A STAT3 dimer formed by inter-chain disulphide bridging during oxidative stress
Abstract
Signal transducer and activator of transcription (STAT) proteins are activated by cytokines and growth factors to play distinct roles in immune responses and developmental processes. STATs were thought to exist as latent, cytoplasmic monomers and activation to require dimer formation was mediated exclusively by reciprocal phospho-tyrosine/SH2-domain interactions, but recent evidence of cytoplasmic STAT complexes, including dimers, and unphosphorylated STATs in the nucleus has challenged these notions. STAT complexes detected by conventional SDS-PAGE, including a STAT3 dimer, have been reported. We show that such complexes can form during cell lysis and be disrupted with DTT, suggesting inter-chain disulphide bridging. STAT3 also forms a related complex in cells upon oxidative stress. We map the interaction to the amino-terminal domain of STAT3 and use mass spectrometry to implicate cysteine 259 as the reactive residue. The redox sensitivity of STAT3 may be significant, given its activation in cells in response to reactive oxygen species.
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STAT3 itself can be subject to direct modification by oxidative stress, as 9 of the 14 cysteine residues within STAT3 are redox sensitive.
“STAT3 itself can be subject to direct modification by oxidative stress, as 9 of the 14 cysteine residues within STAT3 have been reported to be redox sensitive.”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Li and Shaw, 2004
Oxidative modifications affect the transcriptional activity of STAT3 through inhibiting Y705 phosphorylation and/or DNA binding, inducing formation of higher order complexes, and interfering with the function of the TAD.
“These modifications affect the transcriptional activity of STAT3 through inhibiting Y705 phosphorylation and/or DNA binding, as well as inducing formation of higher order complexes and interfering with the function of the TAD (Li and Shaw, 2004; Xie et al., 2009; Li et al., 2010a; Kurdi et al., 2012; Butturini et al., 2014; Sobotta et al., 2015).”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Li and Shaw, 2004
Peroxide treatment induces homodimerization of STAT3 through disulfide bonding of cysteines within the amino terminus of STAT3.
“Peroxide treatment induced homodimerization of STAT3 formation through a disulfide bonding of cysteines within the amino terminus of STAT3 (Li and Shaw, 2004).”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Li and Shaw, 2004
Cites
Bowman, T., Garcia, R., Turkson, J., & Jove, R. (2000) · Oncogene · doi:10.1038/sj.onc.1203527 · Cited by 1,743 · see citing works
DNA binding controls inactivation and nuclear accumulation of the transcription factor Stat1
Meyer, T., Marg, A., Lemke, P., Wiesner, B., & Vinkemeier, U. (2003) · Genes & Development · doi:10.1101/gad.268003 · Cited by 161 · see citing works
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Bharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
“…of STAT3 through inhibiting Y705 phosphorylation and/or DNA binding, as well as inducing formation of higher order complexes and interfering with the function of the TAD (Li and Shaw, 2004; Xie et al., 2009; Li et al., 2010a; Kurdi et al., 2012; Butturini et al., 2014; Sobotta et al., 2015).”
Background
- Authors
- Li, L., & Shaw, P. E.
- Affiliations
- University of Nottingham (GB)
- Corresponding author
- Shaw, Peter E.
- ORCID
- Shaw, Peter E.
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2004-09
- Volume
- 322
- Issue
- 3
- Pages
- 1005-1011
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W2022040328
- Cited by
- 79
- References
- 2
- Citations by year
- 2024: 2 · 2023: 3 · 2022: 6 · 2021: 8 · 2020: 4 · 2019: 5 · 2018: 5 · 2017: 8 · 2016: 2 · 2015: 4 · 2014: 4 · 2013: 4 · 2012: 6
- FWCI
- 0.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- STAT3, oxidative stress, N-terminal domain, redox sensitivity, reactive oxygen species, protein dimerization
- MeSH terms
- Acute-Phase Proteins, B-Lymphocytes, Breast Neoplasms, Cell Line, Cysteine, Disulfides, DNA-Binding Proteins, Humans, Kidney, Plasmids, Recombinant Proteins, Transfection, Trans-Activators, Oxidative Stress, Dimerization, Cell Line, Tumor, STAT3 Transcription Factor
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