SIAH2 antagonizes TYK2-STAT3 signaling in lung carcinoma cells
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Sylvia Müller1, Yuan Chen2, Torsten Ginter1, Claudia Schäfer1, Marc Buchwald1, Lienhard M. Schmitz3, Jana Klitzsch4, Alexander Schütz4, Andrea Haitel5, Katharina Schmid6, Richard Moriggl7,8, Lukas Kenner5,7,8, Karlheinz Friedrich9, Claude Haan10, Iver Petersen2, Thorsten Heinzel1, Oliver H. Krämer11
1 Center for Molecular Biomedicine, University of Jena, Department of Biochemistry, Jena, Germany
2 Institute of Pathology, University Clinic Jena, Germany
3 Department of Biochemistry, Faculty of Medicine, Giessen, Germany
4 Institute of Pathology, University of Leipzig, Germany
5 Clinical Institute of Pathology, Medical University of Vienna, Austria
6 Institute of Anatomy and Experimental Morphology, University of Hamburg-Eppendorf, Germany
7 Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
8 University of Veterinary Medicine, Vienna and Medical University of Vienna, Austria
9 Institute of Biochemistry II, University Clinic, Jena, Germany
10 Signal Transduction Laboratory/Life Sciences Research Unit, University of Luxembourg, Luxembourg
11 Department of Toxicology, University Medical Center, Mainz, Germany
Oliver H. Krämer, email:
Keywords: lung cancer, SIAH2, STAT3, TYK2, UBCH8
Received: March 26, 2014 Accepted: April 11, 2014 Published: April 12, 2014
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.
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