Authors:	Müller, Sylvia Chen, Yuan Ginter, Torsten Schäfer, Claudia Buchwald, Marc Schmitz, Lienhard M. Klitzsch, Jana Schütz, Alexander Haitel, Andrea Schmid, Katharina Moriggl, Richard Kenner, Lukas Friedrich, Karlheinz Haan, Claude Petersen, Iver Heinzel, Thorsten Krämer, Oliver
Title:	SIAH2 antagonizes TYK2-STAT3 signaling in lung carcinoma cells
Online publication date:	6-Oct-2022
Year of first publication:	2014
Language:	english
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.
DDC:	610 Medizin 610 Medical sciences
Institution:	Johannes Gutenberg-Universität Mainz
Department:	FB 04 Medizin
Place:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-7880
Version:	Published version
Publication type:	Zeitschriftenaufsatz
License:	CC BY
Information on rights of use:	https://creativecommons.org/licenses/by/3.0/
Journal:	OncoTarget 5 10
Pages or article number:	3184 3196
Publisher:	Impact Journals LLC
Publisher place:	S.l.
Issue date:	2014
ISSN:	1949-2553
Publisher URL:	http://dx.doi.org/10.18632/oncotarget.1899
Publisher DOI:	10.18632/oncotarget.1899
Appears in collections:	DFG-OA-Publizieren (2012 - 2017)