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Type of publication: Journal Article
Type of document: Full Paper

Year: 2014

Authors: Müller, S; Chen, Y; Ginter, T; Schäfer, C; Buchwald, M; Schmitz, LM; Klitzsch, J; Schütz, A; Haitel, A; Schmid, K; Moriggl, R; Kenner, L; Friedrich, K; Haan, C; Petersen, I; Heinzel, T; Krämer, OH

Title: SIAH2 antagonizes TYK2-STAT3 signaling in lung carcinoma cells.

Source: Oncotarget. 2014; 5(10):3184-3196



Authors Vetmeduni Vienna:

Kenner Lukas
Moriggl Richard

Vetmed Research Units
Institute of Pathology, Pathology of Laboratory Animals
Institute of Animal Breeding and Genetics, Unit for Functional Cancer Genomics


Abstract:
The Janus tyrosine kinases JAK1-3 and tyrosine kinase-2 (TYK2) are frequently hyperactivated in tumors. In lung cancers JAK1 and JAK2 induce oncogenic signaling through STAT3. A putative role of TYK2 in these tumors has not been reported. Here, we show a previously not recognized TYK2-STAT3 signaling node in lung cancer cells. We reveal that the E3 ubiquitin ligase seven-in-absentia-2 (SIAH2) accelerates the proteasomal degradation of TYK2. This mechanism consequently suppresses the activation of STAT3. In agreement with these data the analysis of primary non-small-cell lung cancer (NSCLC) samples from three patient cohorts revealed that compared to lung adenocarcinoma (ADC), lung squamous cell carcinoma (SCC) show significantly higher levels of SIAH2 and reduced STAT3 phosphorylation levels. Thus, SIAH2 is a novel molecular marker for SCC. We further demonstrate that an activation of the oncologically relevant transcription factor p53 in lung cancer cells induces SIAH2, depletes TYK2, and abrogates the tyrosine phosphorylation of STAT1 and STAT3. This mechanism appears to be different from the inhibition of phosphorylated JAKs through the suppressor of cytokine signaling (SOCS) proteins. Our study may help to identify molecular mechanisms affecting lung carcinogenesis and potential therapeutic targets.

Keywords Pubmed: Carcinoma, Non-Small-Cell Lung/metabolism*
Cell Line, Tumor
Humans
Immunoblotting
Immunohistochemistry
Immunoprecipitation
Lung Neoplasms/metabolism*
Nuclear Proteins/metabolism*
STAT3 Transcription Factor/metabolism*
Signal Transduction*/physiology
TYK2 Kinase/metabolism*
Tissue Array Analysis
Transfection
Ubiquitin-Protein Ligases/metabolism*


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