SIAH2 antagonizes TYK2-STAT3 signaling in lung carcinoma cells.
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.
Center for Molecular Biomedicine, University of Jena, Department of Biochemistry, Jena, Germany.
Sylvia
S
Müller
Yuan
Y
Chen
Torsten
T
Ginter
Claudia
C
Schäfer
Marc
M
Buchwald
Lienhard M
LM
Schmitz
Jana
J
Klitzsch
Alexander
A
Schütz
Andrea
A
Haitel
Katharina
K
Schmid
Richard
R
Moriggl
Lukas
L
Kenner
Karlheinz
K
Friedrich
Claude
C
Haan
Iver
I
Petersen
Thorsten
T
Heinzel
Oliver H
OH
Krämer
D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D053634:TYK2 Kinase / Q000378:metabolism*; D046888:Tissue Array Analysis; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D000098563:Seven in Absentia Proteins
D009687:Nuclear Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; D053634:TYK2 Kinase; C070139:TYK2 protein, human