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Frontiers in Cell and Developmental... 2022While classic cadherin-actin connections in adherens junctions (AJs) have ancient origins, intermediate filament (IF) linkages with desmosomal cadherins arose in... (Review)
Review
While classic cadherin-actin connections in adherens junctions (AJs) have ancient origins, intermediate filament (IF) linkages with desmosomal cadherins arose in vertebrate organisms. In this mini-review, we discuss how overlaying the IF-desmosome network onto the existing cadherin-actin network provided new opportunities to coordinate tissue mechanics with the positioning and function of chemical signaling mediators in the ErbB family of receptor tyrosine kinases. We focus in particular on the complex multi-layered outer covering of the skin, the epidermis, which serves essential barrier and stress sensing/responding functions in terrestrial vertebrates. We will review emerging data showing that desmosome-IF connections, AJ-actin interactions, ErbB family members, and membrane tension are all polarized across the multiple layers of the regenerating epidermis. Importantly, their integration generates differentiation-specific roles in each layer of the epidermis that dictate the form and function of the tissue. In the basal layer, the onset of the differentiation-specific desmosomal cadherin desmoglein 1 (Dsg1) dials down EGFR signaling while working with classic cadherins to remodel cortical actin cytoskeleton and decrease membrane tension to promote cell delamination. In the upper layers, Dsg1 and E-cadherin cooperate to maintain high tension and tune EGFR and ErbB2 activity to create the essential tight junction barrier. Our final outlook discusses the emerging appreciation that the desmosome-IF scaffold not only creates the architecture required for skin's physical barrier but also creates an immune barrier that keeps inflammation in check.
PubMed: 35686051
DOI: 10.3389/fcell.2022.903696 -
Trends in Cardiovascular Medicine Oct 2021Arrhythmogenic cardiomyopathy (ACM) is a familial disease, with approximately 60% of patients displaying a pathogenic variant. The majority of genes linked to ACM code... (Review)
Review
Arrhythmogenic cardiomyopathy (ACM) is a familial disease, with approximately 60% of patients displaying a pathogenic variant. The majority of genes linked to ACM code for components of the desmosome: plakophilin-2 (PKP2), desmoglein-2 (DSG2) and desmocollin-2 (DSC2), plakoglobin (JUP) and desmoplakin (DSP). Genetic variants involving the desmosomes are known to cause dysfunction of cell-to-cell adhesions and intercellular gap junctions. In turn, this may result in failure to mechanically hold together the cardiomyocytes, fibrofatty myocardial replacement, cardiac conduction delay and ventricular arrhythmias. It is becoming clearer that pathogenic variants in desmosomal genes such as PKP2 are not only responsible for a mechanical dysfunction of the intercalated disc (ID), but are also the cause of various pro-arrhythmic mechanisms. In this review, we discuss in detail the different molecular interactions associated with desmosomal pathogenic variants, and their contribution to various ACM phenotypes.
Topics: Arrhythmias, Cardiac; Arrhythmogenic Right Ventricular Dysplasia; Desmosomes; Humans; Myocardium; Plakophilins
PubMed: 32738304
DOI: 10.1016/j.tcm.2020.07.006 -
Cancers Jan 2015Desmoglein 3 is one of seven desmosomal cadherins that mediate cell-cell adhesion in desmosomes. Desmosomes are the intercellular junctional complexes that anchor the... (Review)
Review
Desmoglein 3 is one of seven desmosomal cadherins that mediate cell-cell adhesion in desmosomes. Desmosomes are the intercellular junctional complexes that anchor the intermediate filaments of adjacent cells and confer strong cell adhesion thus are essential in the maintenance of tissue architecture and structural integrity. Like adherens junctions, desmosomes function as tumour suppressors and are down regulated in the process of epithelial-mesenchymal transition and in tumour cell invasion and metastasis. However, recently several studies have shown that various desmosomal components, including desmoglein 3, are up-regulated in cancer with increased levels of expression correlating with the clinical stage of malignancy, implicating their potentiality to serve as a diagnostic and prognostic marker. Furthermore, in vitro studies have demonstrated that overexpression of desmoglein 3 in cancer cell lines activates several signal pathways that have an impact on cell morphology, adhesion and locomotion. These additional signalling roles of desmoglein 3 may not be associated to its adhesive function in desmosomes but rather function outside of the junctions, acting as a key regulator in the control of actin based cellular processes. This review will discuss recent advances which support the role of desmoglein 3 in cancer progression.
PubMed: 25629808
DOI: 10.3390/cancers7010266 -
The American Journal of Gastroenterology Jul 2021We assessed if obesity perturbs the esophageal epithelial barrier function independent of promotion of gastroesophageal reflux (GER).
INTRODUCTION
We assessed if obesity perturbs the esophageal epithelial barrier function independent of promotion of gastroesophageal reflux (GER).
METHODS
Thirty-eight participants were divided into 4 groups: Obesity-/GER-, Obesity+/GER-, Obesity-/GER+, and Obesity+/GER+. Esophageal intercellular space and desmosome density (structural integrity) and fluorescein leak (functional integrity) were measured.
RESULTS
The Obesity+/GER- group demonstrated increased intercellular space, reduced desmosome density, and increased fluorescein leak compared with control subjects. These changes were similar but not additive to findings seen in Obesity-/GER + and Obesity+/GER+ patients.
DISCUSSION
Central obesity impairs structural and functional integrity of the esophageal barrier independent of GER, likely predisposing to esophageal injury.
Topics: Adult; Aged; Desmosomes; Esophageal Mucosa; Extracellular Space; Female; Gastroesophageal Reflux; Humans; Male; Middle Aged; Obesity, Abdominal; Permeability
PubMed: 33955725
DOI: 10.14309/ajg.0000000000001196 -
Comprehensive review on the pathophysiology, clinical variants and management of pemphigus (Review).Experimental and Therapeutic Medicine Nov 2021Pemphigus represents a group of chronic inflammatory disorders characterized by autoantibodies that target components of desmosomes, leading to the loss of intercellular... (Review)
Review
Pemphigus represents a group of chronic inflammatory disorders characterized by autoantibodies that target components of desmosomes, leading to the loss of intercellular adhesion between keratinocytes and causing intraepithelial blistering. The pemphigus group consists of four main clinical types with several variants: pemphigus vulgaris (with pemphigus vegetans and pemphigus herpetiformis as variants), pemphigus foliaceus, paraneoplastic pemphigus and IgA pemphigus (with two clinical variants: intraepidermal neutrophilic IgA dermatosis and subcorneal pustular dermatosis). Genetic factors are involved in the pathogenesis, with HLA-DR4 (DRB1*0402) and HLA-DRw6 (DQB1*0503) allele more common in patients with pemphigus vulgaris, HLA class II DRB1*0344 and HLA Cw*1445 correlated with paraneoplastic pemphigus, and HLA-DRB1*04:01, HLA-DRB1*04:06, HLA-DRB1*01:01, HLA-DRB1*14, associated with a higher risk of developing pemphigus foliaceus. Autoantibodies are conducted against structural desmosomal proteins in the skin and mucous membranes, mainly desmogleins, desmocollins and plakins. Cell-mediated immunity may also play a role, especially in paraneoplastic pemphigus. Patients may present erythema, blisters, erosions, and ulcers that may affect the skin, as well as mucosal surfaces of the oral cavity, eyes, nose, leading to severe complaints including pain, dysphagia, and fetor. Oral mucosal postbullous erosive lesions are frequently the first sign of disease in pemphigus vulgaris and in paraneoplastic pemphigus, without skin involvement, making the diagnosis difficult. Treatment options classically include immunosuppressive agents, such as corticosteroids and corticosteroid-sparing agents such as azathioprine, mycophenolate mofetil, cyclophosphamide, methotrexate or dapsone. Newer therapies focus on blocking cell signaling events induced by pathogenic autoantibodies and/or targeting specific autoantibodies. The disease evolution is conditioned by the treatment with maximum doses of corticosteroids and the side effects associated with long-term immunosuppressive therapy, which is why patients need a multidisciplinary approach in following the treatment. In this review, we provide a comprehensive overview of the epidemiology, pathophysiology, clinical aspect, diagnosis and management of the main intraepidermal blistering diseases from the pemphigus group.
PubMed: 34630689
DOI: 10.3892/etm.2021.10770 -
Journal of Cardiovascular Magnetic... Jul 2014Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is one of the most arrhythmogenic forms of inherited cardiomyopathy and a frequent cause of sudden death in the... (Review)
Review
Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is one of the most arrhythmogenic forms of inherited cardiomyopathy and a frequent cause of sudden death in the young. Affected individuals typically present between the second and fourth decade of life with arrhythmias coming from the right ventricle. Pathogenic mutations in genes encoding the cardiac desmosome can be found in approximately 60% of index patients, leading to our current perception of ARVC as a desmosomal disease. Although ARVC is known to preferentially affect the right ventricle, early and/or predominant left ventricular involvement is increasingly recognized. Diagnosis is made by combining multiple sources of diagnostic information as prescribed by the "Task Force" criteria. Recent research suggests that electrical abnormalities precede structural changes in ARVC. Cardiovascular Magnetic Resonance (CMR) is an ideal technique in ARVC workup, as it provides comprehensive information on cardiac morphology, function, and tissue characterization in a single investigation. Prevention of sudden cardiac death using implantable cardioverter-defibrillators is the most important management consideration. This purpose of this paper is to provide an updated review of our understanding of the genetics, diagnosis, current state-of-the-art CMR acquisition and analysis, and management of patients with ARVC.
Topics: Arrhythmogenic Right Ventricular Dysplasia; Death, Sudden, Cardiac; Defibrillators, Implantable; Electric Countershock; Genetic Markers; Genetic Predisposition to Disease; Heart Conduction System; Humans; Magnetic Resonance Imaging; Mutation; Myocardium; Phenotype; Predictive Value of Tests; Risk Factors; Treatment Outcome; Ventricular Function, Right
PubMed: 25191878
DOI: 10.1186/s12968-014-0050-8 -
Frontiers in Cell and Developmental... 2019Cell-cell adhesion plays a key role in the maintenance of the epithelial barrier and apicobasal cell polarity, which is crucial for homeostasis. Disruption of cell-cell... (Review)
Review
Cell-cell adhesion plays a key role in the maintenance of the epithelial barrier and apicobasal cell polarity, which is crucial for homeostasis. Disruption of cell-cell adhesion is a hallmark of numerous pathological conditions, including invasive carcinomas. Adhesion between apposing cells is primarily regulated by three types of junctional structures: desmosomes, adherens junctions, and tight junctions. Cell junctional structures are highly regulated multiprotein complexes that also serve as signaling platforms to control epithelial cell function. The biogenesis, integrity, and stability of cell junctions is controlled by complex regulatory interactions with cytoskeletal and polarity proteins, as well as modulation of key component proteins by phosphorylation/dephosphorylation processes. Not surprisingly, many essential signaling molecules, including protein Ser/Thr phosphatase 2A (PP2A) are associated with intercellular junctions. Here, we examine how major PP2A enzymes regulate epithelial cell-cell junctions, either directly by associating with and dephosphorylating component proteins, or indirectly by affecting signaling pathways that control junctional integrity and cytoskeletal dynamics. PP2A deregulation has severe consequences on the stability and functionality of these structures, and disruption of cell-cell adhesion and cell polarity likely contribute to the link between PP2A dysfunction and human carcinomas.
PubMed: 30895176
DOI: 10.3389/fcell.2019.00030 -
Proceedings of the National Academy of... Dec 2020We combine proximity labeling and single molecule binding assays to discover transmembrane protein interactions in cells. We first screen for candidate binding partners...
We combine proximity labeling and single molecule binding assays to discover transmembrane protein interactions in cells. We first screen for candidate binding partners by tagging the extracellular and cytoplasmic regions of a "bait" protein with BioID biotin ligase and identify proximal proteins that are biotin tagged on both their extracellular and intracellular regions. We then test direct binding interactions between proximal proteins and the bait, using single molecule atomic force microscope binding assays. Using this approach, we identify binding partners for the extracellular region of E-cadherin, an essential cell-cell adhesion protein. We show that the desmosomal proteins desmoglein-2 and desmocollin-3, the focal adhesion protein integrin-α2β1, the receptor tyrosine kinase ligand ephrin-B1, and the classical cadherin P-cadherin, all directly interact with E-cadherin ectodomains. Our data shows that combining extracellular and cytoplasmic proximal tagging with a biophysical binding assay increases the precision with which transmembrane ectodomain interactors can be identified.
Topics: Cadherins; Cell Adhesion; Cytoplasm; Desmocollins; Desmoglein 2; Desmoplakins; Desmosomes; Ephrin-B1; Humans; Integrins; Microscopy, Atomic Force; Protein Binding; Protein Domains; Protein Interaction Maps; Single Molecule Imaging
PubMed: 33229577
DOI: 10.1073/pnas.2010209117 -
Molecular Biology of the Cell May 2020Desmosomes are cell-cell adhesions necessary for the maintenance of tissue integrity in the skin and heart. While the core components of desmosomes have been identified,...
Desmosomes are cell-cell adhesions necessary for the maintenance of tissue integrity in the skin and heart. While the core components of desmosomes have been identified, peripheral components that modulate canonical or noncanonical desmosome functions still remain largely unexplored. Here we used targeted proximity labeling approaches to further elaborate the desmosome proteome in epidermal keratinocytes. Quantitative mass spectrometry analysis identified all core desmosomal proteins while uncovering a diverse array of new constituents with broad molecular functions. By individually targeting the inner and outer dense plaques, we defined proteins enriched within these subcompartments. We validated a number of these novel desmosome-associated proteins and find that many are membrane proximal proteins that show a dependence on functional desmosomes for their cortical localization. We further explored the mechanism of localization and function of two novel desmosome-associated adaptor proteins enriched in the desmosome proteome, Crk and Crk-like (CrkL). These proteins interacted with Dsg1 and rely on Dsg1 and desmoplakin for robust cortical localization. Epidermal deletion of both Crk and CrkL resulted in perinatal lethality with defects in desmosome morphology and keratin organization, thus demonstrating the utility of this dataset in identifying novel proteins required for desmosome-dependent epidermal integrity.
Topics: Adaptor Proteins, Signal Transducing; Animals; Cell Adhesion; Cytoskeleton; Desmoplakins; Desmosomes; Epidermal Cells; Epidermis; Humans; Keratinocytes; Keratins; Male; Mass Spectrometry; Membrane Proteins; Mice; Mice, Inbred C57BL; Proteomics; Proto-Oncogene Proteins c-crk; Skin
PubMed: 32238101
DOI: 10.1091/mbc.E19-09-0542 -
Biophysical Reviews Aug 2018Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease, associated with a high risk of sudden cardiac death. ARVC has been termed a... (Review)
Review
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease, associated with a high risk of sudden cardiac death. ARVC has been termed a 'disease of the desmosome' based on the fact that in many cases, it is caused by mutations in genes encoding desmosomal proteins at the specialised intercellular junctions between cardiomyocytes, the intercalated discs. Desmosomes maintain the structural integrity of the ventricular myocardium and are also implicated in signal transduction pathways. Mutated desmosomal proteins are thought to cause detachment of cardiac myocytes by the loss of cellular adhesions and also affect signalling pathways, leading to cell death and substitution by fibrofatty adipocytic tissue. However, mutations in desmosomal proteins are not the sole cause for ARVC as mutations in non-desmosomal genes were also implicated in its pathogenesis. This review will consider the pathology, genetic basis and mechanisms of pathogenesis for ARVC.
PubMed: 29995277
DOI: 10.1007/s12551-018-0437-0