A Novel Sequence in the Coiled-coil Domain of Stat3 Essential for Its Nuclear Translocation
Open accessAbstract
Stat3 is activated by cytokines and growth factors via specific tyrosine phosphorylation, dimerization, and nuclear translocation. However, the mechanism involved in its nuclear translocation is unclear. In this study, by systematic deletion and site-directed mutagenesis we identified Arg-214/215 in the alpha-helix 2 region of the coiled-coil domain of Stat3 as a novel sequence element essential for its nuclear translocation, stimulated by epidermal growth factor as well as by interleukin-6. Furthermore, we identified Arg-414/417 in the DNA binding domain as also required for the nuclear localization of Stat3. This sequence element corresponds to Lys-410/413 of Stat1, a reported sequence for Stat1 nuclear translocation. On the other hand, Leu-411 of Stat3, corresponding to Leu-407 of Stat1, a necessary residue for Stat1 nuclear transport, is not essential for Stat3 nuclear import. The mutant of Arg-214/215 or Arg-414/417 was shown to be tyrosyl-phosphorylated normally but failed to enter the nucleus in response to epidermal growth factor or interleukin-6. The defect, however, can be rescued by the wild-type Stat3 but cannot be compensated by these two mutants. Mutations on Arg-414/417, but not Arg-214/215, destroy the DNA binding activity of Stat3. Our data for the first time identified a sequence element located in the coiled-coil domain that is involved in the ligand-induced nuclear translocation of Stat3. This novel sequence together with a conserved sequence element in th…
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CCD has a large hydrophilic surface predominantly involved in recruitment of STAT3 to its receptor, essential for activation via SH2 domain-mediated receptor binding, phosphorylation, and nuclear translocation.
“CCD has a large hydrophilic surface predominantly involved in the recruitment of STAT3 to its receptor [50], which is essential not only for its activation via SH2 domain‐mediated receptor binding but also for its activation via phosphorylation [51] and nuclear translocation [52].”
From Saikosaponin b1 Attenuates Liver Fibrosis by Blocking STAT3/Gli1 Interaction and Inducing Gli1 Degradation (2025) · cites this paper as [52]
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Activation and Association of Stat3 with Src in v-Src-Transformed Cell Lines
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Dong, J., Cheng, X.-D., Zhang, W.-D., & Qin, J.-J. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00629 · Cited by 232 · see citing works
Mahdavi, A., Davey, R. E., Bhola, P., Yin, T., & Zandstra, P. W. (2007) · PLoS Computational Biology · doi:10.1371/journal.pcbi.0030130 · Cited by 65 · see citing works
Shao, M., Zhang, X., Sun, J., Dong, H., Han, X., Yang, Q., Chen, R., Shen, L., Xu, L., Wang, L., et al. (2025) · Exploration · doi:10.1002/exp.70000 · Cited by 26 · see citing works
- Authors
- Ma, J., Zhang, T., Novotny-Diermayr, V., Tan, A. L. C., & Cao, X.
- Affiliations
- Institute of Molecular and Cell Biology (SG)
- Corresponding author
- Cao, Xinmin
- ORCID
- Ma, Jing
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-08
- Volume
- 278
- Issue
- 31
- Pages
- 29252-29260
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2090160194
- Cited by
- 110
- References
- 1
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 3 · 2023: 2 · 2022: 3 · 2021: 4 · 2020: 4 · 2019: 4 · 2018: 5 · 2017: 3 · 2016: 6 · 2015: 6 · 2014: 9 · 2013: 6 · 2012: 7
- FWCI
- 3.14
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- STAT3, nuclear translocation, coiled-coil domain, DNA-binding domain, epidermal growth factor, interleukin-6, tyrosine phosphorylation, STAT1
- MeSH terms
- Amino Acid Sequence, Animals, Arginine, Binding Sites, Biological Transport, Cell Fractionation, Cell Nucleus, DNA, DNA-Binding Proteins, Epidermal Growth Factor, Fluorescent Antibody Technique, Carcinoma, Hepatocellular, Humans, Immunosorbent Techniques, Leucine, Liver Neoplasms, Models, Molecular, Phosphorylation, Structure-Activity Relationship, Transfection, Tumor Cells, Cultured, Tyrosine, Molecular Structure, Signal Transduction, Trans-Activators, Gene Expression, Polymerase Chain Reaction, Mutagenesis, Site-Directed, Conserved Sequence, Gene Deletion, Protein Structure, Secondary, COS Cells, STAT3 Transcription Factor, Mice
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