ArticleMolecular and cellular biology2014
Signal integration and gene induction by a functionally distinct STAT3 phosphoform.
Article in Molecular and cellular biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 44 citations in OpenAlex.
- Review
- DYRK1A and Parkinson's disease, facts and hypotheses.Neurobiology of disease · 2026Review
- ERK1/2 hijack STAT3 via Thr714 phosphorylation to suppress gene expression.Cell communication and signaling : CCS · 2026Article
- A critical role for STAT3 Thr714 phosphorylation in NPM-ALK-driven tumorigenesis.Scientific reports · 2026Article
- Article
- The Role of Protein Kinases in the Suppressive Phenotype of Myeloid-Derived Suppressor Cells.International journal of molecular sciences · 2025Review
- Unraveling the complexity of STAT3 in cancer: molecular understanding and drug discovery.Journal of experimental & clinical cancer research : CR · 2024Review
- BMX controls 3βHSD1 and sex steroid biosynthesis in cancer.The Journal of clinical investigation · 2023Article
- Review
- Article
- The ZIP6/ZIP10 heteromer is essential for the zinc-mediated trigger of mitosis.Cellular and molecular life sciences : CMLS · 2021Article
- The Dawn of Mitophagy: What Do We Know by Now?Current neuropharmacology · 2021Review
- EGFR-mediated tyrosine phosphorylation of STING determines its trafficking route and cellular innate immunity functions.The EMBO journal · 2020Article
- Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 to Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution.Pharmacological reviews · 2020Review
- Phospho-Ser727 triggers a multistep inactivation of STAT3 by rapid dissociation of pY705-SH2 through C-terminal tail modulation.International immunology · 2020Article
- STAT3 Activation and Oncogenesis in Lymphoma.Cancers · 2019Review
- Contribution of STAT3 to Inflammatory and Fibrotic Diseases and Prospects for its Targeting for Treatment.International journal of molecular sciences · 2018Review
- Granulocyte-macrophage colony-stimulating factor negatively regulates early IL-10-mediated responses.Future science OA · 2018Article
- Keratin 6a reorganization for ubiquitin-proteasomal processing is a direct antimicrobial response.The Journal of cell biology · 2018Article
- Responses to Cytokines and Interferons that Depend upon JAKs and STATs.Cold Spring Harbor perspectives in biology · 2018Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Aberrant activation of the ubiquitous transcription factor STAT3 is a major driver of solid tumor progression and pathological angiogenesis. STAT3 activity is regulated by numerous posttranslational modifications (PTMs), including Tyr(705) phosphorylation, which is widely used as an indicator of canonical STAT3 function. Here, we report a noncanonical mechanism of STAT3 activation that occurs independently of Tyr(705) phosphorylation. Using quantitative liquid chromatography-tandem mass spectrometry, we have discovered and characterized a novel STAT3 phosphoform that is simultaneously phosphorylated at Thr(714) and Ser(727) by glycogen synthase kinase 3α and -β (GSK-3α/β). Both Thr(714) and Ser(727) are required for STAT3-dependent gene induction in response to simultaneous activation of epidermal growth factor receptor (EGFR) and protease-activated receptor 1 (PAR-1) in endothelial cells. In this combinatorial signaling context, preventing formation of doubly phosphorylated STAT3 by depleting GSK-3α/β is sufficient to disrupt signal integration and inhibit STAT3-dependent gene expression. Levels of doubly phosphorylated STAT3 but not of Tyr(705)-phosphorylated STAT3 are remarkably elevated in clear-cell renal-cell carcinoma relative to adjacent normal tissue, suggesting that the GSK-3α/β-STAT3 pathway is active in the disease. Collectively, our results describe a functionally distinct, noncanonical STAT3 phosphoform that positively regulates target gene expression in a combinatorial signaling context and identify GSK-3α/β-STAT3 signaling as a potential therapeutic target in renal-cell carcinoma.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.