Autoren:	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
Titel:	SIAH2 antagonizes TYK2-STAT3 signaling in lung carcinoma cells
Online-Publikationsdatum:	6-Okt-2022
Erscheinungsdatum:	2014
Sprache des Dokuments:	Englisch
Zusammenfassung/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-Sachgruppe:	610 Medizin 610 Medical sciences
Veröffentlichende Institution:	Johannes Gutenberg-Universität Mainz
Organisationseinheit:	FB 04 Medizin
Veröffentlichungsort:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-7880
Version:	Published version
Publikationstyp:	Zeitschriftenaufsatz
Nutzungsrechte:	CC BY
Informationen zu den Nutzungsrechten:	https://creativecommons.org/licenses/by/3.0/
Zeitschrift:	OncoTarget 5 10
Seitenzahl oder Artikelnummer:	3184 3196
Verlag:	Impact Journals LLC
Verlagsort:	S.l.
Erscheinungsdatum:	2014
ISSN:	1949-2553
URL der Originalveröffentlichung:	http://dx.doi.org/10.18632/oncotarget.1899
DOI der Originalveröffentlichung:	10.18632/oncotarget.1899
Enthalten in den Sammlungen:	DFG-OA-Publizieren (2012 - 2017)