and decreased E-cadherin expressions induced by the applied negative pressure gradient of 125 mmHg (NP) have been reported in previous studies. However, the molecular mechanism for E-cadherin regulations under NP remains unexplored. We highlighted the signal transduction involved in NP-induced E-cadherin regulation for keratinocytes in the study. Results: Microarray results showed that catenin 1 (CTNND1) gene, the gene encoding the p120-catenin (p120ctn) in cell-cell junctions, was significantly (p = 0.0005) upregulated in HaCaT cells under NP for 12 hours in comparison with those at ambient pressure (AP). Cell fractionations and immunoblotting data showed that NP increased p120ctn phosphorylation, and resulted in p120ctn translocation from the plasma membrane to the cytoplasm. Fluorescent stains suggested that NP diminished the co-localization of p120ctn and E-cadherin on the plasma membrane. Similar phenomenon was also observed in the cells with overexpressed p120ctn at NP. Interestingly, overexpression of dN- p120ctn, a deletion mutant of p120ctn without the N-terminal phosphorylation sites, restored the adherens junctions (AJ) at NP. Knockdown of p120ctn with lentiviral small hairpin RNA not only diminished E-cadherin expressions but also accelerated cell movement at AP. Conclusions: Phosphorylation of p120ctn is endowed to respond rapidly to NP and contributes to the AJ disassembly. This NP-induced E-cadherin downregulation can possibly accelerate wound-healing process. Conclusions: Phosphorylation of p120ctn is endowed to respond rapidly to NP and contributes to the AJ disassembly. This NP-induced E-cadherin downregulation can possibly accelerate wound-healing process.
2015-12-31 | GSE70512 | GEO
Project description:The poor prognosis of diffuse gliomas is the consequence of adaptive growth and survival programs coupled to their unsurmountable capacity to infiltrate the brain. Diffuse brain infiltration is a particularly detrimental hallmark of gliomas, however the underlying cellular and signaling mechanisms remain elusive. Histological analysis of glioma samples suggests brain invasion by individual glioma cells extending along blood vessels and nerve tracts, consistent with individual-cell growth and invasion programs. However, using thick 3D tissue sections, we here show that human diffuse gliomas consist of multicellular networks in both tumor center and invasion region. This was confirmed in three orthotopic human glioma xenograft models in mouse brain reflecting neuronal, proneural and mesenchymal subtypes. The connections between glioma cells are provided by either branched filamentous protrusions connecting cells across distance or epithelial-like linear adherens junctions between directly adjacent cells. These intercellular contacts showed dynamic turn-over kinetics, which enabled intercellularly synchronized calcium signaling waves, directionally persistent migration as network and network plasticity. Interference with the stability of adherens junction by downregulating p120-catenin causes irreversibly compromised cell-cell interaction, near-complete inhibition of diffuse brain infiltration and a severe growth defect and marginalized microlesions as outcome. Mining of human glioma cohorts revealed an inverse association of p120 with patient survival and, using next-generation RNA sequencing, profound cell reprogramming with perturbed cell adhesion and axonal guidance pathways was uncovered after p120 downregulation. In conclusion, reminiscent of neuronal and glial progenitor programs during morphogenesis and repair, diffuse gliomas progress as neuronal-like, collective network the subunits of which cooperate by complex cell-cell signaling to promote cell growth and detrimental brain infiltration. Targeting adherens junctions and cell-cell cooperation thus represent unanticipated therapeutic principles to prevent glioma progression.
2019-12-02 | GSE73999 | GEO
Project description:Pancreatic cancer is one of the most deadly cancers with a 5 year survival rate of about 5%. Therapeutic options are limited, especially for patients that present with late state disease and metastasis. Although the metastatic burden of pancreatic cancer is usually high, little is known about the mechanisms that regulate delamination and dissemination of epithelial cells from preinvasive and malignant pancreatic lesions. Here, we used a preinvasive mouse model of pancreatic cancer to conditionally knockout p120 catenin (Ctnnd1). Mice with biallelic loss of p120 catenin progressively develop high grade PanIN lesions and neoplasia accompanied by prominent acute and chronic inflammatory processes. Loss of p120 catenin in the context of oncogenic Kras also promotes remarkable apical and basal epithelial cell extrusion. Abundant single epithelial cells exit PanIN epithelium basally, survive, and display features of malignancy. Similar extrusion defects are observed following p120 catenin knockdown in vitro, and these effects are completely abrogated by activation of S1P/S1P2 signaling. Our results establish p120 catenin and S1P/S1P2 signaling as novel regulators of non-EMT mediated epithelial cell invasion in pancreatic neoplasia. Transcriptomes of KCiMist1G; p120wt/wt and KCiMist1G; p120f/f pancreases were compared, with three replicates each, using microarray.
2016-07-25 | E-GEOD-68090 | biostudies-arrayexpress
Project description:Pancreatic cancer is one of the most deadly cancers with a 5 year survival rate of about 5%. Therapeutic options are limited, especially for patients that present with late state disease and metastasis. Although the metastatic burden of pancreatic cancer is usually high, little is known about the mechanisms that regulate delamination and dissemination of epithelial cells from preinvasive and malignant pancreatic lesions. Here, we used a preinvasive mouse model of pancreatic cancer to conditionally knockout p120 catenin (Ctnnd1). Mice with biallelic loss of p120 catenin progressively develop high grade PanIN lesions and neoplasia accompanied by prominent acute and chronic inflammatory processes. Loss of p120 catenin in the context of oncogenic Kras also promotes remarkable apical and basal epithelial cell extrusion. Abundant single epithelial cells exit PanIN epithelium basally, survive, and display features of malignancy. Similar extrusion defects are observed following p120 catenin knockdown in vitro, and these effects are completely abrogated by activation of S1P/S1P2 signaling. Our results establish p120 catenin and S1P/S1P2 signaling as novel regulators of non-EMT mediated epithelial cell invasion in pancreatic neoplasia.
2016-07-25 | GSE68090 | GEO
Project description:ARHGAP35 encoding p190A RhoGAP (p190A) was identified by GWAS as a major human cancer gene. Our published studies have determined that p190A is a tumor suppressor that activates the canonical Hippo pathway. To elucidate how p190A signals in this context, we performed mass spectrometry to identify p190A binding proteins. Two interactors were identified significantly more frequently than others: p120 RasGAP (p120) and ZO-1. Originally p190A was cloned via its direct binding to p120, hence validating our approach. In addition, we found that p190A also binds to ZO-2. The interaction of p190A with ZO-2 is dependent on p120, thus suggesting formation of a ternary complex. Next, we determine that both p120 and ZO-2, but not ZO-1, are necessary for p190A to activate LATS kinases and suppress tumorigenesis in a xenograft mouse model. Moreover, the interactions with p120 and ZO-2 are essential for transcriptional modulation by p190A, including the CDH1 gene encoding E-cadherin, which we previously have demonstrated is essential for p190A signaling. Collectively, this work identifies a novel tumor suppressor interactome of p190A, which includes ZO-2, an established constituent of the Hippo pathway, and p120, which in spite of its strong association with Ras signaling, is essential for p190A to activate LATS kinases.
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Project description:Dysregulated protease activity is often implicated in the initiation of inflammation and immune cell recruitment in gastrointestinal inflammatory diseases. Using N-terminomics/TAILS (terminal amine isotopic labeling of substrates), we compared proteases, along with their substrates and inhibitors, between colonic mucosal biopsies of healthy patients and those with ulcerative colitis (UC). Among the 1,642 N-termini enriched using TAILS, increased endogenous processing of proteins was identified in UC compared to healthy patients. Changes in the reactome pathways for proteins associated with metabolism, adherens junction proteins (E-cadherin, liver-intestinal cadherin, catenin alpha-1 and catenin delta-1) and neutrophil degranulation were identified between the two groups. Increased neutrophil infiltration and distinct proteases observed in ulcerative colitis may result in extensive break down, altered processing or increased remodeling of adherens junctions and other cellular functions. Analysis of the proteolytic preferred cleavage sites indicated that the majority of proteolytic activity and processing comes from host proteases, but that key microbial proteases may also play a role in maintaining homeostasis. Thus, the identification of distinct proteases and processing of their substrates improves the understanding of dysregulated proteolysis in normal intestinal physiology and ulcerative colitis.
2019-09-08 | PXD014479 | Pride