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Cell Adhesion & Migration 2007Desmosomes are cell adhesion structures (junctions) that are particularly abundant in cells derived from the ectodermal lineages. These junctions are required to... (Review)
Review
Desmosomes are cell adhesion structures (junctions) that are particularly abundant in cells derived from the ectodermal lineages. These junctions are required to maintain the integrity of organs subjected to mechanical stress, in particular the skin and the heart. This conclusion is partially based on tissue fragility phenotypes observed in mice with null mutations in certain desmosomal genes. Furthermore, patients have been identified that develop severe skin disorders, and even fatal heart diseases, due to impaired desmosome function. Nevertheless, desmosomes are more than cellular glue. New evidence suggests that these junctions can transmit signals from the extracellular environment to the nucleus, for example by controling the cytoplasmic pool of transcriptional co-factors that belong to the armadillo family of desmosomal proteins (i.e. plakoglobin, plakophilins). Understanding the signaling properties of desmosomes will provide new insights into developmental processes such as skin and skin appendage development. Furthermore, there is evidence to suggest that abnormal signaling through these junctions contributes to the symptoms of certain skin and heart diseases.
Topics: Animals; Armadillo Domain Proteins; Cell Adhesion; Cell Nucleus; Desmosomes; Heart Diseases; Humans; Mice; Mice, Mutant Strains; Signal Transduction; Skin; Skin Diseases
PubMed: 19262094
DOI: 10.4161/cam.1.1.4204 -
Nature Reviews. Cancer May 2011Adherens junctions, which are intercellular adhesive complexes that are crucial for maintaining epithelial homeostasis, are downregulated in many cancers to promote... (Review)
Review
Adherens junctions, which are intercellular adhesive complexes that are crucial for maintaining epithelial homeostasis, are downregulated in many cancers to promote tumour progression. However, the role of desmosomes - adhesion complexes that are related to adherens junctions - in carcinogenesis has remained elusive. Recent studies using mouse genetic approaches have uncovered a role for desmosomes in tumour suppression, demonstrating that desmosome downregulation occurs before that of adherens junctions to drive tumour development and early invasion, suggesting a two-step model of adhesion dysfunction in cancer progression.
Topics: Adherens Junctions; Animals; Desmosomes; Humans; Neoplastic Processes; Tumor Suppressor Proteins
PubMed: 21508970
DOI: 10.1038/nrc3051 -
The Journal of Investigative Dermatology May 2021Intercellular adhesion is essential for tissue integrity and homeostasis. Desmosomes are abundant in the epidermis and the myocardium-tissues, which are under constantly...
Intercellular adhesion is essential for tissue integrity and homeostasis. Desmosomes are abundant in the epidermis and the myocardium-tissues, which are under constantly changing mechanical stresses. Yet, it is largely unclear whether desmosomal adhesion can be rapidly adapted to changing demands, and the mechanisms underlying desmosome turnover are only partially understood. In this study we show that the loss of the actin-binding protein α-adducin resulted in reduced desmosome numbers and prevented the ability of cultured keratinocytes or murine epidermis to withstand mechanical stress. This effect was not primarily caused by decreased levels or impaired adhesive properties of desmosomal molecules but rather by altered desmosome turnover. Mechanistically, reduced cortical actin density in α-adducin knockout keratinocytes resulted in increased mobility of the desmosomal adhesion molecule desmoglein 3 and impaired interactions with E-cadherin, a crucial step in desmosome formation. Accordingly, the loss of α-adducin prevented increased membrane localization of desmoglein 3 in response to cyclic stretch or shear stress. Our data demonstrate the plasticity of desmosomal molecules in response to mechanical stimuli and unravel a mechanism of how the actin cytoskeleton indirectly shapes intercellular adhesion by restricting the membrane mobility of desmosomal molecules.
Topics: Animals; Cadherins; Calcium; Calmodulin-Binding Proteins; Cell Adhesion; Cell Plasticity; Cells, Cultured; Desmoglein 3; Desmosomes; Humans; Mice; Microfilament Proteins
PubMed: 33098828
DOI: 10.1016/j.jid.2020.09.022 -
The Journal of Investigative Dermatology Feb 2022Dominant and recessive mutations in the desmosomal cadherin, desmoglein (DSG) 1, cause the skin diseases palmoplantar keratoderma (PPK) and severe dermatitis, multiple...
Dominant and recessive mutations in the desmosomal cadherin, desmoglein (DSG) 1, cause the skin diseases palmoplantar keratoderma (PPK) and severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome, respectively. In this study, we compare two dominant missense mutations in the DSG1 transmembrane domain (TMD), G557R and G562R, causing PPK (DSG1) and SAM syndrome (DSG1), respectively, to determine the differing pathomechanisms of these mutants. Expressing the DSG1 mutants in a DSG-null background, we use cellular and biochemical assays to reveal the differences in the mechanistic behavior of each mutant. Super-resolution microscopy and functional assays showed a failure by both mutants to assemble desmosomes due to reduced membrane trafficking and lipid raft targeting. DSG1 maintained normal expression levels and turnover relative to wildtype DSG1, but DSG1 lacked stability, leading to increased turnover through lysosomal and proteasomal pathways and reduced expression levels. These results differentiate the underlying pathomechanisms of these disorders, suggesting that DSG1 acts dominant negatively, whereas DSG1 is a loss-of-function mutation causing the milder PPK disease phenotype. These mutants portray the importance of the DSG TMD in desmosome function and suggest that a greater understanding of the desmosomal cadherin TMDs will further our understanding of the role that desmosomes play in epidermal pathophysiology.
Topics: Cell Adhesion; Cell Line, Tumor; Desmoglein 1; Desmosomal Cadherins; Desmosomes; Epidermis; Humans; Keratoderma, Palmoplantar; Loss of Function Mutation; Membrane Microdomains; Mutation, Missense; Protein Domains; Protein Stability
PubMed: 34352264
DOI: 10.1016/j.jid.2021.07.154 -
Desmosome-Dyad Crosstalk: An Arrhythmogenic Axis in Arrhythmogenic Right Ventricular Cardiomyopathy.Circulation May 2020
Topics: Arrhythmogenic Right Ventricular Dysplasia; Catecholamines; Desmosomes; Humans; Integrins; Plakophilins; Ryanodine Receptor Calcium Release Channel; Tachycardia, Ventricular
PubMed: 32364772
DOI: 10.1161/CIRCULATIONAHA.120.046020 -
The Journal of Cell Biology Aug 2011Desmosomes are cell-cell adhesion structures that integrate cytoskeletal networks. In addition to binding intermediate filaments, the desmosomal protein desmoplakin (DP)...
Desmosomes are cell-cell adhesion structures that integrate cytoskeletal networks. In addition to binding intermediate filaments, the desmosomal protein desmoplakin (DP) regulates microtubule reorganization in the epidermis. In this paper, we identify a specific subset of centrosomal proteins that are recruited to the cell cortex by DP upon epidermal differentiation. These include Lis1 and Ndel1, which are centrosomal proteins that regulate microtubule organization and anchoring in other cell types. This recruitment was mediated by a region of DP specific to a single isoform, DPI. Furthermore, we demonstrate that the epidermal-specific loss of Lis1 results in dramatic defects in microtubule reorganization. Lis1 ablation also causes desmosomal defects, characterized by decreased levels of desmosomal components, decreased attachment of keratin filaments, and increased turnover of desmosomal proteins at the cell cortex. This contributes to loss of epidermal barrier activity, resulting in completely penetrant perinatal lethality. This work reveals essential desmosome-associated components that control cortical microtubule organization and unexpected roles for centrosomal proteins in epidermal function.
Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Animals; Carrier Proteins; Cell Differentiation; Cell Proliferation; Cells, Cultured; Desmoplakins; Desmosomes; Epidermis; Fluorescent Antibody Technique; Keratinocytes; Mice; Mice, Knockout; Microtubule-Associated Proteins; Microtubules; Permeability; Protein Transport; Recombinant Fusion Proteins; Transfection; alpha Catenin
PubMed: 21844209
DOI: 10.1083/jcb.201104009 -
FEBS Letters Apr 2014This review summarizes data in support of the notion that the cardiac intercalated disc is the host of a protein interacting network, called "the connexome", where... (Review)
Review
This review summarizes data in support of the notion that the cardiac intercalated disc is the host of a protein interacting network, called "the connexome", where molecules classically defined as belonging to one particular structure (e.g., desmosomes, gap junctions, sodium channel complex) actually interact with others, and together, control excitability, electrical coupling and intercellular adhesion in the heart. The concept of the connexome is then translated into the understanding of the mechanisms leading to two inherited arrhythmia diseases: arrhythmogenic cardiomyopathy, and Brugada syndrome. The cross-over points in these two diseases are addressed to then suggest that, though separate identifiable clinical entities, they represent "bookends" of a spectrum of manifestations that vary depending on the effect that a particular mutation has on the connexome as a whole.
Topics: Arrhythmogenic Right Ventricular Dysplasia; Brugada Syndrome; Connexins; Desmosomes; Gap Junctions; Humans; Plakophilins; Voltage-Gated Sodium Channels
PubMed: 24548564
DOI: 10.1016/j.febslet.2014.02.008 -
Cell Communication & Adhesion Feb 2014Arrhythmogenic cardiomyopathy (AC) is a primary myocardial disorder characterized by a high incidence of ventricular arrhythmias often preceding the onset of ventricular... (Review)
Review
Arrhythmogenic cardiomyopathy (AC) is a primary myocardial disorder characterized by a high incidence of ventricular arrhythmias often preceding the onset of ventricular remodeling and dysfunction. Approximately 50% of patients diagnosed with AC have one or more mutations in genes encoding desmosomal proteins, although non-desmosomal genes have also been associated with the disease. Increasing evidence implicates remodeling of intercalated disk proteins reflecting abnormal responses to mechanical load and aberrant cell signaling pathways in the pathogenesis of AC. This review summarizes recent advances in understanding disease mechanisms in AC that have come from studies of human myocardium and experimental models.
Topics: Animals; Arrhythmogenic Right Ventricular Dysplasia; Desmoplakins; Desmosomes; Disease Models, Animal; Humans; Intercellular Junctions; Ventricular Remodeling; gamma Catenin
PubMed: 24460198
DOI: 10.3109/15419061.2013.876016 -
Cellular and Molecular Gastroenterology... 2022Desmosomes are intercellular junctions connecting keratin intermediate filaments of neighboring cells. The cadherins desmoglein 2 (Dsg2) and desmocollin 2 mediate...
BACKGROUND & AIMS
Desmosomes are intercellular junctions connecting keratin intermediate filaments of neighboring cells. The cadherins desmoglein 2 (Dsg2) and desmocollin 2 mediate cell-cell adhesion, whereas desmoplakin (Dsp) provides the attachment of desmosomes to keratins. Although the importance of the desmosome-keratin network is well established in mechanically challenged tissues, we aimed to assess the currently understudied function of desmosomal proteins in intestinal epithelia.
METHODS
We analyzed the intestine-specific villin-Cre DSP (DSP) and the combined intestine-specific DSG2/DSP (ΔDsg2/Dsp) knockout mice. Cross-breeding with keratin 8-yellow fluorescent protein knock-in mice and generation of organoids was performed to visualize the keratin network. A Dsp-deficient colorectal carcinoma HT29-derived cell line was generated and the role of Dsp in adhesion and mechanical stress was studied in dispase assays, after exposure to uniaxial cell stretching and during scratch assay.
RESULTS
The intestine of DSP mice was histopathologically inconspicuous. Intestinal epithelial cells, however, showed an accelerated migration along the crypt and an enhanced shedding into the lumen. Increased intestinal permeability and altered levels of desmosomal proteins were detected. An inconspicuous phenotype also was seen in ΔDsg2/Dsp mice. After dextran sodium sulfate treatment, DSP mice developed more pronounced colitis. A retracted keratin network was seen in the intestinal epithelium of DSP/keratin 8-yellow fluorescent protein mice and organoids derived from these mice presented a collapsed keratin network. The level, phosphorylation status, and solubility of keratins were not affected. Dsp-deficient HT29 cells had an impaired cell adhesion and suffered from increased cellular damage after stretch.
CONCLUSIONS
Our results show that Dsp is required for proper keratin network architecture in intestinal epithelia, mechanical resilience, and adhesion, thereby protecting from injury.
Topics: Animals; Cell Adhesion; Desmoplakins; Desmosomes; Keratin-8; Keratins; Mice
PubMed: 34929421
DOI: 10.1016/j.jcmgh.2021.12.009 -
Journal of Cell Science Mar 2020Cells and tissues sense, respond to and translate mechanical forces into biochemical signals through mechanotransduction, which governs individual cell responses that... (Review)
Review
Cells and tissues sense, respond to and translate mechanical forces into biochemical signals through mechanotransduction, which governs individual cell responses that drive gene expression, metabolic pathways and cell motility, and determines how cells work together in tissues. Mechanotransduction often depends on cytoskeletal networks and their attachment sites that physically couple cells to each other and to the extracellular matrix. One way that cells associate with each other is through Ca-dependent adhesion molecules called cadherins, which mediate cell-cell interactions through adherens junctions, thereby anchoring and organizing the cortical actin cytoskeleton. This actin-based network confers dynamic properties to cell sheets and developing organisms. However, these contractile networks do not work alone but in concert with other cytoarchitectural elements, including a diverse network of intermediate filaments. This Review takes a close look at the intermediate filament network and its associated intercellular junctions, desmosomes. We provide evidence that this system not only ensures tissue integrity, but also cooperates with other networks to create more complex tissues with emerging properties in sensing and responding to increasingly stressful environments. We will also draw attention to how defects in intermediate filament and desmosome networks result in both chronic and acquired diseases.
Topics: Adherens Junctions; Cadherins; Cell Adhesion; Cytoskeleton; Desmosomes; Intermediate Filaments; Mechanotransduction, Cellular
PubMed: 32179593
DOI: 10.1242/jcs.228031