SIAH2 antagonizes TYK2-STAT3 signaling in lung carcinoma cells

Autoren

Sylvia Müller
Yuan Chen
Torsten Ginter
Claudia Schäfer
Marc Buchwald
Lienhard M Schmitz
Jana Klitzsch
Alexander Schütz
Andrea Haitel
Katharina Schmid
Richard Moriggl
Lukas Kenner
Karlheinz Friedrich
Claude Haan
Iver Petersen
Thorsten Heinzel
Oliver H Krämer

DOI

10.18632/oncotarget.1899

eISSN

1949-2553

Ausgabe der Veröffentlichung

10

Zeitschrift

Oncotarget

Sprache

en

Online publication date

2014

Paginierung

3184 - 3196

Datum der Veröffentlichung

2014

Status

Published

Herausgeber

Impact Journals, LLC

Herausgeber URL

http://dx.doi.org/10.18632/oncotarget.1899

Datum der Datenerfassung

2020

Titel

SIAH2 antagonizes TYK2-STAT3 signaling in lung carcinoma cells

Ausgabe der Zeitschrift

5

Data source: Crossref

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.

Addresses

Center for Molecular Biomedicine, University of Jena, Department of Biochemistry, Jena, Germany.

Autoren

Sylvia Müller
Yuan Chen
Torsten Ginter
Claudia Schäfer
Marc Buchwald
Lienhard M Schmitz
Jana Klitzsch
Alexander Schütz
Andrea Haitel
Katharina Schmid
Richard Moriggl
Lukas Kenner
Karlheinz Friedrich
Claude Haan
Iver Petersen
Thorsten Heinzel
Oliver H Krämer

DOI

10.18632/oncotarget.1899

eISSN

1949-2553

Externe Identifier

PubMed Identifier: 24833526
PubMed Central ID: PMC4102802

Open access

true

ISSN

1949-2553

Ausgabe der Veröffentlichung

10

Zeitschrift

Oncotarget

Schlüsselwörter

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

Sprache

eng

Medium

Print

Open access status

Open Access

Paginierung

3184 - 3196

Datum der Veröffentlichung

2014

Status

Published

Publisher licence

CC BY

Datum der Datenerfassung

2014

Titel

SIAH2 antagonizes TYK2-STAT3 signaling in lung carcinoma cells.

Sub types

Research Support, Non-U.S. Gov't
research-article
Journal Article

Ausgabe der Zeitschrift

5

Files

http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=download&path%5B%5D=1899&path%5B%5D=2553 https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24833526/pdf/?tool=EBI https://europepmc.org/articles/PMC4102802?pdf=render

Data source: Europe PubMed Central

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.

Autoren

Sylvia Müller
Yuan Chen
Torsten Ginter
Claudia Schäfer
Marc Buchwald
Lienhard M Schmitz
Jana Klitzsch
Alexander Schütz
Andrea Haitel
Katharina Schmid
Richard Moriggl
Lukas Kenner
Karlheinz Friedrich
Claude Haan
Iver Petersen
Thorsten Heinzel
Oliver H Krämer

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/24833526

DOI

10.18632/oncotarget.1899

eISSN

1949-2553

Externe Identifier

PubMed Central ID: PMC4102802

Ausgabe der Veröffentlichung

10

Zeitschrift

Oncotarget

Schlüsselwörter

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

Sprache

eng

Country

United States

Paginierung

3184 - 3196

PII

1899

Datum der Veröffentlichung

2014

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2015

Titel

SIAH2 antagonizes TYK2-STAT3 signaling in lung carcinoma cells.

Sub types

Journal Article
Research Support, Non-U.S. Gov't

Ausgabe der Zeitschrift

5

Data source: PubMed

Author's licence

CC-BY

Autoren

Sylvia Müller
Yuan Chen
Torsten Ginter
Claudia Schäfer
Marc Buchwald
Lienhard M Schmitz
Jana Klitzsch
Alexander Schütz
Andrea Haitel
Katharina Schmid
Richard Moriggl
Lukas Kenner
Karlheinz Friedrich
Claude Haan
Iver Petersen
Thorsten Heinzel
Oliver Krämer

Hosting institution

Universitätsbibliothek Mainz

Sammlungen

DFG-OA-Publizieren (2012 - 2017)

Resource version

Published version

DOI

10.18632/oncotarget.1899

Funding acknowledgements

DFG, Open Access-Publizieren Universität Mainz / Universitätsmedizin

File(s) embargoed

false

Open access

true

ISSN

1949-2553

Ausgabe der Veröffentlichung

10

Zeitschrift

OncoTarget

Schlüsselwörter

610 Medizin
610 Medical sciences

Sprache

eng

Open access status

Open Access

Paginierung

3184 - 3196

Datum der Veröffentlichung

2014

Public URL

https://openscience.ub.uni-mainz.de/handle/20.500.12030/7895

Herausgeber

Impact Journals LLC

Herausgeber URL

http://dx.doi.org/10.18632/oncotarget.1899

Datum der Datenerfassung

2022

Datum, an dem der Datensatz öffentlich gemacht wurde

2022

Zugang

Public

Titel

SIAH2 antagonizes TYK2-STAT3 signaling in lung carcinoma cells

Ausgabe der Zeitschrift

5

Files

siah2_antagonizes_tyk2stat3_s-20220915070215809.pdf

Data source: OPENSCIENCE.UB

SIAH2 antagonizes TYK2-STAT3 signaling in lung carcinoma cells

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