Dsg2 via Src-mediated transactivation shapes EGFR signaling towards cell adhesion

Ungewiß, Hanna; Rötzer, Vera; Meir, Michael; Fey, Christina; Diefenbacher, Markus E.; Schlegel, Nicolas; Waschke, Jens

doi:10.1007/s00018-018-2869-x

Cited by 35 publications

(38 citation statements)

References 97 publications

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“…In cardiomyocytes, DSG2 and the plaque protein Desmoplakin were shown to directly regulate gap junctions so that mutations of both contribute to the severe cardiac phenotype (40,41). In enterocytes, DSG2 regulates other signaling pathways including cell proliferation, cell death, and tight junction integrity (7,38,42). These may be compensated under basal conditions when DSG2 mutations are present, which may explain the missing intestinal phenotype.…”

Section: Methodsmentioning

confidence: 99%

Neurotrophic factor GDNF regulates intestinal barrier function in inflammatory bowel disease

Meir

Burkard

Ungewiß

et al. 2019

Journal of Clinical Investigation

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Section: Methodsmentioning

confidence: 99%

Neurotrophic factor GDNF regulates intestinal barrier function in inflammatory bowel disease

Meir

Burkard

Ungewiß

et al. 2019

Journal of Clinical Investigation

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“…Desmogleins consist of DSG1, DSG2, DSG3 and DSG4. DSG2 is expressed in all desmosome-bearing tissues and some epithelial tissues, such as cardiac muscle, skin and intestinal epithelium (Schafer, Stumpp & Franke, 1996;Ungewiss et al, 2018). As a member of cadherins, DSG2 is an important regulator of growth and survival signaling pathways, cell proliferation, apoptosis, migration and invasion and oncogenesis (Brennan et al, 2007;Cooper et al, 2018;Nava et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Upregulation of desmoglein 2 and its clinical value in lung adenocarcinoma: a comprehensive analysis by multiple bioinformatics methods

Sun

Wang

Yang

2020

PeerJ

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Background Desmoglein-2 (DSG2), a desmosomal adhesion molecule, is found to be closely related to tumorigenesis in recent years. However, the clinical value of DSG2 in lung adenocarcinoma remains unclear. Methods Real-time reverse transcription-quantitative polymerase chain reaction (qRT-PCR) was utilized to detect the expression of DSG2 in 40 paired lung adenocarcinoma tissues and corresponding non-cancerous tissues. Data from The Cancer Genome Atlas (TCGA) and Oncomine datasets were also downloaded and analyzed. The correlation between DSG2 and clinicopathological features was investigated. The expression of DSG2 protein by immunohistochemical was also detected from tissue microarray and the Human Protein Atlas database. Integrated meta-analysis combining the three sources (qRT-PCR data, TCGA data and Oncomine datasets) was performed to evaluate the clinical value of DSG2. Univariate and multivariate Cox regression analyses were used to explore the prognostic value of DSG2. Then, co-expressed genes were calculated by Pearson correlation analysis. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to investigate the underlying molecular mechanism. The expression level in lung adenocarcinoma and prognostic significance of the top ten co-expressed genes were searched from Gene Expression Profiling Interactive Analysis (GEPIA) online database. Results DSG2 was highly expressed in lung adenocarcinoma tissues based on qRT-PCR, TCGA and Oncomine datasets. The protein expression of DSG2 was also higher in lung adenocarcinoma. According to qRT-PCR and TCGA, high DSG2 expression was positively associated with tumor size (p = 0.027, p = 0.001), lymph node metastasis (p = 0.014, p < 0.001) and TNM stage (p = 0.023, p < 0.001). The combined standard mean difference values of DSG2 expression based on the three sources were 1.30 (95% confidence interval (CI): 1.08–1.52) using random effect model. The sensitivity and specificity were 0.73 (95% CI [0.69–0.76]) and 0.96 (95% CI [0.89–0.98]). The area under the curve based on summarized receiver operating characteristic (SROC) curve was 0.79 (95% CI [0.75–0.82]). Survival analysis revealed that high DSG2 expression was associated with a short overall survival (hazard ratio [HR] = 1.638; 95% CI [1.214–2.209], p = 0.001) and poor progression-free survival (HR = 1.475; 95% CI [1.102–1.974], p < 0.001). A total of 215 co-expressed genes were identified. According to GO and KEGG analyses, these co-expressed genes may be involved in “cell division”, “cytosol”, “ATP binding” and “cell cycle”. Based on GEPIA database, seven of the top ten co-expressed genes were highly expressed in lung adenocarcinoma (DSC2, SLC2A1, ARNTL2, ERO1L, ECT2, ANLN and LAMC2). High expression of these genes had shorter overall survival. Conclusions The expression of DSG2 is related to the tumor size, lymph node metastasis and TNM stage. Also, DSG2 predicts poor prognosis in lung adenocarcinoma.

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“…Recently, a direct DSG2‐EGFR interaction on the cell surface, regulating the switch between adhesive and proliferative states in intestinal epithelial cells, was reported. [ ] This study has identified a new role for DSG2 in regulating EGFR activity via a novel signalling complex consisting of DSG2 and EGFR. In DSG2 deficient cells, unbound EGFR was activated by ligand bindings that induced cell proliferation, whereas re‐expression of DSG2 suppressed cell proliferation in DSG2‐deficient cells.…”

Section: Discussionmentioning

confidence: 99%

A potential link between desmoglein 3 and epidermal growth factor receptor in oral squamous cell carcinoma and its effect on cetuximab treatment efficacy

Minabe

Akiyama

Higa

et al. 2019

Experimental Dermatology

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Desmoglein (DSG) 3 is overexpressed in oral squamous cell carcinoma (OSCC). Epidermal growth factor receptor (EGFR) inhibitor cetuximab is widely used for OSCC treatment. Several evidences suggest a correlation between DSG3 and EGFR in epidermal keratinocytes. EGFR inhibition has been shown to enhance cell‐cell adhesion and induce terminal differentiation in epidermal cells. Thus, here we investigated the DSG3‐EGFR interaction in OSCC and its effect on cetuximab treatment. Cell lines established from the primary tumor and metastatic lymph nodes of four OSCC patients and three commercial OSCC cell lines were used for the experiments. Cells from metastatic lymph nodes of each patient expressed increased DSG3 and EGFR than cells from the primary tumor in the same patient. Cetuximab treatment increased DSG3 expression by up to 3.5‐fold in seven of the 11 cell lines. A high calcium concentration increased the expression of DSG3 and EGFR in a dose‐dependent manner. Strikingly, a high calcium‐associated DSG3 induction enhanced cetuximab efficacy by up to 23% increase in cetuximab‐low‐sensitive cell lines. Our findings also suggest a correlation between DSG3 and EGFR in OSCC, and this affects cetuximab treatment efficacy.

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Dsg2 via Src-mediated transactivation shapes EGFR signaling towards cell adhesion

Cited by 35 publications

References 97 publications

Neurotrophic factor GDNF regulates intestinal barrier function in inflammatory bowel disease

Neurotrophic factor GDNF regulates intestinal barrier function in inflammatory bowel disease

Upregulation of desmoglein 2 and its clinical value in lung adenocarcinoma: a comprehensive analysis by multiple bioinformatics methods

A potential link between desmoglein 3 and epidermal growth factor receptor in oral squamous cell carcinoma and its effect on cetuximab treatment efficacy

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