Serine Phosphorylation and Negative Regulation of Stat3 by JNK
Open accessAbstract
STATs are activated by various cytokines and growth factors via tyrosine phosphorylation, which leads to sequential dimer formation, nuclear translocation, binding to specific DNA sequences, and regulation of gene expression. Recently, serine phosphorylation of Stat3 on Ser-727 by ERK has been identified in response to epidermal growth factor (EGF). Here, we report that Ser-727 phosphorylation of Stat3 can also be induced by JNK and activated either by stress or by its upstream kinase and that various stress treatments induce serine phosphorylation of Stat3 in the absence of tyrosine phosphorylation. Inhibitors of ERK and p38 did not inhibit UV-induced Stat3 serine phosphorylation, suggesting that neither of them is involved. We further demonstrate that JNK1, activated by its upstream kinase MKK7, negatively regulated the tyrosine phosphorylation and DNA binding and transcriptional activities of Stat3 stimulated by EGF. Correspondingly, pretreatment of cells with UV reduced the EGF-stimulated tyrosine phosphorylation and phosphotyrosine-dependent activities of Stat3. The inhibitory effect was not observed for Stat1. Our results suggest that Stat3 is a target of JNK that may regulate Stat3 activity via both Ser-727 phosphorylation-dependent and -independent mechanisms.
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Mutation of STAT3 Ser727 to Ala modulates STAT3 transcriptional activity.
“Previous studies have reported that mutation of Ser727 in STAT3 to Ala modulates its transcriptional activity (Chung et al., 1997; Kim and Baumann, 1997; Lim and Cao, 1999; Wen et al., 1995; Yokogami et al., 2000).”
From CDK8 fine-tunes IL-6 transcriptional activities by limiting STAT3 resident time at the gene loci (2020) · cites this paper as Lim and Cao, 1999
Ser727Ala mutation impairs transcriptional activity by different STATs.
“several studies have shown that Ser727Ala mutation impairs transcriptional activity by different STATs (Levy and Darnell, 2002; Lim and Cao, 1999; Sadzak et al., 2008; Wen et al., 1995)”
From CDK8 fine-tunes IL-6 transcriptional activities by limiting STAT3 resident time at the gene loci (2020) · cites this paper as Lim and Cao, 1999
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References 52 · Cited by 225
Research works printed but not linked: 5
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- Xu, S., Robbins, D., Frost, J., Dang, A., Lange-Carter, C., and Cobb, M. H. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 6808 -6812
- Dudley, D. T., Pang, L., Decker, S. J., Bridges, A. J., and Saltiel, A. R. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 7686 -7689
- Tournier, C., Whitmarsh, A. J., Cavanagh, J., Barrett, T., and Davis, R. J. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 7337-7342
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- Authors
- Lim, C. P., & Cao, X.
- Affiliations
- National University of Singapore (SG)
- Corresponding author
- Cao, Xinmin
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1999-10
- Volume
- 274
- Issue
- 43
- Pages
- 31055-31061
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1979785616
- Cited by
- 225
- References
- 52
- Citations by year
- 2026: 6 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 2 · 2021: 6 · 2020: 10 · 2019: 11 · 2018: 6 · 2017: 5 · 2016: 9 · 2015: 9 · 2014: 10 · 2013: 16 · 2012: 7
- FWCI
- 4.05
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion)
- 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, serine phosphorylation, JNK, JNK1, MKK7, tyrosine phosphorylation, epidermal growth factor, UV stress, STAT1, DNA binding, transcriptional activity
- MeSH terms
- Animals, DNA-Binding Proteins, Enzyme Activation, Enzyme Inhibitors, Epidermal Growth Factor, Flavonoids, Gene Expression Regulation, Imidazoles, Phosphorylation, Phosphoserine, Pyridines, Recombinant Fusion Proteins, Serine, Transfection, Ultraviolet Rays, Signal Transduction, Trans-Activators, Mutagenesis, Site-Directed, Point Mutation, COS Cells, Amino Acid Substitution, Mitogen-Activated Protein Kinases, JNK Mitogen-Activated Protein Kinases, p38 Mitogen-Activated Protein Kinases, STAT3 Transcription Factor
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