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OncoTargets and Therapy 2017Desmosomes, which are intercellular adhesive complexes, are essential for the maintenance of epithelial homeostasis. They are located at the cell membrane, where they... (Review)
Review
Desmosomes, which are intercellular adhesive complexes, are essential for the maintenance of epithelial homeostasis. They are located at the cell membrane, where they act as anchors for intermediate filaments. Downregulation of desmosome proteins in various cancers promotes tumor progression. However, the role of desmosomes in carcinogenesis is still being elucidated. Recent studies revealed that desmosome family members play a crucial role in tumor suppression or tumor promotion. This review focuses on studies that provide insights into the role of desmosomes in carcinogenesis and address their molecular functions.
PubMed: 28860814
DOI: 10.2147/OTT.S136367 -
Current Opinion in Cell Biology Feb 2015Epithelial cells constitute the main barrier between the inside and outside of organs, acting as gatekeepers of their structure and integrity. Hemidesmosomes and... (Review)
Review
Epithelial cells constitute the main barrier between the inside and outside of organs, acting as gatekeepers of their structure and integrity. Hemidesmosomes and desmosomes are respectively cell-matrix and cell-cell adhesions coupled to the intermediate filament cytoskeleton. These adhesions ensure mechanical integrity of the epithelial barrier. Although desmosomes and hemidesmosomes are essential in maintaining strong cell-cell and cell-matrix adhesions, there is an emerging view that they should be remodeled in order to maintain epithelial homeostasis. Here we review the adhesion properties of desmosomes and hemidesmosomes, as well as the mechanisms driving their remodeling. We also discuss recent data suggesting that keratin-coupled adhesion complexes can sense the biomechanical cellular environment and participate in the cellular response to such external cues.
Topics: Animals; Biomechanical Phenomena; Cell Adhesion; Cell-Matrix Junctions; Cytoskeleton; Desmosomes; Epithelial Cells; Humans; Keratins
PubMed: 25460779
DOI: 10.1016/j.ceb.2014.10.004 -
JPMA. the Journal of the Pakistan... Aug 2020Cell-adhesion complex within a tissue is important for its stability, structural integrity, functioning, cellular migration and morphogenesis. Disruption of desmosomal... (Review)
Review
Cell-adhesion complex within a tissue is important for its stability, structural integrity, functioning, cellular migration and morphogenesis. Disruption of desmosomal cell-adhesions complex results in epithelial conditions such as epidermolysis bullosa and bullous pemphigoid. Desmosome assembly and disassembly is regulated post-translationally by calcium, kinase/phosphatase activity, proteolytic processing, and also through adhesive junctions. Altered functions of desmosomal proteins desmocollin and desmoglein can cause blistering disorders, such as pemphigus foliaceus and pemphigus vulgaris, and non-Hodgkin Lymphoma while defective desmoplakin can cause supra-basal clefting in epithelium and conditions such as Carvajal syndrome, palmo-plantar keratoderma etc. This review summarises major functions of demosomal complex family and how mis-regulation of demosomal structural proteins occur in pathogenesis of non-, pre- and malignant oral lesions with disrupted epithelium.
Topics: Desmosomes; Humans; Mouth Mucosa; Pemphigus
PubMed: 32794499
DOI: 10.5455/JPMA.15798 -
Current Heart Failure Reports Dec 2021Arrhythmogenic cardiomyopathy (ACM) is a genetic disease characterized by life-threatening ventricular arrhythmias and sudden cardiac death (SCD) in apparently healthy... (Review)
Review
PURPOSE OF REVIEW
Arrhythmogenic cardiomyopathy (ACM) is a genetic disease characterized by life-threatening ventricular arrhythmias and sudden cardiac death (SCD) in apparently healthy young adults. Mutations in genes encoding for cellular junctions can be found in about half of the patients. However, disease onset and severity, risk of arrhythmias, and outcome are highly variable and drug-targeted treatment is currently unavailable.
RECENT FINDINGS
This review focuses on advances in clinical risk stratification, genetic etiology, and pathophysiological concepts. The desmosome is the central part of the disease, but other intercalated disc and associated structural proteins not only broaden the genetic spectrum but also provide novel molecular and cellular insights into the pathogenesis of ACM. Signaling pathways and the role of inflammation will be discussed and targets for novel therapeutic approaches outlined. Genetic discoveries and experimental-driven preclinical research contributed significantly to the understanding of ACM towards mutation- and pathway-specific personalized medicine.
Topics: Arrhythmias, Cardiac; Arrhythmogenic Right Ventricular Dysplasia; Death, Sudden, Cardiac; Heart Failure; Humans; Mutation
PubMed: 34478111
DOI: 10.1007/s11897-021-00532-z -
Kidney International May 2024Desmosomes are multi-protein cell-cell adhesion structures supporting cell stability and mechanical stress resilience of tissues, best described in skin and heart. The...
Desmosomes are multi-protein cell-cell adhesion structures supporting cell stability and mechanical stress resilience of tissues, best described in skin and heart. The kidney is exposed to various mechanical stimuli and stress, yet little is known about kidney desmosomes. In healthy kidneys, we found desmosomal proteins located at the apical-junctional complex in tubular epithelial cells. In four different animal models and patient biopsies with various kidney diseases, desmosomal components were significantly upregulated and partly miss-localized outside of the apical-junctional complexes along the whole lateral tubular epithelial cell membrane. The most upregulated component was desmoglein-2 (Dsg2). Mice with constitutive tubular epithelial cell-specific deletion of Dsg2 developed normally, and other desmosomal components were not altered in these mice. When challenged with different types of tubular epithelial cell injury (unilateral ureteral obstruction, ischemia-reperfusion, and 2,8-dihydroxyadenine crystal nephropathy), we found increased tubular epithelial cell apoptosis, proliferation, tubular atrophy, and inflammation compared to wild-type mice in all models and time points. In vitro, silencing DSG2 via siRNA weakened cell-cell adhesion in HK-2 cells and increased cell death. Thus, our data show a prominent upregulation of desmosomal components in tubular cells across species and diseases and suggest a protective role of Dsg2 against various injurious stimuli.
Topics: Animals; Humans; Mice; Cell Adhesion; Desmoglein 2; Desmosomes; Heart; Kidney Diseases
PubMed: 38395410
DOI: 10.1016/j.kint.2024.01.037 -
Cell and Tissue Research Jun 2015The stratum corneum of the epidermis is composed of stacked dead corneocytes embedded in lipid layers and is the main protective shield of the skin. The thickness of the... (Review)
Review
The stratum corneum of the epidermis is composed of stacked dead corneocytes embedded in lipid layers and is the main protective shield of the skin. The thickness of the stratum corneum is maintained fairly constantly through the balance between new cell creation and old cell removal. Corneodesmosomes are the main intercellular adhesive structures in the stratum corneum. They are transformed from desmosomes at the most superficial layer of the stratum granulosum of the epidermis. The major compositional distinction from desmosomes is the presence of corneodesmosin in the extracellular portion. Furthermore, corneodesmosomes are structurally different from desmosomes in that (1) they do not have a tri-lamellar desmoglea but rather one that is homogeneously electron-dense and (2) attachment plaques are integrated into a part of the cornified cell envelopes. When the extracellular regions of corneodesmosomes are fully degraded, desquamation occurs. The degradation process of corneodesmosomes is carefully controlled by a number of proteases and their inhibitors. The most important proteases involved in this process are the kallikrein-related peptidases. Their main inhibitor is the lympho-epithelial Kazal-type related inhibitor. Other regulators of this process include matriptase, meprin and mesotrypsin.
Topics: Animals; Desmosomes; Epidermis; Humans; Models, Biological; Proteolysis
PubMed: 25407522
DOI: 10.1007/s00441-014-2037-z -
Oral Diseases Mar 2017The large number of diseases occurring when desmosome constituents are impaired provides striking evidence for the key role of desmosomes in maintaining tissue... (Review)
Review
The large number of diseases occurring when desmosome constituents are impaired provides striking evidence for the key role of desmosomes in maintaining tissue integrity. A detailed understanding of the molecular alterations causing desmosomal dysfunction has, in turn, underpinned the development of novel diagnostic tools. This has salient clinical implications for dentists and oral medicine practitioners because the majority of desmosomal diseases affect the oral cavity. In the present article, we review the autoimmune, infectious, genetic, and neoplastic diseases that target the desmosome, with particular emphasis on clinical manifestations, diagnostic pathways, and relevant laboratory investigations.
Topics: Autoantibodies; Desmoglein 1; Desmoglein 2; Desmosomes; Genetic Diseases, Inborn; Humans; Infections; Mouth Diseases; Pemphigus
PubMed: 27329525
DOI: 10.1111/odi.12527 -
The Journal of Dermatology Feb 2023The major autoantigens for pemphigus are desmogleins (Dsgs), cell-cell adhesive structure proteins, one of the desmosomal cadherins. Recent progress in molecular biology... (Review)
Review
The major autoantigens for pemphigus are desmogleins (Dsgs), cell-cell adhesive structure proteins, one of the desmosomal cadherins. Recent progress in molecular biology has revealed that IgG autoantibodies of classical pemphigus react with Dsg1 or Dsg3. Desmocollins (Dscs) also belong to the cadherin supergene family that provides structure to the desmosomes and play an important role in cell-to-cell adhesion. In addition to the presence of four desmosomal Dsg isoforms, i.e. Dsg1-4, Dsc1, 2 and 3, all of which are derived from different genes, Dsc1 has been previously identified as the target antigen of IgA autoantibodies in the subcorneal pustular dermatosis (SPD)-type of intercellular IgA dermatosis. In addition to the IgA anti-Dsc1 autoantiboides, the presence of IgG anti-Dsc autoantibodies is described in patients of some autoimmune bullous diseases. In particular, the current pemphigus detecting autoantibodies to Dscs has shown a tendency in atypical variants of pemphigus. Therefore, autoantibodies against Dscs alone may cause detachment of cell-cell adhesion in the epidermis in some pemphigus. However, except for the findings of a few in vitro and in vivo studies, there is currently no clear evidence for the pathogenicity of anti-Dsc autoantibodies in pemphigus, whereas significance of anti-Dsg autoantibodies is well established. This article describes the structure and function of the Dscs, and explores the evidence regarding the pathogenic role of anti-Dsc autoantibodies in pemphigus.
Topics: Humans; Pemphigus; Autoantibodies; Desmocollins; Skin Diseases, Vesiculobullous; Desmoglein 1; Desmoglein 3; Immunoglobulin A; Immunoglobulin G
PubMed: 36578135
DOI: 10.1111/1346-8138.16660 -
Journal of Cell Science Jun 2024Desmosomes are relatives of ancient cadherin-based junctions, which emerged late in evolution to ensure the structural integrity of vertebrate tissues by coupling the... (Review)
Review
Desmosomes are relatives of ancient cadherin-based junctions, which emerged late in evolution to ensure the structural integrity of vertebrate tissues by coupling the intermediate filament cytoskeleton to cell-cell junctions. Their ability to dynamically counter the contractile forces generated by actin-associated adherens junctions is particularly important in tissues under high mechanical stress, such as the skin and heart. Much more than the simple cellular 'spot welds' depicted in textbooks, desmosomes are in fact dynamic structures that can sense and respond to changes in their mechanical environment and external stressors like ultraviolet light and pathogens. These environmental signals are transmitted intracellularly via desmosome-dependent mechanochemical pathways that drive the physiological processes of morphogenesis and differentiation. This Cell Science at a Glance article and the accompanying poster review desmosome structure and assembly, highlight recent insights into how desmosomes integrate chemical and mechanical signaling in the epidermis, and discuss desmosomes as targets in human disease.
Topics: Desmosomes; Humans; Animals; Epidermis
PubMed: 38940346
DOI: 10.1242/jcs.261899 -
Apremilast prevents blistering in human epidermis and stabilizes keratinocyte adhesion in pemphigus.Nature Communications Jan 2023Pemphigus vulgaris is a life-threatening blistering skin disease caused by autoantibodies destabilizing desmosomal adhesion. Current therapies focus on suppression of...
Pemphigus vulgaris is a life-threatening blistering skin disease caused by autoantibodies destabilizing desmosomal adhesion. Current therapies focus on suppression of autoantibody formation and thus treatments directly stabilizing keratinocyte adhesion would fulfill an unmet medical need. We here demonstrate that apremilast, a phosphodiesterase 4 inhibitor used in psoriasis, prevents skin blistering in pemphigus vulgaris. Apremilast abrogates pemphigus autoantibody-induced loss of keratinocyte cohesion in ex-vivo human epidermis, cultured keratinocytes in vitro and in vivo in mice. In parallel, apremilast inhibits keratin retraction as well as desmosome splitting, induces phosphorylation of plakoglobin at serine 665 and desmoplakin assembly into desmosomal plaques. We established a plakoglobin phospho-deficient mouse model that reveals fragile epidermis with altered organization of keratin filaments and desmosomal cadherins. In keratinocytes derived from these mice, intercellular adhesion is impaired and not rescued by apremilast. These data identify an unreported mechanism of desmosome regulation and propose that apremilast stabilizes keratinocyte adhesion and is protective in pemphigus.
Topics: Humans; Mice; Animals; Pemphigus; gamma Catenin; Cell Adhesion; Keratinocytes; Epidermis; Blister; Autoantibodies; Keratins; Desmosomes
PubMed: 36624106
DOI: 10.1038/s41467-022-35741-0