A Desmoplakin Point Mutation with Enhanced Keratin Association Ameliorates Pemphigus Vulgaris Autoantibody-Mediated Loss of Cell Cohesion

Dehner, Carina; Rötzer, Vera; Waschke, Jens; Spindler, Volker

doi:10.1016/j.ajpath.2014.05.016

Cited by 37 publications

(40 citation statements)

References 30 publications

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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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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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“…Desmoplakin is phosphorylated in the presence of Pemphigus Vulgaris autoimmune antibodies, which decreases cytokeratin intermediate filament binding to desmosomes (Fig. 5; Dehner et al 2014). Thus, all components of desmosomes are required to maintain normal function, and structural integrity of the epidermis.…”

Section: Epidermis Organization and Regulation Of Homeostasismentioning

confidence: 99%

Cell–Cell Junctions Organize Structural and Signaling Networks

García

Nelson

Chavez

2017

Cold Spring Harb Perspect Biol

340

253

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Cell-cell junctions link cells to each other in tissues, and regulate tissue homeostasis in critical cell processes that include tissue barrier function, cell proliferation and migration. Defects in cell-cell junctions give rise to a wide range of tissue abnormalities that disrupt homeostasis and are common in genetic abnormalities and cancers. Here, we discuss the organization and function of cell-cell junctions primarily involved in adhesion (Tight Junction, Adherens Junction, and Desmosomes) in two different epithelial tissues: a simple epithelium (intestine) and a stratified epithelium (epidermis). Studies in these tissues reveal similarities and differences in the organization and functions of different cell-cell junctions that meet the requirements for the specialized functions of each tissue. We discuss cell-cell junction responses to genetic and environmental perturbations that provide further insights into their roles in maintaining tissue homeostasis.

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“…1e). Although the applied PV-IgG fraction contains both Dsg3 and Dsg1 autoantibodies, we focused on Dsg3 because under the culture conditions used for this study HaCaTs express Dsg3 but not Dsg1 [14].…”

Section: E-cadherin Compensates For Effects Of Desmosomal Perturbationmentioning

confidence: 99%

E-cadherin and Src associate with extradesmosomal Dsg3 and modulate desmosome assembly and adhesion

Rötzer

Hartlieb

Vielmuth

et al. 2015

Cell. Mol. Life Sci.

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Desmosomes provide strong intercellular cohesion essential for the integrity of cells and tissues exposed to continuous mechanical stress. For desmosome assembly, constitutively synthesized desmosomal cadherins translocate to the cell-cell border, cluster and mature in the presence of Ca(2+) to stable cell contacts. As adherens junctions precede the formation of desmosomes, we investigated in this study the relationship between the classical cadherin E-cadherin and the desmosomal cadherin Desmoglein 3 (Dsg3), the latter of which is indispensable for cell-cell adhesion in keratinocytes. By using autoantibodies from patients with the blistering skin disease pemphigus vulgaris (PV), we showed in loss of function studies that E-cadherin compensates for effects of desmosomal disassembly. Overexpression of E-cadherin reduced the loss of cell cohesion induced by PV autoantibodies and attenuated activation of p38 MAPK. Silencing of E-cadherin abolished the localization of Dsg3 at the membrane and resulted in a shift of Dsg3 from the cytoskeletal to the non-cytoskeletal protein pool which conforms to the notion that E-cadherin regulates desmosome assembly. Mechanistically, we identified a complex consisting of extradesmosomal Dsg3, E-cadherin, β-catenin and Src and that the stability of this complex is regulated by Src. Moreover, Dsg3 and E-cadherin are phosphorylated on tyrosine residues in a Src-dependent manner and Src activity is required for recruiting Dsg3 to the cytoskeletal pool as well as for desmosome maturation towards a Ca(2+)-insensitive state. Our data provide new insights into the role of E-cadherin and the contribution of Src signaling for formation and maintenance of desmosomal junctions.

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A Desmoplakin Point Mutation with Enhanced Keratin Association Ameliorates Pemphigus Vulgaris Autoantibody-Mediated Loss of Cell Cohesion

Cited by 37 publications

References 30 publications

Desmoglein 3-Dependent Signaling Regulates Keratinocyte Migration and Wound Healing

Desmoglein 3-Dependent Signaling Regulates Keratinocyte Migration and Wound Healing

Cell–Cell Junctions Organize Structural and Signaling Networks

E-cadherin and Src associate with extradesmosomal Dsg3 and modulate desmosome assembly and adhesion

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