Adducin Is Required for Desmosomal Cohesion in Keratinocytes

Rötzer, Vera; Breit, Andreas; Waschke, Jens; Spindler, Volker

doi:10.1074/jbc.m113.527127

Cited by 40 publications

(46 citation statements)

References 57 publications

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“…It was shown to colocalize with E-cadherin and CTNNB1 (or ␤-catenin) at AJs in epithelial cells, and knockdown of adducin significantly attenuated calcium-dependent AJ and TJ assembly and accelerated junctional disassembly, indicating that it is essential for the stability of epithelial junctions (62). ADD3 was also shown to be required for desmosomal cohesion in keratinocytes (63). It is notable that these roles are regulated by phosphorylation, as is the stability of the protein (64).…”

Section: Discussionmentioning

confidence: 99%

Determination of a Comprehensive Alternative Splicing Regulatory Network and Combinatorial Regulation by Key Factors during the Epithelial-to-Mesenchymal Transition

Yang

Park

Bebee

et al. 2016

Molecular and Cellular Biology

133

165

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fThe epithelial-to-mesenchymal transition (EMT) is an essential biological process during embryonic development that is also implicated in cancer metastasis. While the transcriptional regulation of EMT has been well studied, the role of alternative splicing (AS) regulation in EMT remains relatively uncharacterized. We previously showed that the epithelial cell-type-specific proteins epithelial splicing regulatory proteins 1 (ESRP1) and ESRP2 are important for the regulation of many AS events that are altered during EMT. However, the contributions of the ESRPs and other splicing regulators to the AS regulatory network in EMT require further investigation. Here, we used a robust in vitro EMT model to comprehensively characterize splicing switches during EMT in a temporal manner. These investigations revealed that the ESRPs are the major regulators of some but not all AS events during EMT. We determined that the splicing factor RBM47 is downregulated during EMT and also regulates numerous transcripts that switch splicing during EMT. We also determined that Quaking (QKI) broadly promotes mesenchymal splicing patterns. Our study highlights the broad role of posttranscriptional regulation during the EMT and the important role of combinatorial regulation by different splicing factors to fine tune gene expression programs during these physiological and developmental transitions.A lternative splicing (AS) is a process by which a single gene transcript can be differentially spliced to yield numerous splice variants that can encode different protein isoforms and thereby greatly expand the protein coding capacity of the genome. Nearly all human genes are alternatively spliced, and cell-typespecific protein isoforms have been shown to be functionally essential for cell fate and viability (1-3). This process is under complex regulation by various cis elements in pre-mRNAs and their cognate binding partners, mainly RNA-binding proteins (RBPs). Splicing-regulatory RBPs recruited to their respective binding sites can have positive or negative effects on the splicing of different exons or splice sites. Many RBPs with largely ubiquitous expression in different tissues and cells have been shown to have broad impacts on splicing and important cell functions, such as SR and hnRNP protein families (4). However, several tissue-specific RBPs, such as NOVA, PTBP2 (nPTB), MBNL, and RBFOX proteins, have recently been described as having important roles as essential regulators of tissue-or cell-type-specific splicing (5-9). In order to further define a "splicing code" that controls broad patterns of tissue-specific splicing, as well as those that occur during developmental transitions, it is essential to characterize in greater detail how these tissue-specific regulators fine-tune AS programs combinatorially with more ubiquitously expressed splicing regulators (10).The epithelial-to-mesenchymal transition (EMT) is a process by which epithelial cells transdifferentiate into mesenchymal cells, which involves extensive changes at the cellular ...

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Section: Discussionmentioning

confidence: 99%

Determination of a Comprehensive Alternative Splicing Regulatory Network and Combinatorial Regulation by Key Factors during the Epithelial-to-Mesenchymal Transition

Yang

Park

Bebee

et al. 2016

Molecular and Cellular Biology

133

165

View full text Add to dashboard Cite

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“…Alterations in intracellular signaling in response to autoantibody treatment typically occur within the first 30 to 120min (Berkowitz et al, 2005;Chernyavsky et al, 2007;Rotzer et al, 2014). We thus focused on the early events after application of autoantibodies and first correlated quick morphological changes observed by AFM with loss of intercellular adhesion detected by dispase-based dissociation assays during the first 2h.…”

Section: Loss Of Cell Cohesion Correlates With Early Morphological Chmentioning

confidence: 98%

Loss of Desmoglein Binding Is Not Sufficient for Keratinocyte Dissociation in Pemphigus

Vielmuth

Waschke

Spindler

2015

Journal of Investigative Dermatology

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Pemphigus vulgaris (PV) is a severe autoimmune disease in which autoantibodies against the desmosomal cell adhesion molecules desmoglein (Dsg) 1 and Dsg3 cause intraepidermal blister formation. Mechanistically, the fundamental question is still unresolved whether loss of cell cohesion is a result of (1) direct inhibition of Dsg interaction by autoantibodies or (2) intracellular signaling events, which are altered in response to antibody binding and finally cause desmosome destabilization. We used atomic force microscopy (AFM) to perform Dsg3 adhesion measurements on living keratinocytes to investigate the contributions of direct inhibition and signaling to loss of cell cohesion after autoantibody treatment. Dsg3 binding was rapidly blocked following antibody exposure under conditions where no depletion of surface Dsg3 was detectable, demonstrating direct inhibition of Dsg3 interaction. Inhibition of p38MAPK, a central signaling molecule in PV pathogenesis, abrogated loss of cell cohesion, but had a minor effect on loss of Dsg3 binding. Similarly, the cholesterol-depleting agent methyl-β-cyclodextrin (β-MCD) fully blocked cell dissociation, but did not restore Dsg3 interactions or prevent the activation of p38MAPK. These results demonstrate that inhibition of Dsg3 binding is not sufficient to cause loss of cell cohesion, but rather alters signaling events which, in lipid raft-dependent manner, induce cell dissociation.

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“…It was suggested that primarily the nondesmosomal Dsg3 molecules present on the cell surface and not connected to the keratin filaments sense the initial binding of autoantibodies and relay this signal into the cell, which results in pronounced p38MAPK-dependent Dsg3 depletion (Müller et al, 2008;Spindler and Waschke, 2014;Vielmuth et al, 2015). Furthermore, PKC is activated following a rapid Ca 2+ influx after PV-IgG application (Osada et al, 1997;Rotzer et al, 2014;Seishima et al, 1995) which switches the Ca 2+ -independent, hyperadhesive desmosomes found in fully confluent keratinocytes to a Ca 2+ -dependent phenotype (Cirillo et al, 2010;Dehner et al, 2014). This in turn favors the loss of Dsg3, probably by reorganization of the desmosomal plaque in response to desmoplakin phosphorylation and via mechanisms involving plakophilin-1 Spindler et al, 2011;Tucker et al, 2014).…”

Section: Wounded Keratinocytes Show Remarkable Similarities To Keratimentioning

confidence: 98%

Desmoglein 3-Dependent Signaling Regulates Keratinocyte Migration and Wound Healing

Rötzer

Hartlieb

Winkler

et al. 2016

Journal of Investigative Dermatology

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The desmosomal transmembrane adhesion molecules desmoglein 3 (Dsg3) and desmocollin 3 (Dsc3) are required for strong keratinocyte cohesion. Recently, we have shown that Dsg3 associates with p38MAPK and suppresses its activity. Here, we further investigated the role of Dsg3-dependent control of p38MAPK function. Dsg3-deficient mice display recurrent spontaneously healing skin erosions. In lesional and perilesional biopsies, p38MAPK activation was detectable compared to control animals. This led us to speculate that Dsg3 regulates wound repair in a p38MAPK-dependent manner. Indeed, scratch wounded keratinocyte monolayers exhibited p38MAPK activation and loss of Dsg3 in cells lining the wound edge. Human keratinocytes after silencing of Dsg3 as well as primary cells isolated from Dsg3 knockout animals exhibited accelerated migration, which was further corroborated in an ex vivo skin outgrowth assay. Importantly, migration was efficiently blocked by inhibition of p38MAPK, indicating that p38MAPK mediates the effects observed upon loss of Dsg3. In line with this, we show that levels of active p38MAPK associated with Dsc3 are increased in Dsg3-deficient cells. These data indicate that Dsg3 controls a switch from an adhesive to a migratory keratinocyte phenotype via p38MAPK inhibition. Thus, loss of Dsg3 adhesion may foster wound closure by allowing p38MAPK-dependent migration.Journal of Investigative Dermatology accepted article preview online, 30 September 2015. doi:10.1038/jid.2015.380.

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Adducin Is Required for Desmosomal Cohesion in Keratinocytes

Cited by 40 publications

References 57 publications

Determination of a Comprehensive Alternative Splicing Regulatory Network and Combinatorial Regulation by Key Factors during the Epithelial-to-Mesenchymal Transition

Determination of a Comprehensive Alternative Splicing Regulatory Network and Combinatorial Regulation by Key Factors during the Epithelial-to-Mesenchymal Transition

Loss of Desmoglein Binding Is Not Sufficient for Keratinocyte Dissociation in Pemphigus

Desmoglein 3-Dependent Signaling Regulates Keratinocyte Migration and Wound Healing

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