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

Fuchs, Michael; Kugelmann, Daniela; Schlegel, Nicolas; Vielmuth, Franziska; Waschke, Jens

doi:10.1016/j.bpj.2022.02.023

Cited by 15 publications

(15 citation statements)

References 59 publications

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“…However, expression of E-cadherin by islet cells, and its close proximity to DSG2 (Supplementary Fig. S1 ) suggests that these two cadherin proteins could interact and supports documentation of this occurring on other cell types [ 25 , 38 , 39 ].…”

Section: Resultssupporting

confidence: 55%

“…Most recently, it has been shown that DSG2 can engage with non-desmosomal cadherins (e.g. E- and N-cadherin) to support cell-cell adhesion [ 25 ], harness Rap1 and downstream TGFβ signaling to influence both cell spreading and focal adhesion protein phosphorylation [ 26 ] and modulate the production and release of extracellular vesicles from keratinocytes [ 27 , 28 ]. Important post-translational modification of DSG2, via palmitoylation, regulates the transport of proteins to the plasma membrane [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

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Desmoglein-2 is important for islet function and β-cell survival

et al. 2022

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Type 1 diabetes is a complex disease characterized by the lack of endogenous insulin secreted from the pancreatic β-cells. Although β-cell targeted autoimmune processes and β-cell dysfunction are known to occur in type 1 diabetes, a complete understanding of the cell-to-cell interactions that support pancreatic function is still lacking. To characterize the pancreatic endocrine compartment, we studied pancreata from healthy adult donors and investigated a single cell surface adhesion molecule, desmoglein-2 (DSG2). Genetically-modified mice lacking Dsg2 were examined for islet cell mass, insulin production, responses to glucose, susceptibility to a streptozotocin-induced mouse model of hyperglycaemia, and ability to cure diabetes in a syngeneic transplantation model. Herein, we have identified DSG2 as a previously unrecognized adhesion molecule that supports β-cells. Furthermore, we reveal that DSG2 is within the top 10 percent of all genes expressed by human pancreatic islets and is expressed by the insulin-producing β-cells but not the somatostatin-producing δ-cells. In a Dsg2 loss-of-function mice (Dsg2lo/lo), we observed a significant reduction in the number of pancreatic islets and islet size, and consequently, there was less total insulin content per islet cluster. Dsg2lo/lo mice also exhibited a reduction in blood vessel barrier integrity, an increased incidence of streptozotocin-induced diabetes, and islets isolated from Dsg2lo/lo mice were more susceptible to cytokine-induced β-cell apoptosis. Following transplantation into diabetic mice, islets isolated from Dsg2lo/lo mice were less effective than their wildtype counterparts at curing diabetes. In vitro assays using the Beta-TC-6 murine β-cell line suggest that DSG2 supports the actin cytoskeleton as well as the release of cytokines and chemokines. Taken together, our study suggests that DSG2 is an under-appreciated regulator of β-cell function in pancreatic islets and that a better understanding of this adhesion molecule may provide new opportunities to combat type 1 diabetes.

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Section: Resultssupporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Desmoglein-2 is important for islet function and β-cell survival

et al. 2022

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“…However, it might also be that active EGFR is disturbing the interaction possibility of the binding partner with the DSG2-coated AFM tip, which is restored upon EGFR inhibition. In a cell-free AFM setting DSG2 does not only interact homophilically with DSG2, but also heterophilically with DSC2 (Fuchs et al, 2022). In the AFM setting, only interactions with “free” proteins can be measured.…”

Section: Discussionmentioning

confidence: 99%

EGFR inhibition led ROCK activation enhances desmosome assembly and cohesion in cardiomyocytes

Shoykhet

Dervishi

Menauer

et al. 2022

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The epidermal growth factor receptor (EGFR) is a ubiquitously expressed receptor tyrosine kinase, which is dysregulated in several kinds of cancer and heart diseases. Arrhythmogenic cardiomyopathy (AC) is a familial heart disease in part caused by impaired desmosome turnover. Thus, stabilization of desmosome integrity, may provide potential new treatment options. Desmosomes, apart from cellular cohesion, provide the structural framework of a signaling hub. Here, we investigated the role of EGFR inhibition on cardiomyocyte cohesion under physiological and pathophysiological conditions using the murine plakoglobin knockout AC model, in which EGFR was upregulated. EGFR inhibition led to enhanced cardiomyocyte cohesion. Immunoprecipitation showed an interaction of EGFR and desmoglein 2 (DSG2). Immunostaining and AFM revealed enhanced DSG2 localization and binding at cell borders upon EGFR inhibition. Enhanced area composita length and desmosome assembly was observed upon EGFR inhibition, confirmed by enhanced DSG2 and desmoplakin (DP) recruitment to the cell borders. Thus, inhibiting EGFR, thereby stabilizing desmosome integrity, may provide new treatment options for AC.

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“…For this, we performed atomic force microscopy (AFM) using HL‐1 cardiomyocytes as described before 10 . In this experiment, a cantilever with a DSG2 protein‐coated tip approached the cells, where the DSG2 at the tip could eventually interact with the available DSG2, desmocollin (DSC) 2, or N‐CAD, all of which are binding partners for DSG2 14 at the cell border and surface. The areas were chosen using a topography image of the cells, acquired in the force‐based quantitative imaging mode (Figure 2A).…”

Section: Resultsmentioning

confidence: 99%

Cholinergic signaling impairs cardiomyocyte cohesion

et al. 2022

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Aim Cardiac autonomic nervous system (ANS) dysregulation is a hallmark of several cardiovascular diseases. Adrenergic signaling enhanced cardiomyocyte cohesion via PKA‐mediated plakoglobin phosphorylation at serine 665, referred to as positive adhesiotropy. This study investigated cholinergic regulation of cardiomyocyte cohesion using muscarinic receptor agonist carbachol (CCH). Methods Dissociation assays, Western blot analysis, immunostaining, atomic force microscopy (AFM), immunoprecipitation, transmission electron microscopy (TEM), triton assays, and siRNA knockdown of genes were performed in either HL‐1 cells or plakoglobin (PG) wild type (Jup+/+) and knockout (Jup−/−) mice, which served as a model for arrhythmogenic cardiomyopathy. Results In HL‐1 cells grown in norepinephrine (NE)‐containing medium for baseline adrenergic stimulation, and murine cardiac slice cultures from Jup+/+ and Jup−/− mice CCH treatment impaired cardiomyocyte cohesion. Immunostainings and AFM experiments revealed that CCH reduced desmoglein 2 (DSG2) localization and binding at cell borders. Furthermore, CCH reduced intercalated disc plaque thickness in both Jup+/+ and Jup−/−mice, evidenced by TEM analysis. Immunoprecipitation experiments in HL‐1 cells revealed no changes in DSG2 interaction with desmoplakin (DP), plakophilin 2 (PKP2), PG, and desmin (DES) after CCH treatment. However, knockdown of any of the above proteins abolished CCH‐mediated loss of cardiomyocyte cohesion. Furthermore, in HL‐1 cells, CCH inhibited adrenergic‐stimulated ERK phosphorylation but not PG phosphorylation at serine 665. In addition, CCH activated the AKT/GSK‐3β axis in the presence of NE. Conclusion Our results demonstrate that cholinergic signaling antagonizes the positive effect of adrenergic signaling on cardiomyocyte cohesion and thus causes negative adhesiotropy independent of PG phosphorylation.

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

Cited by 15 publications

References 59 publications

Desmoglein-2 is important for islet function and β-cell survival

Desmoglein-2 is important for islet function and β-cell survival

EGFR inhibition led ROCK activation enhances desmosome assembly and cohesion in cardiomyocytes

Cholinergic signaling impairs cardiomyocyte cohesion

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