Critical Role for Lysine 685 in Gene Expression Mediated by Transcription Factor Unphosphorylated STAT3
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STAT3 is a pleiotropic transcription factor that is activated by the phosphorylation of tyrosine 705 in response to many cytokines and growth factors. STAT3 without Tyr-705 phosphorylation (U-STAT3) is also a potent transcription factor, and its concentration in cells increases greatly in response to STAT3 activation because the STAT3 gene can be driven by phosphorylated STAT3 dimers. We have now searched for post-translational modifications of U-STAT3 that might have a critical role in its function. An analysis by mass spectroscopy indicated that U-STAT3 is acetylated on Lys-685, and the integrity of Lys-685 is required for the expression of most U-STAT3-dependent genes. In contrast, we found only a very minor role for Lys-685 in gene expression induced in response to tyrosine-phosphorylated STAT3. U-STAT3 plays an important role in angiotensin II-induced gene expression and in the consequent development of cardiac hypertrophy and dysfunction. Mutation of Lys-685 inhibits this function of STAT3, providing new information on the role of U-STAT3 in augmenting the development of heart failure.
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Nonpeptidic tyrosine kinase-targeted inhibitors have diminished efficacy because the inherent transcriptional activity of unphosphorylated STAT3 can drive MET and MRAS by binding NF-κB.
“However, their efficacy is diminished because the inherent transcriptional activity of unphosphorylated STAT3 could also drive the expression of oncogenes such as MET and MRAS by binding to NF-κB (18–21).”
From Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer (2022) · cites this paper as [18]
The Discussion (page unavailable) says that overexpression of unphosphorylated STAT3 drives MET and MRAS expression. Another passage (indexed as Abstract; page unavailable) says unphosphorylated STAT3 can activate some genes by binding NF-κB, but does not identify MET or MRAS as genes activated by that mechanism. The paper does not report diminished efficacy of nonpeptidic tyrosine kinase-targeted inhibitors. (LLM, conf=0.88)
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References 29 · Cited by 64
Research works printed but not linked: 1
- [1]1. Akira, S. ∙ Nishio, Y. ∙ Inoue, M. ... Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway Cell. 1994; 77:63-71
- Authors
- Dasgupta, M., Unal, H., Willard, B., Yang, J., Karnik, S. S., & Stark, G. R.
- Affiliations
- Cleveland Clinic (US)
- Corresponding author
- Stark, George R.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 289
- Issue
- 44
- Pages
- 30763-30771
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4215253
- OpenAlex
- W2078929930
- Cited by
- 64
- References
- 29
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 4 · 2023: 2 · 2022: 5 · 2021: 10 · 2020: 5 · 2019: 4 · 2018: 7 · 2017: 5 · 2016: 9 · 2015: 5
- FWCI
- 3.06
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lanzhou University Institutional Repository (submittedVersion, cc-by-nc)
- Funders
- National Institutes of Health (CA062220, 1S10RR031537-01)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- STAT3, lysine acetylation, post-translational modification, transcriptional regulation, gene expression, angiotensin II, cardiac hypertrophy, heart failure, tyrosine phosphorylation
- MeSH terms
- Acetylation, Angiotensin II, Cell Line, Cardiomegaly, Humans, Lysine, Phosphorylation, Protein Processing, Post-Translational, Transcriptional Activation, Interleukin-6, Mutation, Missense, STAT3 Transcription Factor
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