Desmosomes as Signaling Hubs in the Regulation of Cell Behavior

Müller, Lisa; Hatzfeld, Meçhthild; Keil, René

doi:10.3389/fcell.2021.745670

Cited by 39 publications

(37 citation statements)

References 228 publications

(307 reference statements)

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“…However, to our knowledge in cardiomyocytes this complex was not known before. It has been very well demonstrated that desmosomes in the epithelia or ICDs in the cardiomyocytes not only provide cellular cohesion but can also be part of a signaling hub (Broussard et al, 2015, Najor et al, 2017, Muller et al, 2021, Yeruva and Waschke, 2022), thus disrupting EGFR signaling in this context might lead to changes at the desmosome.…”

Section: Discussionmentioning

confidence: 99%

“…Several pathways regulating cardiomyocyte cohesion have been identified so far (Genet et al, 2012, Schlipp et al, 2014, Schinner et al, 2017, Zhao et al, 2019, Shoykhet et al, 2020). Furthermore, there is increasing evidence that desmosomes not only provide cellular cohesion, but also act as signaling hubs (Waschke, 2019, Muller et al, 2021), meaning that desmosomes can influence, but are also influenced by cellular signaling processes. Recent advancement in research suggests that similar molecular mechanisms are present in AC and pemphigus, an autoimmune skin disease, as well as inflammatory bowel diseases (Waschke, 2019, Shoykhet et al, 2020, Schmitt and Waschke, 2021, Yeruva and Waschke, 2022).…”

Section: Introductionmentioning

confidence: 99%

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

Shoykhet

Dervishi

Menauer

et al. 2022

Preprint

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Shoykhet

Dervishi

Menauer

et al. 2022

Preprint

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“…Since desmosomes fulfill the function of a signaling hub in the cell orchestrating cellular processes such as cell-cell adhesion [48], proliferation, or migration, we envisaged…”

Section: Discussionmentioning

confidence: 99%

“…Since desmosomes fulfill the function of a signaling hub in the cell orchestrating cellular processes such as cell-cell adhesion [48], proliferation, or migration, we envisaged a potentially important role for development and differentiation. While the loss of DSC2 resulted in a moderate decrease in DE formation, PP differentiation was only impaired under specific culture conditions.…”

Section: Discussionmentioning

confidence: 99%

Functional Genomic Screening in Human Pluripotent Stem Cells Reveals New Roadblocks in Early Pancreatic Endoderm Formation

Krüger

Breunig

Pasquini

et al. 2022

Cells

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Human pluripotent stem cells, with their ability to proliferate indefinitely and to differentiate into virtually all cell types of the human body, provide a novel resource to study human development and to implement relevant disease models. Here, we employed a human pancreatic differentiation platform complemented with an shRNA screen in human pluripotent stem cells (PSCs) to identify potential drivers of early endoderm and pancreatic development. Deep sequencing followed by abundancy ranking pinpointed six top hit genes potentially associated with either improved or impaired endodermal differentiation, which were selected for functional validation in CRISPR-Cas9 mediated knockout (KO) lines. Upon endoderm differentiation (DE), particularly the loss of SLC22A1 and DSC2 led to impaired differentiation efficiency into CXCR4/KIT-positive DE cells. qPCR analysis also revealed changes in differentiation markers CXCR4, FOXA2, SOX17, and GATA6. Further differentiation of PSCs to the pancreatic progenitor (PP) stage resulted in a decreased proportion of PDX1/NKX6-1-positive cells in SLC22A1 KO lines, and in DSC2 KO lines when differentiated under specific culture conditions. Taken together, our study reveals novel genes with potential roles in early endodermal development.

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“…This is supported by animal models where loss of Dsg1 caused lethal skin blisters in superficial epidermis, whose localization is similar to patients with PF ( 16 , 17 ). The mechanisms of antibody induced acantholysis are manifold and include direct inhibition of desmosomal cadherin binding as well as an activation of numerous signaling pathways such as p38MAPK, PKC, EGFR, PLC and ERK1/2 ( 18 – 20 ). In this regard, desmosomes are suggested to play a key role in serving as signaling hubs ( 18 , 19 , 21 ).…”

Section: Introductionmentioning

confidence: 99%

Pemphigus Foliaceus Autoantibodies Induce Redistribution Primarily of Extradesmosomal Desmoglein 1 in the Cell Membrane

et al. 2022

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The autoimmune dermatosis pemphigus foliaceus (PF) is predominantly caused by IgG autoantibodies against the desmosomal cadherin desmoglein (Dsg) 1. The exact mechanisms that lead to the characteristic epidermal blistering are not yet fully understood. In the present study, we used a variety of biophysical methods to examine the fate of membrane-bound Dsg1 after incubation with PF patients’ IgG. Dispase-based dissociation assays confirmed that PF-IgG used for this study reduced intercellular adhesion in a manner dependent on phospholipase C (PLC)/Ca2+ and extracellular signal-regulated kinase (ERK) 1/2 signaling. Atomic force microscopy (AFM) revealed that Dsg1 binding on single molecule level paralleled effects on keratinocyte adhesion under the different conditions. Stimulated emission depletion (STED) super-resolution microscopy was used to investigate the localization of Dsg1 after PF-IgG incubation for 24 h. Under control conditions, Dsg1 was found to be in part co-localized with desmoplakin and thus inside of desmosomes as well as extra-desmosomal along the cell border. Incubation with PF-IgG reduced the extra-desmosomal Dsg1 fraction. In line with this, fluorescence recovery after photobleaching (FRAP) experiments demonstrated a strongly reduced mobility of Dsg1 in the cell membrane after PF-IgG treatment indicating remaining Dsg1 molecules were primarily located inside desmosomes. Mechanistically, experiments confirmed the involvement of PLC/Ca2+ since inhibition of PLC or 1,4,5-trisphosphate (IP3) receptor to reduce cytosolic Ca2+ reverted the effects of PF-IgG on Dsg1 intra-membrane mobility and localization. Taken together, our findings suggest that during the first 24 h PF-IgG induce redistribution predominantly of membrane-bound extradesmosomal Dsg1 in a PLC/Ca2+ dependent manner whereas Dsg1-containing desmosomes remain.

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Desmosomes as Signaling Hubs in the Regulation of Cell Behavior

Cited by 39 publications

References 228 publications

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

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

Functional Genomic Screening in Human Pluripotent Stem Cells Reveals New Roadblocks in Early Pancreatic Endoderm Formation

Pemphigus Foliaceus Autoantibodies Induce Redistribution Primarily of Extradesmosomal Desmoglein 1 in the Cell Membrane

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