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Carcinogenesis Apr 2019The permeability of endothelial cells is regulated by the stability of the adherens junctions, which is highly sensitive to kinase-mediated phosphorylation and...
The permeability of endothelial cells is regulated by the stability of the adherens junctions, which is highly sensitive to kinase-mediated phosphorylation and endothelial nitric oxide synthase (eNOS)-mediated S-nitrosylation of its protein components. Solid tumors can produce a variety of factors that stimulate these signaling pathways leading to endothelial cell hyperpermeability. This generates stromal conditions that facilitate tumoral growth and dissemination. Galectin-8 (Gal-8) is overexpressed in several carcinomas and has a variety of cellular effects that can contribute to tumor pathogenicity, including angiogenesis. Here we explored whether Gal-8 has also a role in endothelial permeability. We show that recombinant Gal-8 activates eNOS, induces S-nitrosylation of p120-catenin (p120) and dissociation of adherens junction, leading to hyperpermeability of the human endothelial cell line EAhy926. This pathway involves focal-adhesion kinase (FAK) activation downstream of eNOS as a requirement for eNOS-mediated p120 S-nitrosylation. This suggests a reciprocal, yet little understood, regulation of phosphorylation and S-nitrosylation events acting upon adherens junction permeability. In addition, glutathione S-transferase (GST)-Gal-8 pull-down experiments and function-blocking β1-integrin antibodies point to β1-integrins as cell surface components involved in Gal-8-induced hyperpermeability. Endogenous Gal-8 secreted from the breast cancer cell line MCF-7 has similar hyperpermeability and signaling effects. Furthermore, the mouse cremaster model system showed that Gal-8 also activates eNOS, induces S-nitrosylation of adherens junction components and is an effective hyperpermeability agent in vivo. These results add endothelial permeability regulation by S-nitrosylation as a new function of Gal-8 that can potentially contribute to the pathogenicity of tumors overexpressing this lectin.
Topics: Adherens Junctions; Animals; Cell Line, Tumor; Endothelial Cells; Focal Adhesion Kinase 1; Galectins; Glutathione Transferase; Humans; MCF-7 Cells; Male; Mice; Nitric Oxide Synthase Type III; Phosphorylation; Signal Transduction
PubMed: 30624618
DOI: 10.1093/carcin/bgz002 -
F1000Research 2019Mechanical forces drive the remodeling of tissues during morphogenesis. This relies on the transmission of forces between cells by cadherin-based adherens junctions,... (Review)
Review
Mechanical forces drive the remodeling of tissues during morphogenesis. This relies on the transmission of forces between cells by cadherin-based adherens junctions, which couple the force-generating actomyosin cytoskeletons of neighboring cells. Moreover, components of cadherin adhesions adopt force-dependent conformations that induce changes in the composition of adherens junctions, enabling transduction of mechanical forces into an intracellular response. Cadherin mechanotransduction can mediate reinforcement of cell-cell adhesions to withstand forces but also induce biochemical signaling to regulate cell behavior or direct remodeling of cell-cell adhesions to enable cell rearrangements. By transmission and transduction of mechanical forces, cadherin adhesions coordinate cellular behaviors underlying morphogenetic processes of collective cell migration, cell division, and cell intercalation. Here, we review recent advances in our understanding of this central role of cadherin adhesions in force-dependent regulation of morphogenesis.
Topics: Adherens Junctions; Cadherins; Cell Adhesion; Mechanotransduction, Cellular; Morphogenesis
PubMed: 31327995
DOI: 10.12688/f1000research.18779.1 -
EMBO Reports Oct 2019Serine/threonine phosphatases achieve substrate diversity by forming distinct holoenzyme complexes in cells. Although the PPP family of serine/threonine phosphatase...
Serine/threonine phosphatases achieve substrate diversity by forming distinct holoenzyme complexes in cells. Although the PPP family of serine/threonine phosphatase family members such as PP1 and PP2A are well known to assemble and function as holoenzymes, none of the PPM family members were so far shown to act as holoenzymes. Here, we provide evidence that PPM1G, a member of PPM family of serine/threonine phosphatases, forms a distinct holoenzyme complex with the PP2A regulatory subunit B56δ. B56δ promotes the re-localization of PPM1G to the cytoplasm where the phosphatase can access a discrete set of substrates. Further, we unveil α-catenin, a component of adherens junction, as a new substrate for the PPM1G-B56 phosphatase complex in the cytoplasm. B56δ-PPM1G dephosphorylates α-catenin at serine 641, which is necessary for the appropriate assembly of adherens junctions and the prevention of aberrant cell migration. Collectively, we reveal a new holoenzyme with PPM1G-B56δ as integral components, in which the regulatory subunit provides accessibility to distinct substrates for the phosphatase by defining its cellular localization.
Topics: Adherens Junctions; Cell Line, Tumor; Cell Movement; HEK293 Cells; Holoenzymes; Humans; Phosphorylation; Protein Binding; Protein Phosphatase 2; Protein Phosphatase 2C; Substrate Specificity; alpha Catenin
PubMed: 31432583
DOI: 10.15252/embr.201846965 -
Cellular and Molecular Gastroenterology... 2019
Topics: Adherens Junctions; Amino Acid Sequence; Antigens, CD; Caco-2 Cells; Cadherins; Epithelial Cells; Humans; Leukocyte Elastase; Peptides; Proteolysis; Wound Healing
PubMed: 30827416
DOI: 10.1016/j.jcmgh.2018.10.012 -
Current Opinion in Cell Biology Oct 2018The adherens junction has been historically considered an essential structural component of epithelial tissues. Although primarily discussed as targets of signaling... (Review)
Review
The adherens junction has been historically considered an essential structural component of epithelial tissues. Although primarily discussed as targets of signaling pathways responsible for cell fate and tissue remodeling, they have also emerged as critical signaling regulators in developmental processes or in disease progression. The recent discovery of a functional localized RNA interference (RNAi) machinery at epithelial adherens junctions revealed a new layer of signaling regulation that is directly associated with the structure itself. This and other findings also indicate that our view of the subcellular localization of RNAi requires revisiting. A number of questions emerge regarding the physiological role and the modes of regulation of the junctional RNAi machinery, pointing towards new directions of investigation.
Topics: Adherens Junctions; Animals; Cell Differentiation; Humans; Models, Biological; RNA; RNA Interference
PubMed: 29587176
DOI: 10.1016/j.ceb.2018.03.001 -
Current Topics in Microbiology and... 2017Highly organized intercellular tight and adherens junctions are crucial structural components for establishing and maintenance of epithelial barrier functions, which... (Review)
Review
Highly organized intercellular tight and adherens junctions are crucial structural components for establishing and maintenance of epithelial barrier functions, which control the microbiota and protect against intruding pathogens in humans. Alterations in these complexes represent key events in the development and progression of multiple infectious diseases as well as various cancers. The gastric pathogen Helicobacter pylori exerts an amazing set of strategies to manipulate these epithelial cell-to-cell junctions, which are implicated in changing cell polarity, migration and invasive growth as well as pro-inflammatory and proliferative responses. This chapter focuses on the H. pylori pathogenicity factors VacA, CagA, HtrA and urease, and how they can induce host cell signaling involved in altering cell-to-cell permeability. We propose a stepwise model for how H. pylori targets components of tight and adherens junctions in order to disrupt the gastric epithelial cell layer, giving fresh insights into the pathogenesis of this important bacterium.
Topics: Adherens Junctions; Animals; Bacterial Proteins; Epithelial Cells; Gastric Mucosa; Helicobacter Infections; Helicobacter pylori; Humans; Signal Transduction; Stomach; Tight Junctions; Virulence Factors
PubMed: 28124155
DOI: 10.1007/978-3-319-50520-6_9 -
Biology Open Mar 2023The Drosophila eye develops from the larval eye disc, a flattened vesicle comprised of continuous retinal and peripodial epithelia (PE). The PE is an epithelium that...
The Drosophila eye develops from the larval eye disc, a flattened vesicle comprised of continuous retinal and peripodial epithelia (PE). The PE is an epithelium that plays a supporting role in retinal neurogenesis, but gives rise to cuticle in the adult. We report here that the PE is also necessary to preserve the morphology of the retinal epithelium. Depletion of the adherens junction (AJ) components β-Catenin (β-Cat), DE-Cadherin or α-Catenin from the PE leads to altered disc morphology, characterized by retinal displacement (RDis); so too does loss of the Ajuba protein Jub, an AJ-associated regulator of the transcriptional coactivator Yorkie (Yki). Restoring AJs or overexpressing Yki in β-Cat deficient PE results in suppression of RDis. Additional suppressors of AJ-dependent RDis include knockdown of Rho kinase (Rok) and Dystrophin (Dys). Furthermore, knockdown of βPS integrin (Mys) from the PE results in RDis, while overexpression of Mys can suppress RDis induced by the loss of β-Cat. We thus propose that AJ-Jub-Yki signaling in PE cells regulates PE cell contractile properties and/or attachment to the extracellular matrix to promote normal eye disc morphology.
Topics: Animals; Adherens Junctions; Drosophila Proteins; Trans-Activators; Signal Transduction; Epithelium; Drosophila
PubMed: 36912729
DOI: 10.1242/bio.059579 -
Journal of Cellular Biochemistry 2002Cytoplasmic proteins associated with adherens junctions were identified in the chicken ocular lens. The catenins, alpha, beta, and gamma, were present in epithelial and...
Cytoplasmic proteins associated with adherens junctions were identified in the chicken ocular lens. The catenins, alpha, beta, and gamma, were present in epithelial and fiber cells, although their pattern of distribution changed with fiber cell differentiation. The sharp decline in alpha-catenin with fiber cell formation and the increasing Triton-insolubility of N-cadherin suggests that another subtype of alpha-catenin exists in the lens.
Topics: Adherens Junctions; Animals; Cadherins; Cells, Cultured; Chickens; Crystallins; Cytoskeletal Proteins; Electrophoresis, Polyacrylamide Gel; Immunoblotting; Lens, Crystalline; Octoxynol; Solubility
PubMed: 12210736
DOI: 10.1002/jcb.10258 -
PloS One 2012Endothelial cell junctions control blood vessel permeability. Altered permeability can be associated with vascular fragility that leads to vessel weakness and...
BACKGROUND
Endothelial cell junctions control blood vessel permeability. Altered permeability can be associated with vascular fragility that leads to vessel weakness and haemorrhage formation. In vivo studies on the function of genes involved in the maintenance of vascular integrity are essential to better understand the molecular basis of diseases linked to permeability defects. Ve-ptp (Vascular Endothelial-Protein Tyrosine Phosphatase) is a transmembrane protein present at endothelial adherens junctions (AJs).
METHODOLOGY/PRINCIPAL FINDINGS
We investigated the role of Ve-ptp in AJ maturation/stability and in the modulation of endothelial permeability using zebrafish (Danio rerio). Whole-mount in situ hybridizations revealed zve-ptp expression exclusively in the developing vascular system. Generation of altered zve-ptp transcripts, induced separately by two different splicing morpholinos, resulted in permeability defects closely linked to vascular wall fragility. The ultrastructural analysis revealed a statistically significant reduction of junction complexes and the presence of immature AJs in zve-ptp morphants but not in control embryos.
CONCLUSIONS/SIGNIFICANCE
Here we show the first in vivo evidence of a potentially critical role played by Ve-ptp in AJ maturation, an important event for permeability modulation and for the development of a functional vascular system.
Topics: Adherens Junctions; Animals; Base Sequence; Blood Vessels; Blotting, Western; Cells, Cultured; DNA Primers; Fluorescent Antibody Technique; Humans; In Situ Hybridization; Neovascularization, Physiologic; Receptor-Like Protein Tyrosine Phosphatases, Class 3; Reverse Transcriptase Polymerase Chain Reaction; Zebrafish
PubMed: 23251467
DOI: 10.1371/journal.pone.0051245 -
Inflammation Research : Official... May 2021As an integral part of the innate immune system, the epithelial membrane is exposed to an array of insults that may trigger an immune response. One of the immune... (Review)
Review
As an integral part of the innate immune system, the epithelial membrane is exposed to an array of insults that may trigger an immune response. One of the immune system's main functions is to regulate the level of communications between the mucosa and the lumen of various tissues. While it is clear that inhaled or ingested substances, or microorganisms may induce changes that affect the epithelial barrier in various ways, the proteins involved in the signaling cascades and physiological events leading to the regulation and maintenance of the barrier are not always well characterized. We review here some of the signaling components involved in regulating the barrier's paracellular permeability, and their potential effects on the activation of an immune response. While an effective immune response must be launched against pathogenic insults, tolerance must also be maintained for non-pathogenic antigens such as those in the commensal flora or for endogenous metabolites. Along with other members of the innate and adaptive immunity, the endocannabinoid system also plays an instrumental role in maintaining the balance between inflammation and tolerance. We discuss the potential effects of endo- and phytocannabinoids on epithelial permeability and how the dysregulation of this system could be involved in diseases and targeted for therapy.
Topics: Adherens Junctions; Animals; Cell Polarity; Epithelial Cells; Humans; Permeability; Tight Junctions
PubMed: 33721031
DOI: 10.1007/s00011-021-01454-1