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James K Wahl - One of the best experts on this subject based on the ideXlab platform.
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stratifin 14 3 3 σ limits plakophilin 3 exchange with the desmosomal plaque
PLOS ONE, 2013Co-Authors: Brett J. Roberts, Roopa Reddy, James K WahlAbstract:Desmosomes are prominent cell-cell adhesive junctions in stratified squamous epithelia and disruption of desmosomal adhesion has been shown to have dramatic effects on the function and integrity of these tissues. During normal physiologic processes, such as tissue development and wound healing, intercellular adhesion must be modified locally to allow coordinated cell movements. The mechanisms that control junction integrity and adhesive strength under these conditions are poorly understood. We utilized a proteomics approach to identify plakophilin-3 associated proteins and identified the 14-3-3 family member stratifin. Stratifin interacts specifically with plakophilin-3 and not with other plakophilin isoforms and mutation analysis demonstrated the binding site includes serine 285 in the amino terminal head domain of plakophilin-3. Stratifin interacts with a cytoplasmic pool of plakophilin-3 and is not associated with the Desmosome in cultured cells. FRAP analysis revealed that decreased stratifin expression leads to an increase in the exchange rate of cytoplasmic plakophilin-3/GFP with the pool of plakophilin-3/GFP in the Desmosome resulting in decreased desmosomal adhesion and increased cell migration. We propose a model by which stratifin plays a role in regulating plakophilin-3 incorporation into the desmosomal plaque by forming a plakophilin-3 stratifin complex in the cytosol and thereby affecting Desmosome dynamics in squamous epithelial cells.
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carboxyl terminus of plakophilin 1 recruits it to plasma membrane whereas amino terminus recruits desmoplakin and promotes Desmosome assembly
Journal of Biological Chemistry, 2006Co-Authors: Tammy Sobolikdelmaire, Dawn M Katafiasz, James K WahlAbstract:Plakophilins are armadillo repeat-containing proteins, initially identified as desmosomal plaque proteins that have subsequently been shown to also localize to the nucleus. Loss of plakophilin-1 is the underlying cause of ectodermal dysplasia/skin fragility syndrome, and skin from these patients exhibits Desmosomes that are reduced in size and number. Thus, it has been suggested that plakophilin-1 plays an important role in Desmosome stability and/or assembly. In this study, we used a cell culture system (A431DE cells) that expresses all of the proteins necessary to assemble a Desmosome, except plakophilin-1. Using this cell line, we sought to determine the role of plakophilin-1 in de novo Desmosome assembly. When exogenous plakophilin-1 was expressed in these cells, Desmosomes were assembled, as assessed by electron microscopy and immunofluorescence localization of desmoplakin, into punctate structures. Deletion mutagenesis experiments revealed that amino acids 686–726 in the carboxyl terminus of plakophilin-1 are required for its localization to the plasma membrane. In addition, we showed that amino acids 1–34 in the amino terminus were necessary for subsequent recruitment of desmoplakin to the membrane and Desmosome assembly.
R A J Eady - One of the best experts on this subject based on the ideXlab platform.
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Desmosomes exhibit site specific features in human palm skin
Experimental Dermatology, 2003Co-Authors: Hong Wan, Patricia J C Doppinghepenstal, M J Gratian, John A Mcgrath, Michael G Stone, R A J EadyAbstract:Hereditary skin disorders resulting from Desmosome gene pathology may preferentially involve the palms and soles. Why this is so is not clear. Moreover, even in normal control skin it is unknown whether there are differences in Desmosome number, size or structural organization in palmoplantar sites compared with skin from other body regions. Therefore, we sought evidence for such differences by examining Desmosome expression in relation to epidermal differentiation in both epidermis and cultured keratinocytes from normal human palm and breast skin samples. Confocal microscopy of skin biopsy material showed relative differences in the expression profiles of several desmosomal proteins (desmogleins, desmocollins, desmoplakin, plakoglobin and plakophilin 1) between the two sites. Western blotting revealed a higher expression level of all five proteins in palm compared with breastcultured keratinocytes. Staining for the differentiation-associated component, involucrin, suggested an earlier onset of synthesis of this protein in palm epidermis, and a suspension-induced differentiation assay showed that involucrin synthesis began earlier in palm keratinocytes than in breast cells. At 4-8 h, the number of involucrin-positive cells in palm keratinocytes was almost twice that in breast. Morphometric analysis showed that, overall, Desmosomes were larger but of similar population density in the palm compared with breast skin. These findings demonstrate differences in Desmosome structure and protein expression between the two sites, possibly reflecting the needs of palms and soles to withstand constant mechanical stress. They may also help to explain the preferential involvement of this region in certain hereditary disorders (palmoplantar keratodermas), associated with mutations in desmoplakin or desmoglein 1.
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mutations in the plakophilin 1 gene result in ectodermal dysplasia skin fragility syndrome
Nature Genetics, 1997Co-Authors: John A Mcgrath, David R. Garrod, James R Mcmillan, I M Leigh, Carrie S Shemanko, S K Runswick, E B Lane, R A J EadyAbstract:Members of the armadillo protein gene family, which includes plakoglobin and beta-catenin, have important functions in cytoskeleton/cell membrane interactions. These proteins may act as linker molecules at adherens junctions and Desmosomes at the plasma membrane; in addition, they may have pivotal roles in signal transduction pathways and significant effects on cell behaviour during development. Here, we describe the first human mutations in one of these dual function proteins, plakophilin 1 (band-6 protein; refs 8-10). The affected individual has a complete absence of immunostaining for plakophilin 1 in the skin and is a compound heterozygote for autosomal-recessively inherited premature termination codons of translation on both alleles of the plakophilin 1 gene (PKP1). Clinically, there are features of both cutaneous fragility and congenital ectodermal dysplasia affecting skin, hair and nails. There is no evidence of significant abnormalities in other epithelia or tissues. Desmosomes in the skin are small and poorly formed with widening of keratinocyte intercellular spaces and perturbed Desmosome/keratin intermediate filament interactions. The molecular findings and clinical observations in this patient attest to the dual importance of plakophilin 1 in both cutaneous cell-call adhesion and epidermal morphogenesis.
Kathleen J Green - One of the best experts on this subject based on the ideXlab platform.
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tracing the evolutionary origin of Desmosomes
Current Biology, 2020Co-Authors: Kathleen J Green, Carien M. Niessen, Quinn R Rothcarter, Scott A NicholsAbstract: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.
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Desmosomes regulators of cellular signaling and adhesion in epidermal health and disease
Cold Spring Harbor Perspectives in Medicine, 2014Co-Authors: Jodi L Johnson, Nicole A Najor, Kathleen J GreenAbstract:Desmosomes are intercellular junctions that mediate cell-cell adhesion and anchor the intermediate filament network to the plasma membrane, providing mechanical resilience to tissues such as the epidermis and heart. In addition to their critical roles in adhesion, desmosomal proteins are emerging as mediators of cell signaling important for proper cell and tissue functions. In this review we highlight what is known about desmosomal proteins regulating adhesion and signaling in healthy skin-in morphogenesis, differentiation and homeostasis, wound healing, and protection against environmental damage. We also discuss how human diseases that target Desmosome molecules directly or interfere indirectly with these mechanical and signaling functions to contribute to pathogenesis.
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Desmosomes: new perspectives on a classic
The Journal of investigative dermatology, 2007Co-Authors: Kathleen J Green, Cory L. SimpsonAbstract:Desmosomes are highly specialized anchoring junctions that link intermediate filaments to sites of intercellular adhesion, thus facilitating the formation of a supracellular scaffolding that distributes mechanical forces throughout a tissue. These junctions are thus particularly important for maintaining the integrity of tissues that endure physical stress, such as the epidermis and myocardium. The importance of the classic mechanical functions of desmosomal constituents is underscored by pathologies reported in animal models and an ever-expanding list of human mutations that target both desmosomal cadherins and their associated cytoskeletal anchoring proteins. However, the notion that Desmosomes are static structures that exist simply to glue cells together belies their susceptibility to remodeling in response to environmental cues and their important tissue-specific roles in cell behavior and signaling. Here, we review the molecular blueprint of the Desmosome and models for assembling its protein components to form an adhesive interface and the desmosomal plaque. We also discuss emerging evidence of supra-adhesive roles for desmosomal proteins in regulating tissue morphogenesis and homeostasis. Finally, we highlight the dynamic nature of these adhesive organelles, examining mechanisms in health and disease for modulating adhesive strength and stability of Desmosomes.
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mechanisms of plakoglobin dependent adhesion Desmosome specific functions in assembly and regulation by epidermal growth factor receptor
Journal of Biological Chemistry, 2005Co-Authors: Taofei Yin, Andrew P. Kowalczyk, Eliane J Muller, Spiro Getsios, Reto Caldelari, Lisa M Godsel, Kathleen J GreenAbstract:Plakoglobin (PG) is a member of the Armadillo family of adhesion/signaling proteins that can be incorporated into both adherens junctions and Desmosomes. Loss of PG results in defects in the mechanical integrity of heart and skin and decreased adhesive strength in keratinocyte cultures established from the skin of PG knock-out (PG-/-) mice, the latter of which cannot be compensated for by overexpressing the closely related beta-catenin. In this study, we examined the mechanisms of PG-regulated adhesion in murine keratinocytes. Biochemical and morphological analyses indicated that junctional incorporation of desmosomal, but not adherens junction, components was impaired in PG-/- cells compared with PG+/- controls. Re-expression of PG, but not beta-catenin, in PG-/- cells largely reversed these effects, indicating a key role for PG in Desmosome assembly. Epidermal growth factor (EGF) receptor activation resulted in Tyr phosphorylation of PG, which was accompanied by a loss of desmoplakin from Desmosomes and decreased adhesive strength following 18-h EGF treatment. Importantly, introduction of a phosphorylation-deficient PG mutant into PG null cells prevented the EGF receptor-dependent loss of desmoplakin from junctions, attenuating the effects of long term EGF treatment on cell adhesion. Therefore, PG is essential for maintaining and regulating adhesive strength in keratinocytes largely through its contributions to Desmosome assembly and structure. As a target for modulation by EGF, regulation of PG-dependent adhesion may play an important role during wound healing and tumor metastasis.
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the head domain of plakophilin 1 binds to desmoplakin and enhances its recruitment to Desmosomes implications for cutaneous disease
Journal of Biological Chemistry, 1999Co-Authors: Mechthild Hatzfeld, Elayne A. Bornslaeger, Jeffrey E. Borgwardt, Connie M. Corcoran, Daniel S Kopp, Aaron Settler, Kathleen J GreenAbstract:The contribution of Desmosomes to epidermal integrity is evident in the inherited blistering disorder associated with the absence of a functional gene for plakophilin-1. To define the function of plakophilin-1 in Desmosome assembly, interactions among the desmosomal cadherins, desmoplakin, and the armadillo family members plakoglobin and plakophilin-1 were examined. In transient expression assays, plakophilin-1 formed complexes with a desmoplakin amino-terminal domain and enhanced its recruitment to cell-cell borders; this recruitment was not dependent on the equimolar expression of desmosomal cadherins. In contrast to desmoplakin-plakoglobin interactions, the interaction between desmoplakin and plakophilin-1 was not mediated by the armadillo repeat domain of plakophilin-1 but by the non-armadillo head domain, as assessed by yeast two-hybrid and recruitment assays. We propose a model whereby plakoglobin serves as a linker between the cadherins and desmoplakin, whereas plakophilin-1 enhances lateral interactions between desmoplakin molecules. This model suggests that epidermal lesions in patients lacking plakophilin-1 are a consequence of the loss of integrity resulting from a decrease in binding sites for desmoplakin and intermediate filaments at Desmosomes.
John A Mcgrath - One of the best experts on this subject based on the ideXlab platform.
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Desmosomes exhibit site specific features in human palm skin
Experimental Dermatology, 2003Co-Authors: Hong Wan, Patricia J C Doppinghepenstal, M J Gratian, John A Mcgrath, Michael G Stone, R A J EadyAbstract:Hereditary skin disorders resulting from Desmosome gene pathology may preferentially involve the palms and soles. Why this is so is not clear. Moreover, even in normal control skin it is unknown whether there are differences in Desmosome number, size or structural organization in palmoplantar sites compared with skin from other body regions. Therefore, we sought evidence for such differences by examining Desmosome expression in relation to epidermal differentiation in both epidermis and cultured keratinocytes from normal human palm and breast skin samples. Confocal microscopy of skin biopsy material showed relative differences in the expression profiles of several desmosomal proteins (desmogleins, desmocollins, desmoplakin, plakoglobin and plakophilin 1) between the two sites. Western blotting revealed a higher expression level of all five proteins in palm compared with breastcultured keratinocytes. Staining for the differentiation-associated component, involucrin, suggested an earlier onset of synthesis of this protein in palm epidermis, and a suspension-induced differentiation assay showed that involucrin synthesis began earlier in palm keratinocytes than in breast cells. At 4-8 h, the number of involucrin-positive cells in palm keratinocytes was almost twice that in breast. Morphometric analysis showed that, overall, Desmosomes were larger but of similar population density in the palm compared with breast skin. These findings demonstrate differences in Desmosome structure and protein expression between the two sites, possibly reflecting the needs of palms and soles to withstand constant mechanical stress. They may also help to explain the preferential involvement of this region in certain hereditary disorders (palmoplantar keratodermas), associated with mutations in desmoplakin or desmoglein 1.
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mutations in the plakophilin 1 gene result in ectodermal dysplasia skin fragility syndrome
Nature Genetics, 1997Co-Authors: John A Mcgrath, David R. Garrod, James R Mcmillan, I M Leigh, Carrie S Shemanko, S K Runswick, E B Lane, R A J EadyAbstract:Members of the armadillo protein gene family, which includes plakoglobin and beta-catenin, have important functions in cytoskeleton/cell membrane interactions. These proteins may act as linker molecules at adherens junctions and Desmosomes at the plasma membrane; in addition, they may have pivotal roles in signal transduction pathways and significant effects on cell behaviour during development. Here, we describe the first human mutations in one of these dual function proteins, plakophilin 1 (band-6 protein; refs 8-10). The affected individual has a complete absence of immunostaining for plakophilin 1 in the skin and is a compound heterozygote for autosomal-recessively inherited premature termination codons of translation on both alleles of the plakophilin 1 gene (PKP1). Clinically, there are features of both cutaneous fragility and congenital ectodermal dysplasia affecting skin, hair and nails. There is no evidence of significant abnormalities in other epithelia or tissues. Desmosomes in the skin are small and poorly formed with widening of keratinocyte intercellular spaces and perturbed Desmosome/keratin intermediate filament interactions. The molecular findings and clinical observations in this patient attest to the dual importance of plakophilin 1 in both cutaneous cell-call adhesion and epidermal morphogenesis.
David R. Garrod - One of the best experts on this subject based on the ideXlab platform.
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Desmosomal cadherins in zebrafish epiboly and gastrulation
BMC developmental biology, 2012Co-Authors: Alexander Goonesinghe, Xing-ming Luan, Adam Hurlstone, David R. GarrodAbstract:The desmosomal cadherins (DCs), desmocollin (Dsc) and desmoglein (Dsg), are the adhesion molecules of Desmosomes, intercellular adhesive junctions of epithelia and cardiac muscle. Both the DCs and Desmosomes have demonstrably essential roles in mammalian development. In order to initiate their study in a more tractable developmental system we have characterised zebrafish DCs and examined their roles in early zebrafish development. We find that zebrafish possess one Dsc, the orthologue of mammalian Dsc1, which we designate zfDsc. Unlike mammalian Dscs, zfDsc exists only as the "a" form since it lacks the alternatively-spliced mini-exon that shortens the cytoplasmic domain to produce the "b" form. Zebrafish possess two Dsgs, designated zfDsgα and zfDsgβ, orthologues of mammalian Dsg2. They show 43.8% amino acid identity and the α form has a 43 amino acid glycine-rich sequence of unknown function in its extracellular domain. Both zfDsc and zfDsgα were present as maternal and zygotic transcripts whereas zfDsgβ was first expressed from 8 hours post-fertilisation (hpf). All three transcripts were present throughout subsequent stages of development. Morpholino knockdown of both zfDsc and zfDsgα expression produced similar defects in epiboly, axis elongation and somite formation, associated with abnormal Desmosomes or reduced Desmosome numbers. These results demonstrate an important role for DCs and Desmosomes in the early morphogenesis of the zebrafish embryo, provide a basis for more detailed analysis of their role and raise interesting questions relating to the evolution and functional significance of DC isoforms.
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The cell adhesion molecule nectin-1 is critical for normal enamel formation in mice
Human molecular genetics, 2008Co-Authors: Martin J. Barron, Steven J. Brookes, Clare E. Draper, David R. Garrod, Jennifer Kirkham, Roger C. Shore, Michael J. DixonAbstract:Nectin-1 is a member of a sub-family of immunoglobulin-like adhesion molecules and a component of adherens junctions. In the current study, we have shown that mice lacking nectin-1 exhibit defective enamel formation in their incisor teeth. Although the incisors of nectin-1-null mice were hypomineralized, the protein composition of the enamel matrix was unaltered. While strong immunostaining for nectin-1 was observed at the interface between the maturation-stage ameloblasts and the underlying cells of the stratum intermedium (SI), its absence in nectin-1-null mice correlated with separation of the cell layers at this interface. Numerous, large Desmosomes were present at this interface in wild-type mice; however, where adhesion persisted in the mutant mice, the Desmosomes were smaller and less numerous. Nectins have been shown to regulate tight junction formation; however, this is the first report showing that they may also participate in the regulation of Desmosome assembly. Importantly, our results show that integrity of the SI-ameloblast interface is essential for normal enamel mineralization.
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Desmosomes are reduced in the mouse uterine luminal epithelium during the preimplantation period of pregnancy a mechanism for facilitation of implantation
Biology of Reproduction, 2000Co-Authors: Ian M Illingworth, David R. Garrod, Irena Kiszka, Steven Bagley, Grenham Ireland, Susan J KimberAbstract:Dynamic regulation of intercellular junctions is an essential aspect of many developmental, reproductive, and physiological processes. We have shown that expression of the desmosomal protein desmoplakin decreases in the luminal uterine epithelium during the preimplantation period of pregnancy in mice. By the time of implantation (between Days 4.5 and 5 of pregnancy), desmoplakin protein can barely be detected by SDS-PAGE and Western blotting, and by immunocytochemistry, it is restricted to well-spaced, punctate dots at the apicolateral junction. Using confocal XZ series and electron microscope quantitation, both the density and distribution of Desmosomes along the lateral cell surfaces of luminal epithelial cells were observed to change during early pregnancy. On Day 1 of pregnancy, Desmosomes were found at high density in the apicolateral junctional complex, being present here in 79% of ultrathin sections examined, whereas on Day 5, the density was much reduced (present in only 18% of ultrathin sections examined). Desmosomes were found along the lateral surfaces, at or below the level of the nucleus, in 15% of ultrathin sections examined on Day 1 of pregnancy but in only 1% on Day 5. Desmoplakin mRNA declined during the first 4-5 days of pregnancy, along with the protein, suggesting that these changes are controlled at the level of mRNA. This study shows that Desmosomes are regulated during early pregnancy, and we propose that a reduction in Desmosome adhesion facilitates penetration of the luminal epithelium by trophoblast cells at implantation.
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mutations in the plakophilin 1 gene result in ectodermal dysplasia skin fragility syndrome
Nature Genetics, 1997Co-Authors: John A Mcgrath, David R. Garrod, James R Mcmillan, I M Leigh, Carrie S Shemanko, S K Runswick, E B Lane, R A J EadyAbstract:Members of the armadillo protein gene family, which includes plakoglobin and beta-catenin, have important functions in cytoskeleton/cell membrane interactions. These proteins may act as linker molecules at adherens junctions and Desmosomes at the plasma membrane; in addition, they may have pivotal roles in signal transduction pathways and significant effects on cell behaviour during development. Here, we describe the first human mutations in one of these dual function proteins, plakophilin 1 (band-6 protein; refs 8-10). The affected individual has a complete absence of immunostaining for plakophilin 1 in the skin and is a compound heterozygote for autosomal-recessively inherited premature termination codons of translation on both alleles of the plakophilin 1 gene (PKP1). Clinically, there are features of both cutaneous fragility and congenital ectodermal dysplasia affecting skin, hair and nails. There is no evidence of significant abnormalities in other epithelia or tissues. Desmosomes in the skin are small and poorly formed with widening of keratinocyte intercellular spaces and perturbed Desmosome/keratin intermediate filament interactions. The molecular findings and clinical observations in this patient attest to the dual importance of plakophilin 1 in both cutaneous cell-call adhesion and epidermal morphogenesis.