Reduced phosphorylation of Stat3 at Ser-727 mediated by casein kinase 2 - protein phosphatase 2A enhances Stat3 Tyr-705 induced tumorigenic potential of glioma cells
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Signal transducer and activator of transcription 3 (Stat3) is a transcription factor that is involved in cell survival and proliferation and has been found to be persistently activated in most human cancers mainly through its phosphorylation at Tyr-705. However, the role and regulation of Stat3 Ser-727 phosphorylation in cancer cells have not been clearly evaluated. In our findings, correlation studies on the expression of CK2 and Stat3 Ser-727 phosphorylation levels in human glioma patient samples as well as rat orthotopic tumor model show a degree of negative correlation. Moreover, brain tumor cell lines were treated with various pharmacological inhibitors to inactivate the CK2 pathway. Here, increased Stat3 Ser-727 phosphorylation upon CK2 inhibition was observed. Overexpression of CK2 (α, α' or β subunits) by transient transfection resulted in decreased Stat3 Ser-727 phosphorylation. Stat3 Tyr-705 residue was conversely phosphorylated in similar situations. Interestingly, we found PP2A, a protein phosphatase, to be a mediator in the negative regulation of Stat3 Ser-727 phosphorylation by CK2. In vitro assays prove that Ser-727 phosphorylation of Stat3 affects the transcriptional activity of its downstream targets like SOCS3, bcl-xl and Cyclin D1. Stable cell lines constitutively expressing Stat3 S727A mutant showed increased survival, proliferation and invasion which are characteristics of a cancer cell. Rat tumor models generated with the Stat3 S727A mutant cell line for…
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In some instances, S727 phosphorylation counteracts Y705 function; for example, cdk5-mediated pS727 represses FoxP3 upregulation and limits T regulatory cell development, and reduction in pS727 by CK2-protein phosphatase 2A enhances pY-STAT3-induced tumorigenic potential of glioma cells.
“However, there are instances when pS727 appears to counteract pY705 function. e.g., cdk5-mediated pS727 repressed FoxP3 upregulation, thereby limiting T regulatory cell (Treg) development (Lam et al., 2015), and reduction in pS727 by CK2–protein phosphatase 2A enhanced pY-STAT3–induced tumorigenic potential of glioma cells (Mandal et al., 2014).”
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 Mandal et al., 2014
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CIP2A inhibits PP2A in human malignancies
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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
- Authors
- Mandal, T., Bhowmik, A., Chatterjee, A., Chatterjee, U., Chatterjee, S., & Ghosh, M. K.
- Affiliations
- Indian Institute of Chemical Biology (IN)
- Corresponding author
- Ghosh, Mrinal Kanti
- Venue
- Cellular Signalling
- Publisher
- Elsevier BV
- Published
- 2014-08
- Volume
- 26
- Issue
- 8
- Pages
- 1725-1734
- ISSN
- 0898-6568 (ISSN-L)
- OpenAlex
- W1984413677
- Cited by
- 65
- References
- 3
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 1 · 2023: 3 · 2022: 6 · 2021: 6 · 2020: 3 · 2019: 6 · 2018: 3 · 2017: 9 · 2016: 6 · 2015: 8 · 2014: 5
- FWCI
- 4.50
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cellular Signalling (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- CSIR (EMPOWER-OLP-2, MEDCHEM-BSC0108, miND-BSC0115)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Keywords
- STAT3, casein kinase 2, protein phosphatase 2A, glioma, tumorigenicity, SOCS3, Bcl-xL, cyclin D1, CK2 inhibition, cell proliferation and invasion
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Animals, Brain Neoplasms, Cell Movement, Cell Transformation, Neoplastic, Glioma, Humans, Phosphorylation, Serine, Transplantation, Heterologous, Rats, Sprague-Dawley, Okadaic Acid, Cyclin D1, Cell Line, Tumor, Casein Kinase II, STAT3 Transcription Factor, Suppressor of Cytokine Signaling Proteins, bcl-X Protein, Rats, Protein Phosphatase 2, HEK293 Cells
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