ArticleInternational immunology2020
Phospho-Ser727 triggers a multistep inactivation of STAT3 by rapid dissociation of pY705-SH2 through C-terminal tail modulation.
Article in International immunology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 26 citations in OpenAlex.
- Piperine attenuates fibrogenesis and inflammation in hepatic fibrosis by switching STAT3 phosphorylation at Ser727.Chinese herbal medicines · 2026Article
- STAT3 signaling in cancer: mechanisms and targeting therapeutic.Frontiers in immunology · 2026Review
- Loss of tuberous sclerosis complex 2 confers inflammation via dysregulation of nuclear factor kappa-light-chain-enhancer of activated B cells.Journal of inflammation (London, England) · 2025Article
- Signal Transducer and Activator of Transcription 3 (STAT3) Variant p.K709N Causes Hyper-IgE Syndrome Likely by Impaired STAT3-Dimer Formation.European journal of immunology · 2025Article
- IL-6 Does Not Influence the Expression ofInternational journal of molecular sciences · 2024Article
- Curcumin: A Potential Weapon in the Prevention and Treatment of Head and Neck Cancer.ACS pharmacology & translational science · 2024Review
- Molecular crosstalk between MUC1 and STAT3 influences the anti-proliferative effect of Napabucasin in epithelial cancers.Scientific reports · 2024Article
- PKCι induces differential phosphorylation of STAT3 to modify STAT3-related signaling pathways in pancreatic cancer cells.Journal of cell communication and signaling · 2023Article
- STAT3 modulates CD4Aging cell · 2023Article
- Article
- Cold Storage Followed by Transplantation Induces Interferon-Gamma and STAT-1 in Kidney Grafts.International journal of molecular sciences · 2023Article
- Role of Endothelial STAT3 in Cerebrovascular Function and Protection from Ischemic Brain Injury.International journal of molecular sciences · 2022Article
- STAT3-mediated osteogenesis and osteoclastogenesis in osteoporosis.Cell communication and signaling : CCS · 2022Review
- Article
- Chronic Proinflammatory Signaling Accelerates the Rate of Degeneration in a Spontaneous Polygenic Model of Inherited Retinal Dystrophy.Frontiers in pharmacology · 2022Article
- Regulation of STAT3 and its role in cardioprotection by conditioning: focus on non-genomic roles targeting mitochondrial function.Basic research in cardiology · 2021Review
- Discovery and Validation of Nitroxoline as a Novel STAT3 Inhibitor in Drug-resistant Urothelial Bladder Cancer.International journal of biological sciences · 2021Article
- CDK8 Fine-Tunes IL-6 Transcriptional Activities by Limiting STAT3 Resident Time at the Gene Loci.Cell reports · 2020Article
- Article
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Signal transducer and activator of transcription 3 (STAT3) is involved in many biological processes, including immunity and cancer. STAT3 becomes phosphorylated at Tyr705 and Ser727 on IL-6 stimulation. Phospho-Tyr705 (pY705) stabilizes the STAT3 dimer with reciprocal interactions between pY705 and the SH2 of the other molecule and phospho-Ser727 (pS727) accelerates pY705 dephosphorylation. We study how pS727 regulates STAT3 in both structural and biological perspectives. Using STAT3 reconstituted in HepG2-stat3-knockout cells, we show that pS727, together with a handshake N-terminal domain (NTD) interaction, causes rapid inactivation of STAT3 for pY705 dephosphorylation and a chromosome region maintenance 1 (CRM1)-independent nuclear export, which is critical for faithful STAT3 response to the cellular signals. The various N-terminal tags, GFP-related Ruby and FLAG, rendered the export CRM1-dependent and especially FLAG-tag caused nuclear accumulation of STAT3, indicating the presence of conformational changes in inactivation. Impaired reactivation of STAT3 by S727A or FLAG-tag delayed or inhibited the IL-6-induced saa1 mRNA expression, respectively. The detailed analysis of the pY705-SH2 structure identified the C-terminal tail (CTT) from L706 to P715 as a key regulator of the CTT-CTT intermolecular and the CTT-SH2 intramolecular interactions that support pY705-SH2 association. The functional studies using multiple STAT3 mutants indicated that the degree of the two interactions determines the stability of pY705-SH2 interaction. Importantly, Pro715 was critical for the pS727's destabilizing activity and the known phosphorylation and acetylation at the CTT structurally inhibited the pY705-SH2 interaction. Thus, pS727 triggers pY705-SH2 dissociation by weakening the supportive interactions likely through CTT modulation, inducing rapid cycles of STAT3 activation-inactivation for proper function of STAT3.
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