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Journal of Cell Science Sep 2014Desmosomes are prominent adhesive junctions found in various epithelial tissues. The cytoplasmic domains of desmosomal cadherins interact with a host of desmosomal...
Desmosomes are prominent adhesive junctions found in various epithelial tissues. The cytoplasmic domains of desmosomal cadherins interact with a host of desmosomal plaque proteins, including plakophilins, plakoglobin and desmoplakin, which, in turn, recruit the intermediate filament cytoskeleton to sites of cell-cell contact. Although the individual components of the desmosome are known, mechanisms regulating the assembly of this junction are poorly understood. Protein palmitoylation is a posttranslational lipid modification that plays an important role in protein trafficking and function. Here, we demonstrate that multiple desmosomal components are palmitoylated in vivo. Pharmacologic inhibition of palmitoylation disrupts desmosome assembly at cell-cell borders. We mapped the site of plakophilin palmitoylation to a conserved cysteine residue present in the armadillo repeat domain. Mutation of this single cysteine residue prevents palmitoylation, disrupts plakophilin incorporation into the desmosomal plaque and prevents plakophilin-dependent desmosome assembly. Finally, plakophilin mutants unable to become palmitoylated act in a dominant-negative manner to disrupt proper localization of endogenous desmosome components and decrease desmosomal adhesion. Taken together, these data demonstrate that palmitoylation of desmosomal components is important for desmosome assembly and adhesion.
Topics: Cell Line, Tumor; Cell Movement; Desmoplakins; Desmosomes; Humans; Lipoylation; Plakophilins; gamma Catenin
PubMed: 25002405
DOI: 10.1242/jcs.149849 -
Cell Communication & Adhesion Dec 2014Desmosomes are the most important intercellular adhering junctions that adhere two adjacent keratinocytes directly with desmosomal cadherins, that is, desmogleins (Dsgs)... (Review)
Review
Desmosomes are the most important intercellular adhering junctions that adhere two adjacent keratinocytes directly with desmosomal cadherins, that is, desmogleins (Dsgs) and desmocollins, forming an epidermal sheet. Recently, two cell-cell adhesion states of desmosomes, that is, "stable hyper-adhesion" and "dynamic weak-adhesion" conditions have been recognized. They are mutually reversible through cell signaling events involving protein kinase C (PKC), Src and epidermal growth factor receptor (EGFR) during Ca(2+)-switching and wound healing. This remodeling is impaired in pemphigus vulgaris (PV, an autoimmune blistering disease), caused by anti-Dsg3 antibodies. The antibody binding to Dsg3 activates PKC, Src and EGFR, linked to generation of dynamic weak-adhesion desmosomes, followed by p38MAPK-mediated endocytosis of Dsg3, resulting in the specific depletion of Dsg3 from desmosomes and acantholysis. A variety of pemphigus outside-in signaling may explain different clinical (non-inflammatory, inflammatory, and necrolytic) types of pemphigus. Pemphigus could be referred to a "desmosome-remodeling disease involving pemphigus IgG-activated outside-in signaling events".
Topics: Animals; Desmosomes; Humans; Keratins; Models, Biological; Pemphigus; Signal Transduction
PubMed: 25078507
DOI: 10.3109/15419061.2014.943397 -
Cell Motility and the Cytoskeleton 1995Desmosomes are one component of the intercellular junctional complex in epithelia. In cultures of epithelial cells, desmosome assembly can be regulated by modulating the...
Desmosomes are one component of the intercellular junctional complex in epithelia. In cultures of epithelial cells, desmosome assembly can be regulated by modulating the calcium concentrations of the growth media. At present, very little is known about the intracellular signal transduction mechanisms that regulate desmosome assembly and disassembly in response to changing extracellular calcium concentrations. We have used inhibitors of protein kinases and phosphatases in a combined biochemical and morphological approach to analyze the role of protein phosphorylation in the assembly and disassembly of desmosomes in Madin-Darby canine kidney epithelial cells. Our results suggest that desmosomal proteins (desmoplakins I/II and desmoglein 1) are primarily phosphorylated on serine residues. Electron microscopic analyses of desmosome assembly upon induction of cell-cell contact, in the presence of protein kinase inhibitor, H-7, revealed an apparently normal assembly of desmosomes. However, complete disassembly of desmosomes was inhibited by H-7 upon removal of extracellular calcium. Under these conditions, although desmosomes split, desmosomal plaques and their associated cytokeratin filaments can not be internalized. In contrast, treatment of the cultures with okadaic acid (OA), an inhibitor of protein phosphatases, inhibited desmosome assembly but had no effect on disassembly. In addition, the inhibitory effect of okadaic acid on desmosome assembly was specific to this junction since we observed apparently normal tight junction and adherens junction in okadaic acid-treated cultures. These results suggest that assembly and disassembly of desmosomes may be regulated by extracellular Ca2+ via reversible protein phosphorylation involving both protein kinase and protein phosphatases.
Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Calcium; Cell Line; Cytoskeletal Proteins; Desmoglein 1; Desmogleins; Desmoplakins; Desmosomes; Epithelial Cells; Isoquinolines; Phosphoric Monoester Hydrolases; Phosphorylation; Piperazines; Protein Kinase C; Protein Kinase Inhibitors; Proteins
PubMed: 7606804
DOI: 10.1002/cm.970300203 -
Current Biology : CB May 2020Cadherin-based cell-cell junctions help metazoans form polarized sheets of cells, which are necessary for the development of organs and the compartmentalization of... (Review)
Review
Cadherin-based cell-cell junctions help metazoans form polarized sheets of cells, which are necessary for the development of organs and the compartmentalization of functions. The components of the protein complexes that generate cadherin-based junctions have ancient origins, with conserved elements shared between animals as diverse as sponges and vertebrates. In invertebrates, the formation and function of epithelial sheets depends on classical cadherin-containing adherens junctions, which link actin to the plasma membrane through α-, β- and p120 catenins. Vertebrates also have a new type of cadherin-based intercellular junction called the desmosome, which allowed for the creation of more complex and effective tissue barriers against environmental stress. While desmosomes have a molecular blueprint that is similar to that of adherens junctions, desmosomal cadherins - called desmogleins and desmocollins - link intermediate filaments (IFs) rather than actin to the plasma membrane through protein complexes comprising relatives of β-catenin (plakoglobin) and p120 catenin (plakophilins). In turn, desmosomal catenins interact with members of the IF-binding plakin family to create the desmosome-IF linking complex. In this Minireview, we discuss when and how desmosomal components evolved, and how their ability to anchor the highly elastic and tough IF cytoskeleton endowed vertebrates with robust tissues capable of not only resisting but also properly responding to environmental stress.
Topics: Animals; Biological Evolution; Desmosomes; Gene Expression Regulation; Membrane Proteins
PubMed: 32428495
DOI: 10.1016/j.cub.2020.03.047 -
The Journal of Investigative Dermatology Jan 2016Expression and interaction of desmosomal components and keratins provide stable cell cohesion and protect the epidermis against various types of stress. The...
Expression and interaction of desmosomal components and keratins provide stable cell cohesion and protect the epidermis against various types of stress. The differentiation-specific isotype composition of the keratin cytoskeleton and desmosomes is regarded as a major determinant of adhesive strength. In support, wound healing is characterized by a transient decrease in desmosomal adhesion accompanied by increased expression of keratins K6/K16/K17 at the expense of K1/K10. The significance of altered keratin expression for desmosomal composition and adhesion remains incompletely understood at a mechanistic and functional level. Here, we investigated the respective contribution of K5/K14 or K6/K17 to desmosome adhesion, on their stable re-expression in keratinocytes lacking all keratins. This revealed that K5/K14 filaments support stable desmosomes, whereas "wound healing" keratins K6/K17 induce elevated protein kinase C alpha-mediated desmosome disassembly and subsequent destabilization of epithelial sheets. Moreover, our data suggest that K5/K14 sequester protein kinase C alpha in the cytoplasm, whereas K6/K17 or the absence of all keratins enables protein kinase C alpha translocation to the plasma membrane and induction of desmosome disassembly. Gain- and loss-of-function experiments support a major role of K5 in desmosome stability control via protein kinase C alpha. Our data show that keratin isotypes differently and specifically regulate wound healing and invasion by modulating intercellular adhesion.
Topics: Biotinylation; Blotting, Western; Cell Differentiation; Cell Fractionation; Cells, Cultured; Cytoskeleton; Desmosomes; Epidermal Cells; Epidermis; Gene Silencing; Humans; Keratinocytes; Microscopy, Fluorescence; Protein Kinase C-alpha; Real-Time Polymerase Chain Reaction; Sensitivity and Specificity; Wound Healing
PubMed: 26763440
DOI: 10.1038/JID.2015.403 -
The Journal of Investigative Dermatology Aug 2009
Topics: Adherens Junctions; Animals; Cadherins; Desmosomes; Mice
PubMed: 19262605
DOI: 10.1038/jid.2009.17 -
Current Opinion in Cardiology May 2018To date 16 genes have been associated with arrhythmogenic cardiomyopathy (ACM). Mutations in these genes can lead to a broad spectrum of phenotypic expression ranging... (Review)
Review
PURPOSE OF REVIEW
To date 16 genes have been associated with arrhythmogenic cardiomyopathy (ACM). Mutations in these genes can lead to a broad spectrum of phenotypic expression ranging from disease affecting predominantly the right or left ventricle, to biventricular subtypes. Understanding the genetic causes of ACM is important in diagnosis and management of the disorder. This review summarizes recent advances in molecular genetics and discusses the application of next-generation sequencing technology in genetic testing in ACM.
RECENT FINDINGS
Use of next-generation sequencing methods has resulted in the identification of novel causative variants and genes for ACM. The involvement of filamin C in ACM demonstrates the genetic overlap between ACM and other types of cardiomyopathy. Putative pathogenic variants have been detected in cadherin 2 gene, a protein involved in cell adhesion. Large genomic rearrangements in desmosome genes have been systematically investigated in a cohort of ACM patients.
SUMMARY
Recent studies have identified novel causes of ACM providing new insights into the genetic spectrum of the disease and highlighting an overlapping phenotype between ACM and dilated cardiomyopathy. Next-generation sequencing is a useful tool for research and genetic diagnostic screening but interpretation of identified sequence variants requires caution and should be performed in specialized centres.
Topics: Arrhythmogenic Right Ventricular Dysplasia; DNA; Desmosomes; Genetic Predisposition to Disease; Genetic Testing; Heart Ventricles; Humans; Mutation; Pedigree; Phenotype; Prognosis; Ventricular Function, Left
PubMed: 29543670
DOI: 10.1097/HCO.0000000000000509 -
The Journal of Investigative Dermatology Jan 2007
Topics: Cell Adhesion; Desmoplakins; Desmosomes
PubMed: 21270806
DOI: 10.1038/sj.skinbio.6250002 -
Nature Cell Biology Dec 2001
Review
Topics: Animals; Cytoskeletal Proteins; Desmoplakins; Desmosomes; Epithelial Cells
PubMed: 11781580
DOI: 10.1038/ncb1201-e270 -
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