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EBioMedicine Nov 2020Paracellular barriers play an important role in the pathogenesis of Inflammatory bowel disease (IBD) and maintain gut homeostasis. N-myc downstream-regulated gene 2...
BACKGROUND
Paracellular barriers play an important role in the pathogenesis of Inflammatory bowel disease (IBD) and maintain gut homeostasis. N-myc downstream-regulated gene 2 (NDRG2) has been reported to be a tumour suppressor gene and to inhibit colorectal cancer metastasis. However, whether NDRG2 affects colitis initiation and colitis-associated colorectal cancer is unclear.
METHODS
Intestine-specific Ndrg2 deficiency mice (Ndrg2) were subjected to DSS- or TNBS-induced colitis, and AOM-DSS-induced colitis-associated tumour. HT29 cells, Caco2 cells, primary intestinal epithelial cells (IECs) from Ndrg2 mice, mouse embryo fibroblasts (MEFs) from systemic Ndrg2 knockout mice, HEK293 cells and human UC and DC specimens were used to investigate NDRG2 function in colitis and colitis-associated tumour.
FINDINGS
Ndrg2 loss led to adherens junction (AJ) structure destruction via E-cadherin expression attenuation, resulting in diminished epithelial barrier function and increased intestinal epithelial permeability. Mechanistically, NDRG2 enhanced the interaction of E3 ligase FBXO11 with Snail, the repressor of E-cadherin, to promote Snail degradation by ubiquitination and maintained E-cadherin expression. In human ulcerative colitis patients, reduced NDRG2 expression is positively correlated with severe inflammation.
INTERPRETATION
These findings demonstrate that NDRG2 is an essential colonic epithelial barrier regulator and plays an important role in gut homeostasis maintenance and colitis-associated tumour development.
FUNDING
National Natural Science Foundation of China (No. 81770523, 31571437, 81672751), Creative Research Groups of China (No. 81421003), State Key Laboratory of Cancer Biology Project (CBSKL2019ZZ11, CBSKL201406, CBSKL2017Z08 and CBSKL2017Z11), Fund for Distinguished Young Scholars of ShaanXi province (2019JC-22).
Topics: Adaptor Proteins, Signal Transducing; Adherens Junctions; Animals; Cell Transformation, Neoplastic; Colitis; Colonic Neoplasms; Cytokines; Dextran Sulfate; Disease Models, Animal; Disease Progression; Gene Expression Regulation; Inflammation Mediators; Intestinal Mucosa; Mice; Mice, Knockout; Models, Biological; Permeability
PubMed: 33099085
DOI: 10.1016/j.ebiom.2020.103068 -
Journal of Cardiovascular Pharmacology May 2017Under physiological conditions, the arterial endothelium exerts a powerful protective influence to maintain vascular homeostasis. However, during the development of... (Review)
Review
Under physiological conditions, the arterial endothelium exerts a powerful protective influence to maintain vascular homeostasis. However, during the development of vascular disease, these protective activities are lost, and dysfunctional endothelial cells actually promote disease pathogenesis. Numerous investigations have analyzed the characteristics of dysfunctional endothelium with a view to understanding the processes responsible for the dysfunction and to determining their role in vascular pathology. This review adopts an alternate approach: reviewing the mechanisms that contribute to the initial formation of a healthy protective endothelium and on how those mechanisms may be disrupted, precipitating the appearance of dysfunctional endothelial cells and the progression of vascular disease. This approach, which highlights the role of endothelial adherens junctions and vascular endothelial-cadherin in endothelial maturation and endothelial dysfunction, provides new insight into the remarkable biology of this important cell layer and its role in vascular protection and vascular disease.
Topics: Adherens Junctions; Animals; Antigens, CD; Arteries; Cadherins; Cardiovascular Agents; Drug Design; Endothelial Cells; Endothelium, Vascular; Humans; Molecular Targeted Therapy; Signal Transduction; Vascular Diseases
PubMed: 28328747
DOI: 10.1097/FJC.0000000000000480 -
Cell Death & Disease Jul 2019The functions of Sertoli cells in spermatogenesis have attracted much more attention recently. Normal spermatogenesis depends on Sertoli cells, mainly due to their... (Review)
Review
The functions of Sertoli cells in spermatogenesis have attracted much more attention recently. Normal spermatogenesis depends on Sertoli cells, mainly due to their influence on nutrient supply, maintenance of cell junctions, and support for germ cells' mitosis and meiosis. Accumulating evidence in the past decade has highlighted the dominant functions of the MAPK, AMPK, and TGF-β/Smad signaling pathways during spermatogenesis. Among these pathways, the MAPK signaling pathway regulates dynamics of tight junctions and adherens junctions, proliferation and meiosis of germ cells, proliferation and lactate production of Sertoli cells; the AMPK and the TGF-β/Smad signaling pathways both affect dynamics of tight junctions and adherens junctions, as well as the proliferation of Sertoli cells. The AMPK signaling pathway also regulates lactate supply. These signaling pathways combine to form a complex regulatory network for spermatogenesis. In testicular tumors or infertile patients, the activities of these signaling pathways in Sertoli cells are abnormal. Clarifying the mechanisms of signaling pathways in Sertoli cells on spermatogenesis provides new insights into the physiological functions of Sertoli cells in male reproduction, and also serves as a pre-requisite to identify potential therapeutic targets in abnormal spermatogenesis including testicular tumor and male infertility.
Topics: Adherens Junctions; Animals; Carcinogenesis; Humans; Infertility, Male; Lactic Acid; Male; Sertoli Cells; Signal Transduction; Spermatogenesis; Testicular Neoplasms; Tight Junctions
PubMed: 31316051
DOI: 10.1038/s41419-019-1782-z -
Traffic (Copenhagen, Denmark) Dec 2016Cadherin-based adherens junctions are critical for connecting cells in tissues. Regulated cadherin trafficking also makes these complexes amazingly dynamic, with... (Review)
Review
Cadherin-based adherens junctions are critical for connecting cells in tissues. Regulated cadherin trafficking also makes these complexes amazingly dynamic, with permissive and instructive consequences on multicellular development. Here, we review how cadherin trafficking affects various forms of tissue morphogenesis from Drosophila and Caenorhabditis elegans to zebrafish, Xenopus and mouse. We describe how core trafficking machinery (such as clathrin, dynamin, Rab small G proteins and the exocyst complex) integrates with other molecular systems (transcriptional factors, signaling pathways, microtubules, actin networks, apico-basal polarity proteins and planar cell polarity proteins) to control cadherin endocytosis, exocytosis and recycling. This control can occur at all cell-cell contacts or specific junctions for distinct effects on tissue morphogenesis during animal development.
Topics: Adherens Junctions; Animals; Cadherins; Cell Polarity; Embryonic Development; Endocytosis; Exocytosis; Humans; Morphogenesis; Organogenesis; Protein Transport
PubMed: 27105637
DOI: 10.1111/tra.12407 -
Experimental Cell Research Sep 2017Cadherins are homophilic adhesion molecules with important functions in cell-cell adhesion, tissue morphogenesis, and cancer. In epithelial cells, E-cadherin accumulates... (Review)
Review
Cadherins are homophilic adhesion molecules with important functions in cell-cell adhesion, tissue morphogenesis, and cancer. In epithelial cells, E-cadherin accumulates at areas of cell-cell contact, coalesces into macromolecular complexes to form the adherens junctions (AJs), and associates via accessory partners with a subcortical ring of actin to form the apical zonula adherens (ZA). As a master regulator of the epithelial phenotype, E-cadherin is essential for the overall maintenance and homeostasis of polarized epithelial monolayers. Its expression is regulated by a host of genetic and epigenetic mechanisms related to cancer, and its function is modulated by mechanical forces at the junctions, by direct binding and phosphorylation of accessory proteins collectively termed catenins, by endocytosis, recycling and degradation, as well as, by multiple signaling pathways and developmental processes, like the epithelial to mesenchymal transition (EMT). Nuclear signaling mediated by the cadherin associated proteins β-catenin and p120 promotes growth, migration and pluripotency. Receptor tyrosine kinase, PI3K/AKT, Rho GTPase, and HIPPO signaling, are all regulated by E-cadherin mediated cell-cell adhesion. Finally, the recruitment of the microprocessor complex to the ZA by PLEKHA7, and the subsequent regulation of a small subset of miRNAs provide an additional mechanism by which the state of epithelial cell-cell adhesion affects translation of target genes to maintain the homeostasis of polarized epithelial monolayers. Collectively, the data indicate that loss of E-cadherin function, especially at the ZA, is a common and crucial step in cancer progression.
Topics: Adherens Junctions; Animals; Cadherins; Cell Adhesion; Epithelial Cells; Epithelial-Mesenchymal Transition; Humans; Neoplasms
PubMed: 28412244
DOI: 10.1016/j.yexcr.2017.04.006 -
The Journal of Biological Chemistry Nov 2019To perceive their three-dimensional environment, cells and tissues must be able to sense and interpret various physical forces like shear, tensile, and compression... (Review)
Review
To perceive their three-dimensional environment, cells and tissues must be able to sense and interpret various physical forces like shear, tensile, and compression stress. These forces can be generated both internally and externally in response to physical properties, like substrate stiffness, cell contractility, and forces generated by adjacent cells. Mechanical cues have important roles in cell fate decisions regarding proliferation, survival, and differentiation as well as the processes of tissue regeneration and wound repair. Aberrant remodeling of the extracellular space and/or defects in properly responding to mechanical cues likely contributes to various disease states, such as fibrosis, muscle diseases, and cancer. Mechanotransduction involves the sensing and translation of mechanical forces into biochemical signals, like activation of specific genes and signaling cascades that enable cells to adapt to their physical environment. The signaling pathways involved in mechanical signaling are highly complex, but numerous studies have highlighted a central role for the Hippo pathway and other signaling networks in regulating the YAP and TAZ (YAP/TAZ) proteins to mediate the effects of mechanical stimuli on cellular behavior. How mechanical cues control YAP/TAZ has been poorly understood. However, rapid progress in the last few years is beginning to reveal a surprisingly diverse set of pathways for controlling YAP/TAZ. In this review, we will focus on how mechanical perturbations are sensed through changes in the actin cytoskeleton and mechanosensors at focal adhesions, adherens junctions, and the nuclear envelope to regulate YAP/TAZ.
Topics: Actin Cytoskeleton; Adaptor Proteins, Signal Transducing; Adherens Junctions; Animals; Focal Adhesions; Humans; Mechanotransduction, Cellular; Signal Transduction; Trans-Activators; Transcription Factors; Transcriptional Coactivator with PDZ-Binding Motif Proteins; YAP-Signaling Proteins
PubMed: 31594864
DOI: 10.1074/jbc.REV119.007963 -
Frontiers in Cellular and Infection... 2023disseminates hematogenously to reach the target organs by disrupting epithelial adherens junctions (AJs), thus causing leptospirosis, which is a globally neglected...
disseminates hematogenously to reach the target organs by disrupting epithelial adherens junctions (AJs), thus causing leptospirosis, which is a globally neglected zoonotic disease. induces E-cadherin (E-cad) endocytosis and cytoskeletal rearrangement during AJ disassembly, but the detailed mechanism remains unknown. Elucidation of AJ disassembly mechanisms will guide new approaches to developing vaccines and diagnostic methods. In this study, we combine proteomic and imaging analysis with chemical inhibition studies to demonstrate that disrupting the AJs of renal proximal tubule epithelial cells involves the degradation of two armadillo repeat-containing proteins, p0071 and p120-catenin, that stabilize E-cad at the plasma membrane. Combining proteasomal and lysosomal inhibitors substantially prevented p120-catenin degradation, and monolayer integrity destruction without preventing p0071 proteolysis. In contrast, the pan-caspase inhibitor Z-VAD-FMK inhibited p0071 proteolysis and displacement of both armadillo repeat-containing proteins from the cell-cell junctions. Our results show that induces p120-catenin and p0071 degradation, which mutually regulates E-cad stability by co-opting multiple cellular degradation pathways. This strategy may allow to disassemble AJs and disseminate through the body efficiently.
Topics: Delta Catenin; Adherens Junctions; Leptospira interrogans; Proteomics; Catenins
PubMed: 37795382
DOI: 10.3389/fcimb.2023.1228051 -
Cell Adhesion & Migration 2015This review addresses our current understanding of the regulatory mechanism by which N-cadherin, a classical cadherin, affects neural progenitor cells (NPCs) during... (Review)
Review
This review addresses our current understanding of the regulatory mechanism by which N-cadherin, a classical cadherin, affects neural progenitor cells (NPCs) during development. N-cadherin is responsible for the integrity of adherens junctions (AJs), which develop in the sub-apical region of NPCs in the neural tube and brain cortex. The apical domain, which contains the sub-apical region, is involved in the switching from symmetric proliferative division to asymmetric neurogenic division of NPCs. In addition, N-cadherin-based AJ is deeply involved in the apico-basal polarity of NPCs and the regulation of Wnt-β-catenin, hedgehog (Hh), and Notch signaling. In this review, we discuss the roles of N-cadherin in the maintenance, proliferation, and differentiation of NPCs through components of AJ, β-catenin and αE-catenin.
Topics: Adherens Junctions; Animals; Cadherins; Cell Differentiation; Cell Polarity; Cell Proliferation; Hedgehog Proteins; Humans; Mice; Neural Stem Cells; Neural Tube; Signal Transduction; beta Catenin
PubMed: 25869655
DOI: 10.1080/19336918.2015.1005466 -
Journal of Cell Science Feb 2015The epithelium is a highly organized type of animal tissue. Except for blood and lymph vessels, epithelial cells cover the body, line its cavities in single or... (Review)
Review
The epithelium is a highly organized type of animal tissue. Except for blood and lymph vessels, epithelial cells cover the body, line its cavities in single or stratified layers and support exchange between compartments. In addition, epithelia offer to the body a barrier to pathogen invasion. To transit through or to replicate in epithelia, viruses have to face several obstacles, starting from cilia and glycocalyx where they can be neutralized by secreted immunoglobulins. Tight junctions and adherens junctions also prevent viruses to cross the epithelial barrier. However, viruses have developed multiple strategies to blaze their path through the epithelium by utilizing components of cell–cell adhesion structures as receptors. In this Commentary, we discuss how viruses take advantage of the apical junction complex to spread. Whereas some viruses quickly disrupt epithelium integrity, others carefully preserve it and use cell adhesion proteins and their cytoskeletal connections to rapidly spread laterally. This is exemplified by the hidden transmission of enveloped viruses that use nectins as receptors. Finally, several viruses that replicate preferentially in cancer cells are currently used as experimental cancer therapeutics. Remarkably, these viruses use cell adhesion molecules as receptors, probably because--to reach tumors and metastases--ncolytic viruses must efficiently traverse or break epithelia.
Topics: Adherens Junctions; Cell Adhesion; Cell Adhesion Molecules; Epithelial Cells; Epithelium; Humans; Receptors, Virus; Tight Junctions; Virus Internalization; Viruses
PubMed: 26046138
DOI: 10.1242/jcs.159400 -
Cardiovascular Research Mar 2017This review presents an extensively integrated model of the cardiac intercalated disc (ID), a highly orchestrated structure that connects adjacent cardiomyocytes.... (Review)
Review
This review presents an extensively integrated model of the cardiac intercalated disc (ID), a highly orchestrated structure that connects adjacent cardiomyocytes. Classically, three main structures are distinguished: gap junctions (GJs) metabolically and electrically connect cytoplasm of adjacent cardiomyocytes; adherens junctions (AJs) connect the actin cytoskeleton of adjacent cells; and desmosomes function as cell anchors and connect intermediate filaments. Furthermore, ion channels reside in the ID. Mutations in ID proteins have been associated with cardiac arrhythmias such as Brugada syndrome and arrhythmogenic cardiomyopathy. However, rather than being independent, all ID components work together intensively by multifunctional proteins such as ZO-1, Ankyrin G, and β-catenin, integrating mechanical and electrical functions. GJs form a plaque surrounded by the perinexus in which free connexons reside; the connexome integrates NaV channels, the desmosome and GJs; and the area composita hosts AJs and desmosomes, also integrated as adhering junctions. Furthermore, the transitional junction connects sarcomeres to the plasma membrane. Lastly, this review integrates all these findings in comprehensible figures, illustrating the interdependencies of ID proteins.
Topics: Adherens Junctions; Animals; Arrhythmias, Cardiac; Cell Communication; Desmosomes; Gap Junctions; Genetic Predisposition to Disease; Humans; Intercellular Junctions; Ion Channels; Mechanotransduction, Cellular; Membrane Proteins; Mutation; Myocytes, Cardiac; Signal Transduction
PubMed: 28069669
DOI: 10.1093/cvr/cvw259