IL-6 signaling via the STAT3/SOCS3 pathway: functional analysis of the conserved STAT3 N-domain
Open accessAbstract
The conserved N-domain of the STAT proteins has been implicated in several activities crucial to cytokine signaling including receptor recruitment and STAT activation, cooperative DNA binding and STAT-dependent gene expression. We evaluated the role of the STAT3 N-domain in the IL-6 signal transduction pathway leading to Socs3 gene expression, an essential mechanism that controls the quality and magnitude of IL-6-dependent transcriptional responses. Based on the model for STAT N-domain function in cooperative gene expression and the presence of tandem STAT binding motifs in the murine Socs3 promoter, we anticipated that stabilizing interactions between adjacent STAT3 dimers via N-domain sequences might be essential for Socs3 gene expression. This was underscored by the tight conservation in the location and sequence of the tandem STAT binding sites between the murine and human Socs3 promoters. Using reconstitution into Stat3-/- mouse embryonic fibroblasts (Stat3-/- MEFs), we find that a STAT3 N-domain deletion mutant (Delta 133STAT3) is activated by tyrosine phosphorylation in response to IL-6 and then undergoes dephosphorylation with kinetics similar to full-length STAT3. These results highlight important differences compared to other STATs where the N-domain has been shown to mediate activation (STAT4) or dephosphorylation (STAT1). STAT3 binds predominantly to a single STAT consensus site in the Socs3 promoter, despite the presence of an adjacent STAT motif. Significantly,…
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SOCS3 inhibits signaling between IL-6R and STAT3.
“Another target is SOCS3, which inhibits the signaling between IL-6R and STAT3.”
From Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells (2024) · cites this paper as [42]
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- Authors
- Zhang, L., Badgwell, D. B., Bevers, J. J., Schlessinger, K., Murray, P. J., Levy, D. E., & Watowich, S. S.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- MRC Laboratory for Molecular Cell Biology (GB)
- St. Jude Children's Research Hospital (US)
- New York University (US)
- Corresponding author
- Watowich, Stephanie S.
- Venue
- Molecular and Cellular Biochemistry
- Published
- 2006-05-23
- Volume
- 288
- Issue
- 1-2
- Pages
- 179-189
- ISSN
- 0300-8177 (ISSN-L)
- 1573-4919
- PMC
- PMC2441693
- OpenAlex
- W2023260746
- Cited by
- 89
- References
- 3
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 4 · 2023: 6 · 2022: 3 · 2021: 4 · 2020: 5 · 2019: 8 · 2018: 2 · 2017: 4 · 2016: 2 · 2015: 5 · 2014: 2 · 2013: 5 · 2012: 5
- FWCI
- 2.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Molecular and Cellular Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Gillson Longenbaugh Foundation
- National Institutes of Health
- National Cancer Institute (R01CA077447)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- IL-6 signaling, STAT3, SOCS3, cytokine signaling, STAT3 tyrosine phosphorylation, STAT3 dephosphorylation, STAT3 dimerization, transcriptional regulation
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Animals, Base Sequence, Fibroblasts, Humans, Molecular Sequence Data, Promoter Regions, Genetic, Recombinant Fusion Proteins, Transfection, Signal Transduction, Interleukin-6, Conserved Sequence, Protein Structure, Tertiary, Receptors, Interleukin, Receptors, Interleukin-6, NIH 3T3 Cells, STAT3 Transcription Factor, Suppressor of Cytokine Signaling Proteins, Mice
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