Desmoglein 2 Compensates for Desmoglein 3 but Does Not Control Cell Adhesion via Regulation of p38 Mitogen-activated Protein Kinase in Keratinocytes

Hartlieb, Eva; Rötzer, Vera; Radeva, Mariya Y.; Spindler, Volker; Waschke, Jens

doi:10.1074/jbc.m113.489336

Cited by 42 publications

(71 citation statements)

References 42 publications

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“…2a). In accordance with our previous findings [25], depletion of Dsg3 led to 1.5-fold p38 MAPK activation compared to non-targeting (n.t.) siRNA controls.…”

Section: E-cadherin Compensates For Effects Of Desmosomal Perturbationsupporting

confidence: 80%

“…Dissociation assays showed that 24 h incubation with Decma-1 at high (12.5 lg/ml) as well as low (2.5 lg/ml) doses resulted in loss of cell cohesion (number of fragments per well: 16 ± 2 and 7 ± 1) compared to control cells (1 ± 1). Similar to the situation of impaired Dsg3 binding as previously published [7,25], co-incubation with the p38 MAPK inhibitor SB202190 significantly reduced the number of fragments (12.5 lg/ml Decma-1: 10 ± 2 and 2.5 lg/ml Decma-1: 4 ± 1) (Fig. 1d).…”

Section: E-cadherin Compensates For Effects Of Desmosomal Perturbationsupporting

confidence: 73%

“…In contrast, an association of Dsg3 with E-cadherin and vice versa was detectable within the cytoskeleton-bound pool (TX-100 I) only. Complex formation of p38 MAPK and Dsg3 was detectable in both pools, as it has been observed previously [25], whereas E-cadherin was not associated with p38 MAPK.…”

Section: E-cadherin Interacts With Dsg3 and Regulates Dsg3 Subcellulasupporting

confidence: 62%

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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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“…2a). In accordance with our previous findings [25], depletion of Dsg3 led to 1.5-fold p38 MAPK activation compared to non-targeting (n.t.) siRNA controls.…”

Section: E-cadherin Compensates For Effects Of Desmosomal Perturbationsupporting

confidence: 80%

Section: E-cadherin Compensates For Effects Of Desmosomal Perturbationsupporting

confidence: 73%

Section: E-cadherin Interacts With Dsg3 and Regulates Dsg3 Subcellulasupporting

confidence: 62%

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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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“…Nevertheless, Dsg2 expression was visible which is different from human epidermis, where Dsg2 could be found in hair follicles only. 15 Specific Dsc1 staining was absent. The desmosomal plaque proteins plakoglobin (PG) and desmoplakin (DP) were uniformly expressed throughout all layers (Figs.…”

Section: Characterization Of the Expression Pattern Of Desmosomal Molmentioning

confidence: 99%

“…Genotyping of progeny of heterozygous B6; 129X1-Dsg3 tm1Stan / J mice (Jackson Laboratory, Bar Harbor, ME, USA) 14 was performed as described previously 15 and PCR analyses were done after a well-established protocol. 16 Homozygous Dsg3 À/À animals), the animal and a WT littermate were euthanized and eyes together with eyelids were enucleated as described previously.…”

Section: Dsg3 Mice -Genotyping and Enucleation Of Whole Eyesmentioning

confidence: 99%

Pemphigus Autoantibodies Induce Blistering in Human Conjunctiva

Vielmuth

Rötzer

Hartlieb

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The autoimmune blistering skin disease pemphigus vulgaris (PV) is caused by autoantibodies against desmosomal adhesion molecules. Patients may suffer conjunctival involvement, yet the underlying mechanisms are largely unclear. We characterized human and murine conjunctiva with respect to the PV autoantigens, and evaluated the effects and mechanisms of PV autoantibodies applied to human conjunctiva ex vivo. METHODS.We obtained human conjunctiva specimens from surgical explants and established a short-term culture model to study the alterations induced by antibody fractions of PV patients (PV-IgG). Furthermore, we applied a mouse model depleted of the desmosomal cadherin desmoglein 3 (Dsg3), the primary autoantigen in PV. Murine and human conjunctiva also was used to analyze the expression pattern of desmosomal proteins by immunostaining and Western blotting.RESULTS. Human and murine conjunctiva samples expressed the majority of desmosomal molecules with an expression pattern similar to the epidermis. Interestingly, Dsg3 knock out animals frequently suffer eye lesions, histologically evident as microblisters in the eyelid epidermis and conjunctiva. Incubation of human specimens with PV-IgG for 12 hours caused blistering in the suprabasal layers of the conjunctiva as well as reduction of Dsg1 and Dsg3 protein levels. Furthermore, PV-IgG prompted activation of p38MAPK in the conjunctiva, which is a central pathomechanism leading to blistering in the epidermis.CONCLUSIONS. PV-IgG leads to blister formation and p38MAPK activation in the conjunctiva and, thus, resembles the effects found in the epidermis. Our data indicate that the ocular involvement observed in PV patients is mainly based on conjunctival blistering.

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Non‐invasive placentation in the marsupials Macropus eugenii (Macropodidae) and Trichosurus vulpecula (Phalangeridae) involves redistribution of uterine Desmoglein‐2

Laird

McShea

Murphy

et al. 2018

Molecular Reproduction Devel

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In mammalian pregnancy, the uterus is remodeled to become receptive to embryonic implantation. Since non-invasive placentation in marsupials is likely derived from invasive placentation, and is underpinned by intra-uterine conflict between mother and embryo, species with non-invasive placentation may employ a variety of molecular mechanisms to maintain an intact uterine epithelium and to prevent embryonic invasion. Identifying such modifications to the uterine epithelium of marsupial species with non-invasive placentation is key to understanding how conflict is mediated during pregnancy in different mammalian groups. Desmoglein-2, involved in maintaining lateral cell-cell adhesion of the uterine epithelium, is redistributed before implantation to facilitate embryo invasion in mammals with invasive placentation. We identified localization patterns of this cell adhesion molecule throughout pregnancy in two marsupial species with non-invasive placentation, the tammar wallaby (Macropus eugenii; Macropodidae), and the brushtail possum (Trichosurus vulpecula; Phalangeridae). Interestingly, Desmoglein-2 redistribution also occurs in both M. eugenii and T. vulpecula, suggesting that cell adhesion, and thus integrity of the uterine epithelium, is reduced during implantation regardless of placental type, and may be an important component of uterine remodeling. Desmoglein-2 also localizes to the mesenchymal stromal cells of M. eugenii and to epithelial cell nuclei in T. vulpecula, suggesting its involvement in cellular processes that are independent of adhesion and may compensate for reduced lateral adhesion in the uterine epithelium. We conclude that non-invasive placentation in marsupials involves diverse and complementary strategies to maintain an intact epithelial barrier.

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Desmoglein 2 Compensates for Desmoglein 3 but Does Not Control Cell Adhesion via Regulation of p38 Mitogen-activated Protein Kinase in Keratinocytes

Cited by 42 publications

References 42 publications

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

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

Pemphigus Autoantibodies Induce Blistering in Human Conjunctiva

Non‐invasive placentation in the marsupials Macropus eugenii (Macropodidae) and Trichosurus vulpecula (Phalangeridae) involves redistribution of uterine Desmoglein‐2

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