STAT3 nuclear import is independent of tyrosine phosphorylation and mediated by importin-α3
Open accessAbstract
Signal transducer and activator of transcription (STAT)3 is a member of a family of DNA-binding factors that function to induce expression of responsive genes. STAT3 can act as an oncogene, and its function has been shown to be critical for cellular transformation by a number of oncogenic tyrosine kinases. The role of STAT3 as a DNA-binding transcription factor naturally depends on its ability to gain entrance to the nucleus. In this study, we provide evidence that STAT3 is distinct from previously characterized STAT molecules in that it dynamically shuttles between cytoplasmic and nuclear compartments and maintains prominent nuclear presence. Although tyrosine phosphorylation is required for STAT3 to bind to specific DNA target sites, nuclear import takes place constitutively and independently of tyrosine phosphorylation. We identify a region within the coiled-coil domain of the STAT3 molecule that is necessary for nuclear import and demonstrate that this region is critical for its recognition by specific import carrier importin-alpha3. RNA interference studies were used to verify the role and specificity of importin-alpha3 in STAT3 nuclear translocation. These results distinguish STAT3 cellular localization from other STAT molecules and identify a feature that may be targeted in the clinical intervention of STAT3-dependent neoplasia.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
STAT3 continuously shuttles between cytoplasm and nucleus independent of its activation state.
“STAT3 was shown to continuously shuttle between cytoplasm and nucleus independent of its activation state (Liu et al., 2005; Reich and Liu, 2006).”
From Model Based Targeting of IL-6-Induced Inflammatory Responses in Cultured Primary Hepatocytes to Improve Application of the JAK Inhibitor Ruxolitinib (2017) · cites this paper as Liu et al., 2005
In unstimulated cells, mKate2-STAT3 is equally distributed between cytoplasm and nucleus (nuc/cyt ratio 1).
“In unstimulated cells, mKate2-STAT3 was equally distributed between cytoplasm and nucleus (STAT3 nuc/cyt ratio of 1), in accordance with the previously reported continuous shuttling of STAT3 independent of its activation state (Liu et al., 2005; Reich and Liu, 2006).”
From Model Based Targeting of IL-6-Induced Inflammatory Responses in Cultured Primary Hepatocytes to Improve Application of the JAK Inhibitor Ruxolitinib (2017) · cites this paper as Liu et al., 2005
Phosphorylation of STAT3 Tyr705 by JAKs is critical for STAT3 dimerization and subsequent cytokine-stimulated nuclear translocation.
“the phosphorylation of STAT3 Tyr705 by JAKs (Janus kinases) is critical for STAT3 dimerization and subsequent cytokine-stimulated nuclear translocation”
From Selective STAT3-α or -β expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes (2012) · cites this paper as [6]
Activation of STAT3 requires phosphorylation of Tyr705 and Ser727.
“This activation of STAT3 requires the phosphorylation of Tyr705 and Ser727.”
From Selective STAT3-α or -β expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes (2012) · cites this paper as [6]
Phosphorylation of STAT3 Ser727 by serine/threonine kinases such as MAPKs enhances STAT3 transcriptional activity.
“whereas the phosphorylation of Ser727 by serine/threonine kinases such as the MAPKs (mitogen-activated protein kinases) enhances STAT3 transcriptional activity [5,6].”
From Selective STAT3-α or -β expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes (2012) · cites this paper as [6]
There has been increasing evidence of basal nucleocytoplasmic shuttling of STAT3.
“As there has been increasing evidence of basal nucleocytoplasmic shuttling of STAT3 [6,41–43]”
From Selective STAT3-α or -β expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes (2012) · cites this paper as [6]
Cites
Bowman, T., Garcia, R., Turkson, J., & Jove, R. (2000) · Oncogene · doi:10.1038/sj.onc.1203527 · Cited by 1,743 · see citing works
The role of STATs in transcriptional control and their impact on cellular function
Bromberg, J., & Darnell, J. E. (2000) · Oncogene · doi:10.1038/sj.onc.1203476 · Cited by 1,201 · see citing works
Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis
Bowman, T., Broome, M. A., Sinibaldi, D., Wharton, W., Pledger, W. J., Sedivy, J. M., Irby, R., Yeatman, T., Courtneidge, S. A., & Jove, R. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.131568898 · Cited by 488 · see citing works
Novel roles of unphosphorylated STAT3 in oncogenesis and transcriptional regulation
Yang, J., Chatterjee-Kishore, M., Staugaitis, S. M., Nguyen, H., Schlessinger, K., Levy, D. E., & Stark, G. R. (2005) · Cancer Research · doi:10.1158/0008-5472.939.65.3 · Cited by 405 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo
Bai, L., Zhou, H., Xu, R., Zhao, Y., Chinnaswamy, K., McEachern, D., Chen, J., Yang, C.-Y., Liu, Z., Wang, M., et al. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.10.002 · Cited by 652 · see citing works
Self-citationThe role of STAT3 in autophagy
You, L., Wang, Z., Li, H., Shou, J., Jing, Z., Xie, J., Sui, X., Pan, H., & Han, W. (2015) · Autophagy · doi:10.1080/15548627.2015.1017192 · Cited by 515 · see citing works
The potential and controversy of targeting STAT family members in cancer
Verhoeven, Y., Tilborghs, S., Jacobs, J., De Waele, J., Quatannens, D., Deben, C., Prenen, H., Pauwels, P., Trinh, X. B., Wouters, A., et al. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.10.002 · Cited by 409 · see citing works
Roles of unphosphorylated STATs in signaling
Yang, J., & Stark, G. R. (2008) · Cell Research · doi:10.1038/cr.2008.41 · Cited by 347 · see citing works
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
“, ;40% of total cellular STAT3 (Meyer et al., 2002; Liu et al., 2005), lends further credence to the noncanonical transcriptional role for U-STAT3 in the nucleus.”
BackgroundInfluentialRegulation of MDMX nuclear import and degradation by Chk2 and 14-3-3
LeBron, C., Chen, L., Gilkes, D. M., & Chen, J. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601032 · Cited by 122 · see citing works
STAT3-YAP/TAZ signaling in endothelial cells promotes tumor angiogenesis
Shen, Y., Wang, X., Liu, Y., Singhal, M., Gürkaşlar, C., Valls, A. F., Lei, Y., Hu, W., Schermann, G., Adler, H., et al. (2021) · Science Signaling · doi:10.1126/scisignal.abj8393 · Cited by 121 · see citing works
PTEN functions as a melanoma tumor suppressor by promoting host immune response
Dong, Y., Richards, J.-A., Gupta, R., Aung, P. P., Emley, A., Kluger, Y., Dogra, S. K., Mahalingam, M., & Wajapeyee, N. (2014) · Oncogene · doi:10.1038/onc.2013.409 · Cited by 113 · 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
Ng, I. H. W., Ng, D. C. H., Jans, D. A., & Bogoyevitch, M. A. (2012) · Biochemical Journal · doi:10.1042/bj20120941 · Cited by 63 · see citing works
Martincuks, A., Andryka, K., Küster, A., Schmitz-Van de Leur, H., Komorowski, M., & Müller-Newen, G. (2017) · Cellular Signalling · doi:10.1016/j.cellsig.2017.01.006 · Cited by 45 · see citing works
Sobotta, S., Raue, A., Huang, X., Vanlier, J., Jünger, A., Bohl, S., Albrecht, U., Hahnel, M. J., Wolf, S., Mueller, N. S., et al. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00775 · Cited by 28 · see citing works
“In unstimulated cells, mKate2-STAT3 was equally distributed between cytoplasm and nucleus (STAT3 nuc/cyt ratio of 1), in accordance with the previously reported continuous shuttling of STAT3 independent of its activation state (Liu et al., 2005; Reich and Liu, 2006).”
Background
- Authors
- Liu, L., McBride, K. M., & Reich, N. C.
- Affiliations
- Stony Brook University (US)
- Corresponding author
- McBride, Kevin M.
- Reich, Nancy C.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2005-05-26
- Volume
- 102
- Issue
- 23
- Pages
- 8150-8155
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1149424
- OpenAlex
- W2017716833
- Cited by
- 348
- References
- 4
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 14 · 2023: 11 · 2022: 15 · 2021: 21 · 2020: 15 · 2019: 20 · 2018: 18 · 2017: 24 · 2016: 13 · 2015: 18 · 2014: 20 · 2013: 26 · 2012: 20
- FWCI
- 7.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA050773, R01CA50773)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- STAT3, nuclear import, importin alpha3, tyrosine phosphorylation, nuclear translocation, coiled-coil domain, nucleocytoplasmic shuttling, oncogenes
- MeSH terms
- Animals, Cell Line, Cell Nucleus, Cytoplasm, DNA-Binding Proteins, Humans, Models, Molecular, Phosphorylation, Protein Binding, Protein Conformation, Tyrosine, Trans-Activators, Sequence Deletion, Active Transport, Cell Nucleus, Karyopherins, RNA, Small Interfering, STAT3 Transcription Factor, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
