STAT3 Serine Phosphorylation by ERK-Dependent and -Independent Pathways Negatively Modulates Its Tyrosine Phosphorylation
Open accessAbstract
Recent studies have indicated that serine phosphorylation regulates the activities of STAT1 and STAT3. However, the kinase(s) responsible and the role of serine phosphorylation in STAT function remain unresolved. In the present studies, we examined the growth factor-dependent serine phosphorylation of STAT1 and STAT3. We provide in vitro and in vivo evidence that the ERK family of mitogen-activated protein (MAP) kinases, but not JNK or p38, specifically phosphorylate STAT3 at serine 727 in response to growth factors. Evidence for additional mitogen-regulated serine phosphorylation is also provided. STAT1 is a relatively poor substrate for all MAP kinases tested both in vitro and in vivo. STAT3 serine phosphorylation, not its tyrosine phosphorylation, results in retarded mobility of the STAT3 protein on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Importantly, serine 727 phosphorylation negatively modulates STAT3 tyrosine phosphorylation, which is required for dimer formation, nuclear translocation, and the DNA binding activity of this transcriptional regulator. Interestingly, the cytokine interleukin-6 also stimulates STAT3 serine phosphorylation, but in contrast to growth factors, this occurs by an ERK-independent process.
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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 Chung et al., 1997
The Results section (page not available) reports that the STAT3 S727A mutation increased tyrosine phosphorylation, a step relevant to transcriptional activity. The Discussion proposes an effect on transcription but explicitly says future studies are needed to determine it; this paper does not establish that the mutation modulates transcriptional activity. (LLM, conf=0.87)
Experimental — accuracy not yet measuredSTAT3 Ser phosphorylation plays a negative role in STAT3 nuclear dynamics and transcriptional activities.
“our study and others (Chung et al., 1997; Decker and Kovarik, 2000; Kim and Baumann, 1997) highlight a negative role of STAT3 Ser phosphorylation in STAT3 nuclear dynamics and transcriptional activities.”
From CDK8 fine-tunes IL-6 transcriptional activities by limiting STAT3 resident time at the gene loci (2020) · cites this paper as Chung et al., 1997
The Abstract and the section on STAT3 serine 727 phosphorylation report that serine phosphorylation negatively modulates tyrosine phosphorylation, which is required for nuclear translocation and subsequent transcriptional activity. But the Discussion says its effects on nuclear translocation and transcriptional activity still require study and proposes that serine phosphorylation can also stimulate transcription. The source therefore supports a possible negative effect, not the unqualified claim about both outcomes. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSerin phosphorylation contributes to reduction of STAT3 Y705 phosphorylation, thereby increasing robustness of STAT3 Y705 phosphorylation to varying STAT3 expression.
“Serin phosphorylation contributes to reduction of STAT3 Y705 phosphorylation [46], thereby increasing robustness of STAT3 Y705 phosphorylation to varying STAT3 expression [20].”
From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [46]
S727 phosphorylation of STAT3 is mediated by various serine/threonine kinases depending on the stimulus, upstream signaling pathway, and cell type.
“In addition to phosphorylation on Y705, STAT3 can be phosphorylated on Ser727 within its TAD (Wen et al., 1995) by various serine/threonine kinases, e.g., mitogen-activated protein kinase (MAPK) like MAPK kinase/ERK (Chung et al., 1997; Stephens et al., 1998; Ng et al., 2011), c-Jun N-terminal kinase (JNK) (Zhang et al., 2001; Liu et al., 2012), p38 (Gollob et al., 1999; Lim and Cao, 1999; Turkson”
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 Chung et al., 1997
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“Once these growth factor or cytokine receptors are occupied by their ligands, tyrosine residues in the cytoplasmic domain of the receptors become phosphorylated by cytokine receptor-associated JAK family tyrosine kinases (19, 32) or by the growth factor-activated receptor tyrosine kinases (16, 26, 34).”
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- Authors
- Chung, J., Uchida, E., Grammer, T. C., & Blenis, J.
- Affiliations
- Harvard University (US)
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 1997-11
- Volume
- 17
- Issue
- 11
- Pages
- 6508-6516
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC232504
- OpenAlex
- W2140786721
- Cited by
- 620
- References
- 1
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 9 · 2023: 6 · 2022: 13 · 2021: 25 · 2020: 23 · 2019: 23 · 2018: 18 · 2017: 26 · 2016: 18 · 2015: 19 · 2014: 35 · 2013: 31 · 2012: 18
- FWCI
- 12.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Institutes of Health (CA46595)
- Japan Science and Technology Agency
- National Cancer Institute (CA46595)
- 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, tyrosine phosphorylation, ERK MAP kinase, STAT1, interleukin-6, growth factor signaling, protein dimerization, nuclear translocation, DNA-binding activity, transcriptional regulation
- MeSH terms
- Animals, DNA-Binding Proteins, Phosphorylation, Protein-Tyrosine Kinases, Serine, Substrate Specificity, Tyrosine, Signal Transduction, Trans-Activators, Interleukin-6, Protein Serine-Threonine Kinases, 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, COS Cells, Mitogen-Activated Protein Kinase Kinases, MAP Kinase Kinase 1, STAT1 Transcription Factor, STAT3 Transcription Factor
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