Desmoplakin Maintains Transcellular Keratin Scaffolding and Protects From Intestinal Injury

Groß, Annika; Zhou, Biaohuan; Bewersdorf, Lisa; Schwarz, Nicole; Schacht, Gabriel M.; Hoeft, Konrad; Hoffmann, Bernd; Fuchs, Elaine; Kramann, Rafael; Merkel, Rudolf; Leube, Rudolf E.; Strnad, Pavel

doi:10.1016/j.jcmgh.2021.12.009

Cited by 9 publications

(4 citation statements)

References 40 publications

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“…DSG2 is associated with the armadillo proteins plakophilin (PKP) and the plakin member desmoplakin (DSP), which mediates attachment to the keratin filament network [30]. DSP is necessary for desmosomal integrity and is essential for cell adhesion [31]. To investigate the effect on the subcellular localization of DSG2‐WT and DSG2‐T730D, we isolated the soluble and insoluble protein pools (supplementary material, Figure S3B).…”

Section: Resultsmentioning

confidence: 99%

Serine/threonine‐protein kinase D2‐mediated phosphorylation of DSG2 threonine 730 promotes esophageal squamous cell carcinoma progression

Liu,

Xu,

Zheng

et al. 2024

The Journal of Pathology

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Desmoglein‐2 (DSG2) is a transmembrane glycoprotein belonging to the desmosomal cadherin family, which mediates cell–cell junctions; regulates cell proliferation, migration, and invasion; and promotes tumor development and metastasis. We previously showed serum DSG2 to be a potential biomarker for the diagnosis of esophageal squamous cell carcinoma (ESCC), although the significance and underlying molecular mechanisms were not identified. Here, we found that DSG2 was increased in ESCC tissues compared with adjacent tissues. In addition, we demonstrated that DSG2 promoted ESCC cell migration and invasion. Furthermore, using interactome analysis, we identified serine/threonine‐protein kinase D2 (PRKD2) as a novel DSG2 kinase that mediates the phosphorylation of DSG2 at threonine 730 (T730). Functionally, DSG2 promoted ESCC cell migration and invasion dependent on DSG2‐T730 phosphorylation. Mechanistically, DSG2 T730 phosphorylation activated EGFR, Src, AKT, and ERK signaling pathways. In addition, DSG2 and PRKD2 were positively correlated with each other, and the overall survival time of ESCC patients with high DSG2 and PRKD2 was shorter than that of patients with low DSG2 and PRKD2 levels. In summary, PRKD2 is a novel DSG2 kinase, and PRKD2‐mediated DSG2 T730 phosphorylation promotes ESCC progression. These findings may facilitate the development of future therapeutic agents that target DSG2 and DSG2 phosphorylation. © 2024 The Pathological Society of Great Britain and Ireland.

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Section: Resultsmentioning

confidence: 99%

Serine/threonine‐protein kinase D2‐mediated phosphorylation of DSG2 threonine 730 promotes esophageal squamous cell carcinoma progression

Liu,

Xu,

Zheng

et al. 2024

The Journal of Pathology

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“…66 The plakin family member DP mediates the adhesion of desmosomes and keratins, and loss of DP leads to impaired keratin attachment to desmosomes and altered desmosomal protein levels. 67 Previous research has indicated that only Dsg2 and Dsc2 are expressed in intestinal epitheliums. 68 A Dsg2 antibody targeting the extracellular domain can specifically block hemophilic Dsg2 interactions.…”

Section: The Apical Junctional Complex In the Paracellular Pathways R...mentioning

confidence: 99%

Intestinal absorption of bioactive oligopeptides: paracellular transport and tight junction modulation

Yu,

Liu,

et al. 2024

Food Funct.

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“…Finally, alterations in desmosome ultrastructure have been detected in patients suffering from inflammatory bowel disease (77,78). Because animal models deficient for Dsg2, Dsc2, and Dp have been shown to have intestinal epithelial barrier defects and disturbed wound healing and are prone to colitis (79)(80)(81)(82), several lines of evidence indicate that disturbed desmosomal adhesion contributes to the pathogenesis of inflammatory bowel diseases (83). In this respect, a new function of desmosomes has been elucidated as they control tight junction structure and function (84,85).…”

Section: Other Desmosome-related Diseasesmentioning

confidence: 99%

Mechanisms Causing Acantholysis in Pemphigus-Lessons from Human Skin

2022

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Pemphigus vulgaris (PV) is an autoimmune bullous skin disease caused primarily by autoantibodies (PV-IgG) against the desmosomal adhesion proteins desmoglein (Dsg) 1 and Dsg 3. PV patient lesions are characterized by flaccid blisters and ultrastructurally by defined hallmarks including a reduction in desmosome number and size, formation of split desmosomes, as well as uncoupling of keratin filaments from desmosomes. The pathophysiology underlying the disease is known to involve several intracellular signaling pathways downstream of PV-IgG binding. Here, we summarize our studies in which we used transmission electron microscopy to characterize the roles of signaling pathways in the pathogenic effects of PV-IgG on desmosome ultrastructure in a human ex vivo skin model. Blister scores revealed inhibition of p38MAPK, ERK and PLC/Ca2+ to be protective in human epidermis. In contrast, inhibition of Src and PKC, which were shown to be protective in cell cultures and murine models, was not effective for human skin explants. The ultrastructural analysis revealed that for preventing skin blistering at least desmosome number (as modulated by ERK) or keratin filament insertion (as modulated by PLC/Ca2+) need to be ameliorated. Other pathways such as p38MAPK regulate desmosome number, size, and keratin insertion indicating that they control desmosome assembly and disassembly on different levels. Taken together, studies in human skin delineate target mechanisms for the treatment of pemphigus patients. In addition, ultrastructural analysis supports defining the specific role of a given signaling molecule in desmosome turnover at ultrastructural level.

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Desmoplakin Maintains Transcellular Keratin Scaffolding and Protects From Intestinal Injury

Cited by 9 publications

References 40 publications

Serine/threonine‐protein kinase D2‐mediated phosphorylation of DSG2 threonine 730 promotes esophageal squamous cell carcinoma progression

Serine/threonine‐protein kinase D2‐mediated phosphorylation of DSG2 threonine 730 promotes esophageal squamous cell carcinoma progression

Intestinal absorption of bioactive oligopeptides: paracellular transport and tight junction modulation

Mechanisms Causing Acantholysis in Pemphigus-Lessons from Human Skin

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