Cyclin-dependent kinase 5 represses Foxp3 gene expression and Treg development through specific phosphorylation of Stat3 at Serine 727
Open accessAbstract
Cyclin-dependent kinase 5 (Cdk5) is known as a unique member of the cyclin-dependent family of serine/threonine kinases. Previously, we demonstrated Cdk5 to be an important regulator of T cell function and that disruption of Cdk5 expression ameliorates T cell mediated neuroinflammation. Here, we show a novel role of Cdk5 in the regulation of Foxp3 expression in murine CD4(+) T cells. Our data indicate that disruption of Cdk5 activity in T cells abrogates the IL-6 suppression of Foxp3 expression. This effect is achieved through Cdk5 phosphorylation of the signal transducer and activator of transcription 3 (Stat3) specifically at Serine 727 in T cells, and we show this post-translational modification is required for proper Stat3 DNA binding to the Foxp3 gene on the enhancer II region. Taken together, our data point to an essential role for Cdk5 in the differentiation of T cells as it regulates Foxp3 gene expression through phosphorylation of Stat3.
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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 Lam et al., 2015
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References 27 · Cited by 32
Research works printed but not linked: 25
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- Authors
- Lam, E., Choi, S. H., Pareek, T. K., Kim, B.-G., & Letterio, J. J.
- Affiliations
- Rainbow Babies & Children's Hospital (US)
- Corresponding author
- Letterio, John J.
- Venue
- Molecular Immunology
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 67
- Issue
- 2
- Pages
- 317-324
- ISSN
- 0161-5890 (ISSN-L)
- PMC
- PMC4734131
- OpenAlex
- W1039448529
- Cited by
- 32
- References
- 27
- Citations by year
- 2025: 4 · 2023: 6 · 2021: 2 · 2020: 5 · 2019: 4 · 2018: 5 · 2017: 2 · 2016: 4
- FWCI
- 1.81
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (R01HL111682-02, R01 EY022937-01)
- The Hyundai Hope on Wheels Foundation
- St. Baldrick's Foundation for Pediatric Cancer Research
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- cyclin-dependent kinase 5, Foxp3, regulatory T cells, STAT3 phosphorylation, CD4+ T cells, interleukin-6, transcriptional regulation, T cell differentiation, post-translational modification
- MeSH terms
- Animals, Enhancer Elements, Genetic, Gene Expression Regulation, Mice, Inbred C57BL, Phosphorylation, Phosphoserine, Protein Binding, Repressor Proteins, Interleukin-6, Transforming Growth Factor beta, T-Lymphocytes, Regulatory, STAT3 Transcription Factor, Cyclin-Dependent Kinase 5, Smad Proteins, Forkhead Transcription Factors
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