Phospho-Ser727 of STAT3 regulates STAT3 activity by enhancing dephosphorylation of phospho-Tyr705 largely through TC45
Abstract
Signal transducer and activator of transcription 3 (STAT3) is a latent cytoplasmic transcription factor. It is activated by cytokines, including interleukin-6 (IL-6) through phosphorylation at Tyr705 (pY705), which is required for its dimerization and nuclear translocation. However, the role of Ser727 phosphorylation, occurring during activation, remains poorly understood. Using a combination of HepG2-stat3-knockdown cells reconstituted with various STAT3 mutants and protein kinase inhibitors, we showed that phospho-S727 has an intrinsic mechanism for shortening the duration of STAT3 activity, in turn shortening the duration of socs3 mRNA expression. Both STAT3WT and STAT3Ser727Asp (S727D) but not STAT3Ser727Ala (S727A) showed rapid dephosphorylation of pY705 after the inhibition of tyrosine kinases. We found that the nuclear TC45 phosphatase is most likely responsible for the phospho-S727-dependent pY705 dephosphorylation because TC45 knockdown caused prolonged pY705 with sustained socs3 mRNA expression in STAT3WT but not in STAT3S727A, and overexpressed TC45 caused rapid dephosphorylation of pY705 in STAT3WT but not in STAT3S727A. We further showed that phospho-S727 did not affect the interaction of TC45 with STAT3, and that a reported methylation at K140 of STAT3 occurring after phospho-S727 was not involved in the pY705 regulation. These findings indicate that phospho-Ser727 determines the duration of STAT3 activity largely through TC45.
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pS727 increases STAT3 binding to nuclear tyrosine phosphatase TC45, leading to rapid dephosphorylation of pY705 and shortening the duration of STAT3 activity.
“Furthermore, pS727 increases STAT3 binding to nuclear tyrosine phosphatase TC45 (Wakahara et al., 2012), leading to rapid dephosphorylation of pY705, thereby shortening the duration of STAT3 activity.”
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 Wakahara et al., 2012
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Darnell, J. E., Kerr, L. M., & Stark, G. R. (1994) · Science · doi:10.1126/science.8197455 · Cited by 6,080 · cited 2× · see citing works
“…through tyrosine phosphorylation of its critical tyrosine residue in the carboxy-terminal region, STAT protein homo- or heterodimerizes, translocates to the nucleus, and binds to the specific DNA sequences to regulate mRNA expression from by its target genes (Darnell et al. 1994; Darnell 1997).”
BackgroundBowman, T., Garcia, R., Turkson, J., & Jove, R. (2000) · Oncogene · doi:10.1038/sj.onc.1203527 · Cited by 1,743 · see citing works
A nuclear protein tyrosine phosphatase is required for the inactivation of Stat1
Haspel, R. L., & Darnell, J. E. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.18.10188 · Cited by 203 · see citing works
Ser727-dependent transcriptional activation by association of p300 with STAT3 upon IL-6 stimulation
Schuringa, J.-J., Schepers, H., Vellenga, E., & Kruijer, W. (2001) · FEBS Letters · doi:10.1016/s0014-5793(01)02354-7 · Cited by 124 · see citing works
Pin1 is required for the Ser727 phosphorylation-dependent Stat3 activity
Lufei, C., Koh, T. H., Uchida, T., & Cao, X. (2007) · Oncogene · doi:10.1038/sj.onc.1210567 · Cited by 106 · see citing works
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“Furthermore, pS727 increases STAT3 binding to nuclear tyrosine phosphatase TC45 (Wakahara et al., 2012), leading to rapid dephosphorylation of pY705, thereby shortening the duration of STAT3 activity.”
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Critical analysis of the potential for targeting STAT3 in human malignancy
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“STAT3 activity can be further modulated by the phosphorylation of serine 727, though the context-specific consequences of serine 727 phosphorylation remain incompletely understood.(9,10) In addition, STAT3 activity can be modified by reversible acetylation of lysine 685 (K685), an event that is critical for the format…”
- Authors
- Wakahara, R., Kunimoto, H., Tanino, K., Kojima, H., Inoue, A., Shintaku, H., & Nakajima, K.
- Affiliations
- Osaka City University (JP)
- Corresponding author
- Nakajima, Koichi
- Venue
- Genes to Cells
- Publisher
- Wiley
- Published
- 2012-01-11
- Volume
- 17
- Issue
- 2
- Pages
- 132-145
- ISSN
- 1356-9597 (ISSN-L)
- 1365-2443
- OpenAlex
- W1879729745
- Cited by
- 95
- References
- 5
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 3 · 2023: 9 · 2022: 5 · 2021: 11 · 2020: 11 · 2019: 11 · 2018: 9 · 2017: 3 · 2016: 4 · 2015: 4 · 2014: 10 · 2013: 6
- FWCI
- 3.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Genes to Cells (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (21590317)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- STAT3, SOCS3, IL-6 signaling, tyrosine kinase inhibition
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, DNA Polymerase II, Gene Expression Regulation, Humans, Mutation, Phosphorylation, Promoter Regions, Genetic, Protein Binding, RNA, Messenger, Serine, STAT3 Transcription Factor, Suppressor of Cytokine Signaling Proteins, Protein Tyrosine Phosphatase, Non-Receptor Type 2, Hep G2 Cells, HEK293 Cells
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