Desmoglein 2 can undergo Ca2+-dependent interactions with both desmosomal and classical cadherins including E-cadherin and N-cadherin.

Desmoglein (Dsg) 2 is a ubiquitously expressed desmosomal cadherin. Particularly, it is present in all cell types forming desmosomes, including epithelial cells and cardiac myocytes and is upregulated in the autoimmune skin disease pemphigus. Thus, we here characterized the binding properties of Dsg2 in more detail using atomic force microscopy (AFM). Dsg2 exhibits homophilic interactions and also heterophilic interactions with the desmosomal cadherin desmocollin (Dsc) 2, and further with the classical cadherins E-cadherin (E-Cad) and N-cadherin (N-Cad), which may be relevant for cross talk between desmosomes and adherens junctions in epithelia and cardiac myocytes. We found that all homo- and heterophilic interactions were Ca2+-dependent. All binding forces observed are in the same force range, i.e., 30 to 40 pN, except for the Dsg2/E-Cad unbinding force, which with 45 pN is significantly higher. To further characterize the nature of the interactions, we used tryptophan, a critical amino acid required for trans-interaction, and a tandem peptide (TP) designed to cross-link Dsg isoforms. TP was sufficient to prevent the tryptophan-induced loss of Dsg2 interaction with the desmosomal cadherins Dsg2 and Dsc2; however, not with the classical cadherins E-Cad and N-Cad, indicating that the interaction modes of Dsg2 with desmosomal and classical cadherins differ. TP rescued the tryptophan-induced loss of Dsg2 binding on living enterocytes, suggesting that interaction with desmosomal cadherins may be more relevant. In summary, the data suggest that the ubiquitous desmosomal cadherin Dsg2 enables the cross talk with adherens junctions by interacting with multiple binding partners with implications for proper adhesive function in healthy and diseased states.

Further discussion on the association between desmoglein 2 and tumor size of non-small cell lung cancer.

We have read the article by Cai et al. and find there is a discrepancy between their data and conclusion. Their statement, "Specifically, DSG2 expression was associated with tumor size", is not supported by their own clinicopathological data and analysis. After reviewing some similar articles, we also found no available evidence showed a statistically significant association between them. Therefore, we would like to suggest Cai et al. to rectify the results they published.

Importancia de los hallazgos de la resonancia magnética cardiaca en el diagnóstico de la miocardiopatía arritmogénica del ventrículo izquierdo / Importance of cardiac magnetic resonance findings in the diagnosis of left dominant arrythmogenic cardiomyopathy

INTRODUCCIÓN Y OBJETIVOS: Recientemente, la miocardiopatía arritmogénica del ventrículo izquierdo (MCAVI) ha sido reconocida como parte del espectro de la miocardiopatía arritmogénica. Se caracteriza por el reemplazo fibroadiposo de la pared de dicho ventrículo. Se describen las formas de presentación clínica más frecuentes, hallazgos de imagen y eventos en el seguimiento, destacando la importancia de la resonancia magnética cardiaca (RMC). MÉTODOS: Registro prospectivo de pacientes con hallazgos compatibles con MCAVI. Se realizó análisis de imagen de RMC y seguimiento clínico. El objetivo primario fue la aparición de eventos cardiovasculares adversos mayores (MACE) durante el seguimiento, definidos como muerte súbita cardiaca, arritmias ventriculares sostenidas y trasplante cardiaco. RESULTADOS: Se incluyeron 74 pacientes consecutivos (edad media 48,6 años, 50 varones [67,6%]). Las indicaciones más frecuentes para la RMC fueron dolor torácico con coronariografía normal, arritmias ventriculares y sospecha de miocardiopatías. Los principales hallazgos de RMC fueron: realce tardío meso-subepicárdico (91,9%), infiltración grasa subepicárdica (83,8%) y anomalías segmentarias de la contractilidad del ventrículo izquierdo (47,9%). En un seguimiento medio de 3,74 años, 24 pacientes (32,4%) presentaron un MACE (muerte súbita cardiaca 8,1%, arritmias ventriculares sostenidas 21,6% y trasplante cardiaco 4,1%). La presencia en RMC de realce tardío grave, predice independientemente la aparición de MACE, además del hecho de ser varón y practicar deporte. CONCLUSIONES: La RMC es una herramienta clave para diagnosticar la MCAVI. La infiltración grasa subepicárdica y el realce tardío meso-subepicárdico son hallazgos característicos. El pronóstico de esta población es pobre con una alta incidencia de muerte súbita cardiaca y arritmias ventriculares

INTRODUCTION AND OBJECTIVES: Left dominant arrhythmogenic cardiomyopathy (LDAC) has recently been recognized as falling on the spectrum of arrhythmogenic cardiomyopathy. It is characterized by fibroadipose replacement of the left ventricle. The aim of this study was to describe the most frequent forms of clinical presentation of LDAC, imaging findings, and events at follow-up, highlighting the importance of cardiac magnetic resonance (CMR). METHODS: Prospective registry of patients with findings compatible with LDAC. CMR image analysis and clinical follow-up was performed. The primary endpoint was the appearance of major adverse cardiovascular events (MACE) during follow-up, defined as sudden cardiac death, sustained ventricular arrhythmias, and heart transplant. RESULTS: We included 74 consecutive patients (mean age, 48.6 years; 50 men [67.6%]). The most frequent CMR indications were chest pain with normal coronary angiography, ventricular arrhythmias, and suspicion of cardiomyopathies. The main CMR findings were midwall and/or subepicardial pattern of late gadolinium enhancement (91.9%), fatty epicardial infiltration (83.8%), and left ventricle segmental contractility abnormalities (47.9%). At a mean follow-up of 3.74 years, 24 patients (32.4%) had a MACE (sudden cardiac death 8.1%, sustained ventricular arrhythmias 21.6%, and heart transplant 4.1%). Independent predictors for the appearance for MACE were a CMR study showing severe late gadolinium enhancement, male sex, and practicing sports. CONCLUSIONS: CMR is a key tool for diagnosing LDAC. Characteristic findings are subepicardial fatty infiltration and midwall-subepicardial late gadolinium enhancement. The prognosis of this population is poor with a high incidence of sudden cardiac death and ventricular arrhythmias

Disturbed Desmoglein-2 in the intercalated disc of pediatric patients with dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) leads to disturbed contraction and force transduction, and is associated with substantial mortality in all age groups. Involvement of a disrupted composition of the intercalated disc (ID) has been reported. However, in children, little is established about such subcellular changes during disease, because of the pathological mix-up with the ongoing cardiac maturation. This leaves maladaptive remodeling often undetected. We aimed at illustrating subcellular alterations in children diagnosed with DCM compared to age-matched controls, focusing on ID proteins known to be crucially stable under healthy conditions and destabilized during cardiac injury in adults. Left ventricular or septal pediatric specimens were collected from 7 individuals diagnosed with DCM (age: 23 weeks in utero to 8 weeks postnatal) and age-matched controls that died of non-cardiovascular cause. We determined the amount of fibrosis and localization of ID proteins by immunohistochemistry. In pediatric DCM, most ID proteins follow similar spatiotemporal changes in localization as in controls. However, although no mutations were found, the signal of the desmosomal protein Desmoglein-2 was reduced in all pediatric DCM specimens, but not in controls or adult DCM patients. Endocardial and transmural fibrosis was increased in all pediatric DCM patients compared to age-matched controls. Composition of the ID in pediatric DCM patients is similar to controls, except for the localization of Desmoglein-2 and presence of severe fibrosis. This suggests that the architecture of desmosomes is already disturbed in the early stages of DCM. These findings contribute to the understanding of pediatric DCM.

Loss of desmoglein 2 promotes tumorigenic behavior in pancreatic cancer cells.

The ability to maintain cell-cell adhesion is crucial for tissue integrity and organization. Accordingly, loss of cohesiveness plays a critical role in cancer invasion and metastasis. Desmosomes are cell junctions providing strong intercellular adhesive strength and dysregulation of desmosomal constituents contributes to cancer progression through altered cell signaling pathways. Here, we focused on the desmosomal adhesion molecules Desmoglein 2 (Dsg2) and Desmocollin 2 (Dsc2), and their contribution to migration and invasion in pancreatic cancer cells. Silencing of Dsg2 but not Dsc2 resulted in loss of cell cohesion and enhanced migration, and invasion of pancreatic adenocarcinoma cells. To identify potential pathways regulated by Dsg2, we performed kinase arrays and detected the activity of ERK and growth factor receptors to be significantly enhanced in Dsg2-deficient cells. Consequently, inhibition of ERK phosphorylation in Dsg2 knockdown cells normalized migration. Loss of Dsg2 resulted in reduced levels of the desmosomal adapter protein and transcriptional regulator Plakoglobin (PG) in an ERK-dependent manner, whereas other desmosomal molecules were not altered. Overexpression of PG rescued enhanced migration induced by silencing of Dsg2. These results identify a novel pro-migratory pathway of pancreatic cancer cells in which loss of Dsg2 reduces the levels of PG via deregulated MAPK signaling.

Desmoglein 2 promotes vasculogenic mimicry in melanoma and is associated with poor clinical outcome.

Tumors can develop a blood supply not only by promoting angiogenesis but also by forming vessel-like structures directly from tumor cells, known as vasculogenic mimicry (VM). Understanding mechanisms that regulate VM is important, as these might be exploitable to inhibit tumor progression. Here, we reveal the adhesion molecule desmoglein 2 (DSG2) as a novel mediator of VM in melanoma. Analysis of patient-derived melanoma cell lines and tumor tissues, and interrogation of The Cancer Genome Atlas (TCGA) data, revealed that DSG2 is frequently overexpressed in primary and metastatic melanomas compared to normal melanocytes. Notably, this overexpression was associated with poor clinical outcome. DSG2+ melanoma cells self-organized into tube-like structures on Matrigel, indicative of VM activity, which was inhibited by DSG2 knockdown or treatment with a DSG2-blocking peptide. Mechanistic studies revealed that DSG2 regulates adhesion and cell-cell interactions during tube formation, but does not control melanoma cell viability, proliferation or motility. Finally, analysis of patient tumors revealed a correlation between DSG2 expression, VM network density and expression of VM-associated genes. These studies identify DSG2 as a key regulator of VM activity in human melanoma and suggest this molecule might be therapeutically targeted to reduce tumor blood supply and metastatic spread.

Desmoglein-2 during pregnancy and its role in the evolution of viviparity in a marsupial (Sminthopsis crassicaudata; Dasyuridae).

Attachment of the blastocyst and formation of the placenta during pregnancy is dependent on structural and cellular changes occurring in the uterine epithelium and in particular to the plasma membrane of these uterine cells. Desmosome expression decreases during pregnancy in eutherians and some squamates, presumably allowing for remodeling of the uterine epithelium and invasion of the trophoblast during implantation. Marsupials are a distinct mammalian amniote lineage of viviparity, with a short implantation or attachment period and varying levels of invasive placentation. To test the generality of changes to the uterine epithelium during pregnancy across mammals, we characterized the distribution of desmosomes in the uterine epithelial cells of a marsupial, Sminthopsis crassicaudata, using electron microscopy and immunohistochemistry. The absolute number of desmosomes along the lateral plasma membrane decreases during pregnancy and desmosomes are redistributed towards the apical region of the lateral plasma membrane as pregnancy proceeds, similar to what occurs during pregnancy in eutherian mammals. Despite the lower level of maternal investment in pregnancy and the noninvasive structure of fetal membranes in marsupials there are similarities in number and redistribution of desmosomes along the plasma membrane and changes to the morphology of the uterine epithelial cells suggesting that similar plasma membrane changes occur across all lineages of amniote vertebrates.

Assessment of desmosomal components (desmoglein 1-3, plakoglobin) in cardia mucosa in relation to gastroesophageal reflux disease and Helicobacter pylori infection.

Gastroesophageal reflux disease is associated with impaired epithelial barrier function and abnormal expression of proteins forming cell-cell contacts by tight junctions and desmosomes in distal esophageal squamous mucosa. Although gastroesophageal reflux disease and Helicobacter pylori are both associated with chronic inflammation of the adjacent cardia mucosa, it is not known whether these lead to derangements of the desmosomal complexes. Here, we assessed the expression of 4 proteins (plakoglobin and desmoglein 1, 2, and 3) forming epithelial desmosomal complexes by quantitative reverse transcription polymerase chain reaction and immunohistochemistry in biopsies from 67 patients with gastroesophageal reflux disease and 23 gastroesophageal reflux disease-negative controls. Plakoglobin and desmoglein 2 were ubiquitously expressed in all samples, whereas desmoglein 1 and 3 were not expressed in cardia mucosa. Gastroesophageal reflux disease was specifically associated with elevated transcript levels of desmoglein 2 and plakoglobin. These were significantly increased from 2.0- to 2.7-fold in patients with gastroesophageal reflux disease compared with controls (P < .01), and significantly increased immunohistochemical scores for both proteins were observed (P < .05) as well. The combined presence of gastroesophageal reflux disease and Helicobacter pylori infection had no additional effect on desmosomal gene expression. Taken together, the up-regulation of plakoglobin and desmoglein 2 in cardia mucosa of patients with gastroesophageal reflux disease supports the concept that the "transition zone" between distal esophagus and proximal stomach is affected by gastroesophageal reflux disease as well, and architectural and molecular changes in the desmosomal compartment contribute to the pathogenesis of gastroesophageal reflux disease in the cardia mucosa.

Pathophysiology of nasal polyposis: the role of desmosomal junctions.

BACKGROUND: Many mucosal inflammatory conditions are associated with alterations in epithelial intercellular junctions and barrier function; however, little is known about the role of intercellular junctions in inflammatory diseases of the upper airways. In this study, we examined nasal polyps for altered intercellular junctions and protein expression. METHODS: Biopsy specimens of nasal polyps and normal tissue were obtained intraoperatively from 11 patients and 6 controls. Tissue was analyzed for expression of intercellular junctional proteins by immunofluorescence. In parallel, cultured human bronchial epithelial (HBE) cells were treated with tumor necrosis factor (TNF) alpha, interferon (IFN) gamma, and IL-13 to simulate inflammatory conditions followed by assessment for changes in junctional proteins by immunofluorescence and Western blot. RESULTS: Of the intercellular junctional proteins analyzed, including proteins comprising tight and adherens junctions, the only alterations observed were in desmosomal proteins in nasal polyp epithelium compared with normal controls. Specifically, expression of desmosomal proteins DSG2 and DSG3 were significantly decreased in polyps versus controls (0.53 pixel/microm2 versus 1.09 pixel/microm2 [p = 0.009], and 0.29 pixel/microm2 versus 1.11 pixel/microm2 [p = 0.0078], respectively). In vitro experiments involving exposure of cultured HBE cells with inflammatory cytokines revealed that TNF-alpha treatment resulted in internalization and decreased expression of DSG2 by immunofluorescence and Western blotting. Treatment with IFN-gamma resulted in increased expression of DSG2 and evidence of protein cleavage by Western blot. IL-13 exposure resulted in down-regulation of DSG2 expression and evidence of protein cleavage. CONCLUSION: These results indicate that nasal polyps express decreased levels of DSG2 and DSG3 components of desmosomal junctions. This is likely linked to the mucosal inflammatory response. Exposure of a respiratory cell line to Th1/Th2 cytokines results in similar expressional alterations in DSG2, suggesting protein internalization and cleavage. We speculate that weakened desmosomal junctions in nasal mucosa secondary to inflammatory cytokines may contribute to the formation of nasal polyposis.

The area composita of adhering junctions connecting heart muscle cells of vertebrates. I. Molecular definition in intercalated disks of cardiomyocytes by immunoelectron microscopy of desmosomal proteins.

Among sarcomeric muscles the cardiac muscle cells are unique by, inter alia, a systemic and extended cell-cell contact structure, the intercalated disk (ID), comprising frequent and closely spaced arrays of plaque-coated cell-cell adhering junctions (AJs). As some of these junctions may look somewhat like desmosomes and others like fasciae adhaerentes, the dogma has emerged in the literature that IDs contain - like epithelial cells - both kinds of AJs formed by - for the most - mutually exclusive molecular ensembles. This, however, is not the case. In comprehensive immunoelectron microscopic studies of mammalian (human, bovine, rat, mouse) and non-mammalian (chicken, amphibia, fishes) heart muscle tissues, we have localized major constituents of the desmosomal plaques of polar epithelia, desmoplakin, plakophilin-2 and plakoglobin, as well as the desmosomal cadherins, desmoglein Dsg2 and desmocollin Dsc2, in both kinds of ID AJs, independent of the specific morphological appearance. The desmosomal molecules are not restricted to the desmosome-like-looking junctions but can also be detected in junctions appearing similar to the zonula or fascia adhaerens structures. These AJs of cardiac ID are therefore subsumed under the collective term area composita. We discuss our results with respect to the importance of ID junction molecules for the formation, maintenance and function of the heart, particularly in relation to recent findings that deletions of - or mutations in - genes encoding such proteins can cause severe, sometimes lethal damages.