Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFκB
Open accessAbstract
gp130-linked cytokines such as interleukin-6 (IL-6) stimulate the formation of tyrosine-phosphorylated signal transducer and activator of transcription 3 (P-STAT3), which activates many genes, including the STAT3 gene itself. The resulting increase in the concentration of unphosphorylated STAT3 (U-STAT3) drives a second wave of expression of genes such as RANTES , IL6 , IL8 , MET , and MRAS that do not respond directly to P-STAT3. Thus, U-STAT3 sustains cytokine-dependent signaling at late times through a mechanism completely distinct from that used by P-STAT3. Many U-STAT3-responsive genes have κB elements that are activated by a novel transcription factor complex formed when U-STAT3 binds to unphosphorylated NFκB (U-NFκB), in competition with IκB. The U-STAT3/U-NFκB complex accumulates in the nucleus with help from the nuclear localization signal of STAT3, activating a subset of κB-dependent genes. Additional genes respond to U-STAT3 through an NFκB-independent mechanism. The role of signal-dependent increases in U-STAT3 expression in regulating gene expression is likely to be important in physiological responses to gp130-linked cytokines and growth factors that activate STAT3, and in cancers that have constitutively active P-STAT3.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
The suggested mechanisms for the STAT3-NF-κB crosstalk are often contradictory and a consensus has not been reached.
“Thus, the suggested mechanisms for the STAT3-NF-κB crosstalk are often contradictory and a consensus has not been reached.”
From Synergistic gene expression during the acute phase response is characterized by transcription factor assisted loading (2017) · cites this paper as [18]
The paper’s Abstract and Discussion describe several STAT3–NF-κB interactions with different effects, including enhanced transcription of some genes and inhibition of another. That supports the idea that proposed mechanisms vary, but the paper does not say they are often contradictory or that no consensus has been reached. Page numbers are unavailable in our copy. (LLM, conf=0.83)
Experimental — accuracy not yet measuredBasal STAT3 has been shown to have transcriptional activity under basal conditions.
“and that basal STAT3 has been shown to have transcriptional activity under basal conditions [44,45]”
From Selective STAT3-α or -β expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes (2012) · cites this paper as [45]
The section “RANTES expression is induced cooperatively by p65 and U-STAT3” reports transcriptional activity from unphosphorylated STAT3, including increased RANTES promoter activity. However, the experiments used overexpression of STAT3; they do not establish that STAT3 at basal levels has this activity under basal conditions. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredNonpeptidic 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 [20]
The Discussion (page unavailable) says that increased unphosphorylated STAT3 activates NF-κB and drives expression of MET and MRAS. But the gene-expression results (page unavailable) report that eliminating the NF-κB subunit p65 did not affect MRAS expression, so NF-κB binding is not established as its mechanism. The paper also does not show that this activity diminishes the efficacy of tyrosine kinase-targeted inhibitors. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe crosstalk between STAT3 and NF-κB is an active field of research with studies showing contradictory outcomes of concomitant activation of the two TFs.
“The crosstalk between STAT3 and NF-κB is an active field of research with studies showing contradictory outcomes of concomitant activation of the two TFs.”
From Synergistic gene expression during the acute phase response is characterized by transcription factor assisted loading (2017) · cites this paper as [18]
Some studies suggest cooperation between STAT3 and NF-κB, while others show antagonism.
“Some suggest cooperation between them, while others show antagonism2, 16–21.”
From Synergistic gene expression during the acute phase response is characterized by transcription factor assisted loading (2017) · cites this paper as [18]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Tebbutt, N. C., Giraud, A. S., Inglese, M., Jenkins, B., Waring, P., Clay, F. J., Malki, S., Alderman, B. M., Grail, D., Hollande, F., et al. (2002) · Nature Medicine · doi:10.1038/nm763 · Cited by 474 · 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
Self-citationYU, Z., ZHANG, W., & KONE, B. C. (2002) · Biochemical Journal · doi:10.1042/bj20020588 · Cited by 255 · see citing works
Flagged first, then by citations
Research works printed but not linked: 7
- Kaptein, A., Paillard, V., and Saunders, M. 1996. Dominant negative stat3 mutant inhibits interleukin-6-induced Jak- STAT signal transduction. J. Biol. Chem. 271: 5961-5964.
- Li, Z., Van Calcar, S., Qu, C., Cavenee, W.K., Zhang, M.Q., and Ren, B. 2003. A global transcriptional regulatory role for c- Myc in Burkitt's lymphoma cells. Proc. Natl. Acad. Sci. 100: 8164-8169.
- Liu, L., McBride, K.M., and Reich, N.C. 2005. STAT3 nuclear im- port is independent of tyrosine phosphorylation and mediated by importin-␣3. Proc. Natl. Acad. Sci. 102: 8150-8155.
- Proudfoot, A.E. 2006. The biological relevance of chemokine-pro- teoglycan interactions. Biochem. Soc. Trans. 34: 422-426.
- Schaefer, T.S., Sanders, L.K., and Nathans, D. 1995. Cooperative transcriptional activity of Jun and Stat3 , a short form of Stat3. Proc. Natl. Acad. Sci. 92: 9097-9101.
- Seidel, H.M., Milocco, L.H., Lamb, P., Darnell Jr., J.E., Stein, R.B., and Rosen, J. 1995. Spacing of palindromic half sites as a determinant of selective STAT signal transducers and ac- tivators of transcription DNA binding and transcriptional activity. Proc. Natl. Acad. Sci. 92: 3041-3045.
- Takeda, K., Noguchi, K., Shi, W., Tanaka, T., Matsumoto, M., Yoshida, N., Kishimoto, T., and Akira, S. 1997. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc. Natl. Acad. Sci. 94: 3801-3804.
Cited by
Sorted by citations
STATs in cancer inflammation and immunity: a leading role for STAT3
Yu, H., Pardoll, D., & Jove, R. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2734 · Cited by 4,383 · see citing works
Mechanisms and consequences of Jak–STAT signaling in the immune system
Villarino, A. V., Kanno, Y., & O'Shea, J. J. (2017) · Nature Immunology · doi:10.1038/ni.3691 · Cited by 1,221 · see citing works
Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer
Jones, S. A., & Jenkins, B. J. (2018) · Nature Reviews Immunology · doi:10.1038/s41577-018-0066-7 · Cited by 1,102 · see citing works
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
Constitutive activation of <scp>STAT</scp>3 in breast cancer cells: A review
Banerjee, K., & Resat, H. (2016) · International Journal of Cancer · doi:10.1002/ijc.29923 · Cited by 611 · see citing works
Pleiotropy and specificity: insights from the interleukin 6 family of cytokines
Murakami, M., Kamimura, D., & Hirano, T. (2019) · Immunity · doi:10.1016/j.immuni.2019.03.027 · Cited by 533 · 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
Self-citationBharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
Beck, I. M. E., Vanden Berghe, W., Vermeulen, L., Yamamoto, K. R., Haegeman, G., & De Bosscher, K. (2009) · Endocrine Reviews · doi:10.1210/er.2009-0013 · Cited by 298 · see citing works
Karachaliou, N., Gonzalez-Cao, M., Crespo, G., Drozdowskyj, A., Aldeguer, E., Gimenez-Capitan, A., Teixido, C., Molina-Vila, M. A., Viteri, S., De Los Llanos Gil, M., et al. (2018) · Therapeutic Advances in Medical Oncology · doi:10.1177/1758834017749748 · Cited by 285 · see citing works
IL-6 <i>Trans</i>-Signaling Modulates TLR4-Dependent Inflammatory Responses via STAT3
Greenhill, C. J., Rose-John, S., Lissilaa, R., Ferlin, W., Ernst, M., Hertzog, P. J., Mansell, A., & Jenkins, B. J. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1002971 · Cited by 264 · see citing works
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
Functional characterization of the <i>Aspergillus fumigatus</i> CRZ1 homologue, CrzA
Soriani, F. M., Malavazi, I., Da Silva Ferreira, M. E., Savoldi, M., Von Zeska Kress, M. R., De Souza Goldman, M. H., Loss, O., Bignell, E., & Goldman, G. H. (2008) · Molecular Microbiology · doi:10.1111/j.1365-2958.2008.06122.x · Cited by 168 · see citing works
Dugan, L. L., Ali, S. S., Shekhtman, G., Roberts, A. J., Lucero, J., Quick, K. L., & Behrens, M. M. (2009) · PLoS ONE · doi:10.1371/journal.pone.0005518 · Cited by 165 · see citing works
Kothari, P., Pestana, R., Mesraoua, R., Elchaki, R., Khan, K. M. F., Dannenberg, A. J., & Falcone, D. J. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1301906 · Cited by 137 · see citing works
Janus kinase deregulation in leukemia and lymphoma
Chen, E., Staudt, L. M., & Green, A. R. (2012) · Immunity · doi:10.1016/j.immuni.2012.03.017 · Cited by 123 · see citing works
Goldstein, I., Paakinaho, V., Baek, S., Sung, M.-H., & Hager, G. L. (2017) · Nature Communications · doi:10.1038/s41467-017-02055-5 · Cited by 97 · see citing works
Courapied, S., Sellier, H., de Carné Trécesson, S., Vigneron, A., Bernard, A.-C., Gamelin, E., Barré, B., & Coqueret, O. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.092304 · Cited by 76 · see citing works
Cronin, J. G., Kanamarlapudi, V., Thornton, C. A., & Sheldon, I. M. (2016) · Mucosal Immunology · doi:10.1038/mi.2015.131 · Cited by 73 · see citing works
STAT3 in hepatocellular carcinoma: new perspectives
Svinka, J., Mikulits, W., & Eferl, R. (2014) · Hepatic Oncology · doi:10.2217/hep.13.7 · Cited by 63 · see citing works
Papaioannou, I., Xu, S., Denton, C. P., Abraham, D. J., & Ponticos, M. (2018) · Molecular Biology of the Cell · doi:10.1091/mbc.e17-06-0342 · Cited by 64 · see citing works
Carroll, J. A., Striebel, J. F., Race, B., Phillips, K., & Chesebro, B. (2015) · Journal of Virology · doi:10.1128/jvi.02952-14 · Cited by 63 · 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
Jin, J., Wu, Y., Zhao, Z., Wu, Y., Zhou, Y.-D., Liu, S., Sun, Q., Yang, G., Lin, J., Nagle, D. G., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.160606 · Cited by 57 · 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
Hutchins, A. P., Diez, D., & Miranda-Saavedra, D. (2013) · JAK-STAT · doi:10.4161/jkst.25097 · Cited by 31 · see citing works
Chen, T., Moore, T. M., Ebbert, M. T. W., McVey, N. L., Madsen, S. R., Hallowell, D. M., Harris, A. M., Char, R. E., Mackay, R. P., Hancock, C. R., et al. (2016) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00727.2015 · Cited by 14 · see citing works
- Authors
- Yang, J., Liao, X., Agarwal, M. K., Barnes, L., Auron, P. E., & Stark, G. R.
- Affiliations
- Cleveland Clinic (US)
- University of Pittsburgh (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2007-05-17
- Volume
- 21
- Issue
- 11
- Pages
- 1396-1408
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC1877751
- OpenAlex
- W2103422355
- Cited by
- 611
- References
- 3
- Citations by year
- 2026: 14 · 2025: 17 · 2024: 27 · 2023: 31 · 2022: 33 · 2021: 27 · 2020: 41 · 2019: 45 · 2018: 29 · 2017: 38 · 2016: 38 · 2015: 30 · 2014: 47 · 2013: 37 · 2012: 36
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cleveland Clinic
- Stony Brook University
- National Institutes of Health (STAT3)
- U.S. Public Health Service (R01 A144122)
- National Cancer Institute (P01-CA 62220, P01CA062220)
- National Institute of Allergy and Infectious Diseases
- 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 › Genomics and Chromatin Dynamics
- Keywords
- STAT3, interleukin-6, NF-κB, transcriptional activation, IκB, nuclear localization signal, cytokine signaling, gene expression regulation
- MeSH terms
- Binding Sites, Breast, Cell Nucleus, Cells, Cultured, Epithelial Cells, Gene Expression Regulation, Humans, Phosphorylation, Promoter Regions, Genetic, Transcription, Genetic, Signal Transduction, Biomarkers, Interleukin-6, NF-kappa B, Chemokine CCL5, Nuclear Localization Signals, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Chromatin Immunoprecipitation, Immunoprecipitation, Regulatory Elements, Transcriptional, STAT3 Transcription Factor
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
