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Cold Spring Harbor Perspectives in... Apr 2018Cell-cell junctions link cells to each other in tissues, and regulate tissue homeostasis in critical cell processes that include tissue barrier function, cell... (Review)
Review
Cell-cell junctions link cells to each other in tissues, and regulate tissue homeostasis in critical cell processes that include tissue barrier function, cell proliferation, and migration. Defects in cell-cell junctions give rise to a wide range of tissue abnormalities that disrupt homeostasis and are common in genetic abnormalities and cancers. Here, we discuss the organization and function of cell-cell junctions primarily involved in adhesion (tight junction, adherens junction, and desmosomes) in two different epithelial tissues: a simple epithelium (intestine) and a stratified epithelium (epidermis). Studies in these tissues reveal similarities and differences in the organization and functions of different cell-cell junctions that meet the requirements for the specialized functions of each tissue. We discuss cell-cell junction responses to genetic and environmental perturbations that provide further insights into their roles in maintaining tissue homeostasis.
Topics: Adherens Junctions; Animals; Cell Movement; Cell Proliferation; Desmosomes; Epithelial Cells; Epithelium; Homeostasis; Humans; Intercellular Junctions; Intestinal Mucosa; Signal Transduction; Tight Junctions; Wound Healing
PubMed: 28600395
DOI: 10.1101/cshperspect.a029181 -
Current Biology : CB Nov 2023Various functions within our bodies require the generation and maintenance of compartments with distinct compositions, which in turn necessitate the formation of...
Various functions within our bodies require the generation and maintenance of compartments with distinct compositions, which in turn necessitate the formation of semipermeable cellular diffusion barriers. For example, the blood-brain barrier protects the brain by allowing only specific molecules to pass through. Another instance is the intestinal barrier, which allows the uptake of essential nutrients, while restricting the passage of pathogenic molecules and bacteria. Breakdown of such barriers causes various pathologies, such as brain or retinal edema, or diarrhoea. Epithelia and endothelia are the most common barrier-forming cells. Individual cells in such barriers are held together by cell-cell adhesion structures - also known as intercellular junctions - that are essential for barrier formation and maintenance. Here, we will focus on the structure and assembly of tight junctions (TJs) and their functions as barriers, but will refer to other adhesive structures crucial for barrier regulation such as adherens junctions (AJs) and focal adhesions to the extracellular matrix (ECM) (Figure 1A,B). We will also discuss additional functions of TJs in cell surface polarity and the regulation of gene expression, cell function, and cell behaviour.
Topics: Tight Junctions; Intercellular Junctions; Cell Adhesion; Adherens Junctions; Brain
PubMed: 37935122
DOI: 10.1016/j.cub.2023.09.027 -
The Journal of Clinical Investigation Nov 2019Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with rising incidence. Diseased tissues are heavily vascularized. Surprisingly, the pathogenic impact... (Clinical Trial)
Clinical Trial
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with rising incidence. Diseased tissues are heavily vascularized. Surprisingly, the pathogenic impact of the vasculature in IBD and the underlying regulatory mechanisms remain largely unknown. IFN-γ is a major cytokine in IBD pathogenesis, but in the context of the disease, it is almost exclusively its immune-modulatory and epithelial cell-directed functions that have been considered. Recent studies by our group demonstrated that IFN-γ also exerts potent effects on blood vessels. Based on these considerations, we analyzed the vessel-directed pathogenic functions of IFN-γ and found that it drives IBD pathogenesis through vascular barrier disruption. Specifically, we show that inhibition of the IFN-γ response in vessels by endothelial-specific knockout of IFN-γ receptor 2 ameliorates experimentally induced colitis in mice. IFN-γ acts pathogenic by causing a breakdown of the vascular barrier through disruption of the adherens junction protein VE-cadherin. Notably, intestinal vascular barrier dysfunction was also confirmed in human IBD patients, supporting the clinical relevance of our findings. Treatment with imatinib restored VE-cadherin/adherens junctions, inhibited vascular permeability, and significantly reduced colonic inflammation in experimental colitis. Our findings inaugurate the pathogenic impact of IFN-γ-mediated intestinal vessel activation in IBD and open new avenues for vascular-directed treatment of this disease.
Topics: Adherens Junctions; Adult; Aged; Animals; Antigens, CD; Cadherins; Endothelial Cells; Female; Humans; Imatinib Mesylate; Inflammatory Bowel Diseases; Interferon-gamma; Male; Mice; Mice, Knockout; Middle Aged
PubMed: 31566580
DOI: 10.1172/JCI124884 -
Proceedings of the National Academy of... Jun 2019Increased pulmonary microvessel pressure experienced in left heart failure, head trauma, or high altitude can lead to endothelial barrier disruption referred to as...
Increased pulmonary microvessel pressure experienced in left heart failure, head trauma, or high altitude can lead to endothelial barrier disruption referred to as capillary "stress failure" that causes leakage of protein-rich plasma and pulmonary edema. However, little is known about vascular endothelial sensing and transduction of mechanical stimuli inducing endothelial barrier disruption. Piezo1, a mechanosensing ion channel expressed in endothelial cells (ECs), is activated by elevated pressure and other mechanical stimuli. Here, we demonstrate the involvement of Piezo1 in sensing increased lung microvessel pressure and mediating endothelial barrier disruption. Studies were made in mice in which Piezo1 was deleted conditionally in ECs ( ), and lung microvessel pressure was increased either by raising left atrial pressure or by aortic constriction. We observed that lung endothelial barrier leakiness and edema induced by raising pulmonary microvessel pressure were abrogated in mice. Piezo1 signaled lung vascular hyperpermeability by promoting the internalization and degradation of the endothelial adherens junction (AJ) protein VE-cadherin. Breakdown of AJs was the result of activation of the calcium-dependent protease calpain and degradation of the AJ proteins VE-cadherin, β-catenin, and p120-catenin. Deletion of Piezo1 in ECs or inhibition of calpain similarly prevented reduction in the AJ proteins. Thus, Piezo1 activation in ECs induced by elevated lung microvessel pressure mediates capillary stress failure and edema formation secondary to calpain-induced disruption of VE-cadherin adhesion. Inhibiting Piezo1 signaling may be a useful strategy to limit lung capillary stress failure injury in response to elevated vascular pressures.
Topics: Adherens Junctions; Animals; Antigens, CD; Arterial Pressure; Blood Pressure; Cadherins; Capillary Permeability; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Endothelium, Vascular; Female; Gene Knock-In Techniques; Humans; Hydrostatic Pressure; Intercellular Signaling Peptides and Proteins; Ion Channels; Lung; Male; Mechanotransduction, Cellular; Mice; Mice, Knockout; Microscopy, Electron, Transmission; Microvessels; Primary Cell Culture; Pulmonary Edema; Respiratory Insufficiency; Spider Venoms
PubMed: 31186359
DOI: 10.1073/pnas.1902165116 -
Journal of Gastroenterology Feb 2019Acute and chronic pancreatitises are gastrointestinal inflammatory diseases, the incidence of which is increasing worldwide. Most (~ 80%) acute pancreatitis (AP)... (Review)
Review
Acute and chronic pancreatitises are gastrointestinal inflammatory diseases, the incidence of which is increasing worldwide. Most (~ 80%) acute pancreatitis (AP) patients have mild disease, and about 20% have severe disease, which causes multiple organ failure and has a high mortality rate. Chronic pancreatitis (CP) is characterized by chronic inflammation and destruction of normal pancreatic parenchyma, which leads to loss of exocrine and endocrine tissues. Patients with CP also have a higher incidence of pancreatic ductal adenocarcinoma. Although a number of factors are associated with the development and progression of AP and CP, the underlying mechanism is unclear. Adhesion molecules play important roles in cell migration, proliferation, and signal transduction, as well as in development and tissue repair. Loosening of cell-cell adhesion between pancreatic acinar cells and/or endothelial cells increases solute permeability, resulting in interstitial edema, which promotes inflammatory cell migration and disrupts tissue structure. Oxidative stress, which is one of the important pathogenesis of pancreatitis, leads to upregulation of adhesion molecules. Soluble adhesion molecules are reportedly involved in AP. In this review, we focus on the roles of tight junctions (occludin, tricellulin, claudin, junctional adhesion molecule, and zonula occludin), adherens junctions (E-cadherin and p120-, α-, and β-catenin), and other adhesion molecules (selectin and intercellular adhesion molecules) in the progression of AP and CP. Maintaining the normal function of adhesion molecules and preventing their abnormal activation maintain the structure of the pancreas and prevent the development of pancreatitis.
Topics: Adherens Junctions; Animals; Cadherins; Catenins; Cell Adhesion Molecules; Humans; Intercellular Adhesion Molecule-1; Pancreatitis; Tight Junction Proteins; Tight Junctions
PubMed: 30140950
DOI: 10.1007/s00535-018-1500-0 -
Tissue Barriers 2019The endothelium physically separates blood from surrounding tissue and yet allows for the regulated passage of nutrients, waste, and leukocytes into and out of the... (Review)
Review
The endothelium physically separates blood from surrounding tissue and yet allows for the regulated passage of nutrients, waste, and leukocytes into and out of the circulation. Trans-endothelium flux occurs across endothelial cells (transcellular) and between endothelial cells (paracellular). Paracellular endothelial barrier function depends on the regulation of cell-cell junctions. Interestingly, a functional relationship between cell-cell junctions and cell-matrix adhesions has long been appreciated but the molecular mechanisms underpinning this relationship are not fully understood. Here we review the evidence that supports the notion that cell-matrix interactions contribute to the regulation of cell-cell junctions, focusing primarily on the important adherens junction protein VE-cadherin. In particular, we will discuss recent insights gained into how integrin signaling impacts VE-cadherin stability in adherens junctions and endothelial barrier function.
Topics: Adherens Junctions; Endothelial Cells; Humans; Integrins
PubMed: 31690180
DOI: 10.1080/21688370.2019.1685844 -
Developmental Cell Oct 2018During epithelial tissue development, repair, and homeostasis, adherens junctions (AJs) ensure intercellular adhesion and tissue integrity while allowing for cell and... (Review)
Review
During epithelial tissue development, repair, and homeostasis, adherens junctions (AJs) ensure intercellular adhesion and tissue integrity while allowing for cell and tissue dynamics. Mechanical forces play critical roles in AJs' composition and dynamics. Recent findings highlight that beyond a well-established role in reinforcing cell-cell adhesion, AJ mechanosensitivity promotes junctional remodeling and polarization, thereby regulating critical processes such as cell intercalation, division, and collective migration. Here, we provide an integrated view of mechanosensing mechanisms that regulate cell-cell contact composition, geometry, and integrity under tension and highlight pivotal roles for mechanosensitive AJ remodeling in preserving epithelial integrity and sustaining tissue dynamics.
Topics: Adherens Junctions; Animals; Cadherins; Cell Adhesion; Epithelial Cells; Epithelium; Humans; Mechanotransduction, Cellular; Morphogenesis
PubMed: 30300588
DOI: 10.1016/j.devcel.2018.09.014 -
Nature Aging Sep 2023The age-related decline in the ability of the intestinal barrier to maintain selective permeability can lead to various physiological disturbances. Adherens junctions...
The age-related decline in the ability of the intestinal barrier to maintain selective permeability can lead to various physiological disturbances. Adherens junctions play a vital role in regulating intestinal permeability, and their proper assembly is contingent upon endocytic recycling. However, how aging affects the recycling efficiency and, consequently, the integrity of adherens junctions remains unclear. Here we show that RAB-10/Rab10 functionality is reduced during senescence, leading to impaired adherens junctions in the Caenorhabditis elegans intestine. Mechanistic analysis reveals that SDPN-1/PACSINs is upregulated in aging animals, suppressing RAB-10 activation by competing with DENN-4/GEF. Consistently, SDPN-1 knockdown alleviates age-related abnormalities in adherens junction integrity and intestinal barrier permeability. Of note, the inhibitory effect of SDPN-1 on RAB-10 requires KGB-1/JUN kinase, which presumably enhances the potency of SDPN-1 by altering its oligomerization state. Together, by examining age-associated changes in endocytic recycling, our study sheds light on how aging can impact intestinal barrier permeability.
Topics: Animals; Adherens Junctions; Aging; Biological Transport; Caenorhabditis elegans; Intestines; Caenorhabditis elegans Proteins; JNK Mitogen-Activated Protein Kinases
PubMed: 37640905
DOI: 10.1038/s43587-023-00475-1 -
Journal of Cell Science Jan 2017Mucosal barriers separate self from non-self and are essential for life. These barriers, which are the first line of defense against external pathogens, are formed by... (Review)
Review
Mucosal barriers separate self from non-self and are essential for life. These barriers, which are the first line of defense against external pathogens, are formed by epithelial cells and the substances they secrete. Rather than an absolute barrier, epithelia at mucosal surfaces must allow selective paracellular flux that discriminates between solutes and water while preventing the passage of bacteria and toxins. In vertebrates, tight junctions seal the paracellular space; flux across the tight junction can occur through two distinct routes that differ in selectivity, capacity, molecular composition and regulation. Dysregulation of either pathway can accompany disease. A third, tight-junction-independent route that reflects epithelial damage can also contribute to barrier loss during disease. In this Cell Science at a Glance article and accompanying poster, we present current knowledge on the molecular components and pathways that establish this selectively permeable barrier and the interactions that lead to barrier dysfunction during disease.
Topics: Actomyosin; Adherens Junctions; Animals; Claudins; Humans; Mucins; Mucous Membrane; Permeability; Tight Junctions
PubMed: 28062847
DOI: 10.1242/jcs.193482 -
Advances in Experimental Medicine and... 2017Adhesion, segregation, and cellular plasticity are regulated by actin filaments anchored at the plaques of adherens junctions, sites of mechanical stabilization, and... (Review)
Review
Adhesion, segregation, and cellular plasticity are regulated by actin filaments anchored at the plaques of adherens junctions, sites of mechanical stabilization, and interfaces of multiple signaling networks. Drebrins were originally identified in neuronal cells, but the isoform drebrin E was also detected at adherens junctions of a wide range of non-neuronal cells, including polarized epithelia, endothelia, and fibroblasts. Here the protein is enriched at actin filament bundles associated with junctional plaques. Polarized epithelial cells contain two types of actin-associated complexes, one comprising drebrin but not vinculin and the other involving vinculin, but not drebrin. At gap junctions drebrin interacts with connexin 43, stabilizes this protein at membranes, and links it to the actin cytoskeleton. In vivo drebrin is widespread in diverse non-neuronal tissues of epithelial, endothelial, and smooth muscle origin, but not ubiquitous. In intestinal cells it is involved in cell compaction, linking of actin filaments to microtubules and formation and stabilization of the terminal web. Upregulation of drebrin was noted in several types of cancers, e.g., basal cell carcinomas for which it may serve as marker, liver metastases of colon carcinomas, and bladder cancer, suggesting that it is involved in regulating actin dynamics during tumor development, progression, and metastasis.
Topics: Actin Cytoskeleton; Adherens Junctions; Animals; Biomarkers, Tumor; Connexin 43; Humans; Microtubules; Neoplasms; Neuropeptides; Protein Interaction Maps; Vinculin
PubMed: 28865028
DOI: 10.1007/978-4-431-56550-5_18