Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-β signaling
Abstract
The latent transcription factor Stat3 is activated by gp130, the common receptor for the interleukin (IL)-6 cytokine family and other growth factor and cytokine receptors. Ligand-induced dimerization of gp130 leads to activation of the Stat1, Stat3 and Shp2-Ras-Erk signaling pathways. Here we assess genetically the contribution of exaggerated Stat3 activation to the phenotype of gp130 (Y757F/Y757F) mice, in which a knock-in mutation disrupts the negative feedback mechanism on gp130-dependent Stat signaling. Compared to gp130 (Y757F/Y757F) mice, reduced Stat3 activation in gp130 (Y757F/Y757F) Stat3(+/-) mice increased their lifespan, prevented splenomegaly, normalized exaggerated hepatic acute-phase response and lymphocyte trafficking, and suppressed the growth of spontaneously arising gastric adenomas in young mice. These lesions share histological features of gastric polyps in aging mice with monoallelic null mutations in Smad4, which encodes the common transducer for transforming growth factor (TGF)-beta signaling. Indeed, hyperactivation of Stat3 desensitizes gp130 (Y757F/Y757F) cells to the cytostatic effect of TGF-beta through transcriptional induction of inhibitory Smad7, thereby providing a novel link for cross-talk between Stat and Smad signaling in gastric homeostasis.
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gp130Y757F/Y757F mice show hyper-activation of STAT3 and develop gastric hyperplasia resembling human early-stage gastric cancer.
“Another knock-in mouse strain (gp130Y757F/Y757F mice) having the point mutation Y759F in murine gp130 also shows the hyper-activation of STAT3 and develops gastric hyperplasia resembling human early-stage gastric cancer (64, 256).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [64]
Cites
Principles of interleukin (IL)-6-type cytokine signalling and its regulation
HEINRICH, P. C., BEHRMANN, I., HAAN, S., HERMANNS, H. M., MÜLLER-NEWEN, G., & SCHAPER, F. (2003) · Biochemical Journal · doi:10.1042/bj20030407 · Cited by 3,272 · cited 1× · see citing works
“This strain carries a phenylalanine knock-in substitution of the cytoplasmic Tyr757 residue which, when phosphorylated, provides the competitive docking site for the negative regulator suppressor of cytokine signaling (Socs)-3 and the tyrosine phosphatase Shp2, which mediates Ras-Erk signalin”
BackgroundTranscription factors as targets for cancer therapy
Darnell, J. E. (2002) · Nature Reviews Cancer · doi:10.1038/nrc906 · Cited by 1,194 · see citing works
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
Self-citationTargeted inhibition of Stat3 with a decoy oligonucleotide abrogates head and neck cancer cell growth
Leong, P. L., Andrews, G. A., Johnson, D. E., Dyer, K. F., Xi, S., Mai, J. C., Robbins, P. D., Gadiparthi, S., Burke, N. A., Watkins, S. F., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0534764100 · Cited by 340 · see citing works
Jenkins, B. J., Grail, D., Inglese, M., Quilici, C., Bozinovski, S., Wong, P., & Ernst, M. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.4.1453-1463.2004 · Cited by 43 · cited 1× · see citing works
“We cleared protein lysates, prepared from MEFs or snap-frozen stomachs in ice-cold lysis buffe”
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Cited by
Sorted by citations
A cytokine-mediated link between innate immunity, inflammation, and cancer
Lin, W.-W., & Karin, M. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31537 · Cited by 1,940 · see citing works
IL-6 in inflammation, autoimmunity and cancer
Hirano, T. (2021) · International Immunology · doi:10.1093/intimm/dxaa078 · Cited by 1,453 · see citing works
“AQ13 IL-6 in disease 129 with Y759F mutation (F759 mice) (113) or mice expressing murine gp130 with Y757F mutation (64) display spleno-megaly, lymphadenopathy, an enhanced acute-phase reaction and prolonged STAT3 activation.”
BackgroundMechanisms 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
Self-citationSOCS3, a Major Regulator of Infection and Inflammation
Carow, B., & Rottenberg, M. E. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00058 · Cited by 555 · see citing works
STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation
Verga Falzacappa, M. V., Vujic Spasic, M., Kessler, R., Stolte, J., Hentze, M. W., & Muckenthaler, M. U. (2007) · Blood · doi:10.1182/blood-2006-07-033969 · Cited by 567 · 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
Regulation of TGF-β Family Signaling by Inhibitory Smads
Miyazawa, K., & Miyazono, K. (2017) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a022095 · Cited by 439 · see citing works
Salcedo, R., Worschech, A., Cardone, M., Jones, Y., Gyulai, Z., Dai, R.-M., Wang, E., Ma, W., Haines, D., O'hUigin, C., et al. (2010) · Journal of Experimental Medicine · doi:10.1084/jem.20100199 · Cited by 429 · see citing works
<i>STAT3</i> Plays a Critical Role in <i>KRAS</i> -Induced Pancreatic Tumorigenesis
Corcoran, R. B., Contino, G., Deshpande, V., Tzatsos, A., Conrad, C., Benes, C. H., Levy, D. E., Settleman, J., Engelman, J. A., & Bardeesy, N. (2011) · Cancer Research · doi:10.1158/0008-5472.can-11-0908 · Cited by 413 · see citing works
Signal transduction of inflammatory cytokines and tumor development
Yoshimura, A. (2006) · Cancer Science · doi:10.1111/j.1349-7006.2006.00197.x · Cited by 314 · 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
Self-citationPedroza, M., Le, T. T., Lewis, K., Karmouty‐Quintana, H., To, S., George, A. T., Blackburn, M. R., Tweardy, D. J., & Agarwal, S. K. (2016) · The FASEB Journal · doi:10.1096/fj.15-273953 · Cited by 193 · see citing works
Interleukin-6 signalling: More than Jaks and STATs
Eulenfeld, R., Dittrich, A., Khouri, C., Müller, P. J., Mütze, B., Wolf, A., & Schaper, F. (2012) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2011.09.010 · Cited by 171 · see citing works
New insights into IL-6 family cytokines in metabolism, hepatology and gastroenterology
Giraldez, M. D., Carneros, D., Garbers, C., Rose-John, S., & Bustos, M. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00473-x · Cited by 156 · see citing works
STAT1 plays a role in TLR signal transduction and inflammatory responses
Luu, K., Greenhill, C. J., Majoros, A., Decker, T., Jenkins, B. J., & Mansell, A. (2014) · Immunology & Cell Biology · doi:10.1038/icb.2014.51 · Cited by 151 · see citing works
Self-citationPechkovsky, D. V., Prêle, C. M., Wong, J., Hogaboam, C. M., McAnulty, R. J., Laurent, G. J., Zhang, S. S.-M., Selman, M., Mutsaers, S. E., & Knight, D. A. (2012) · The American Journal of Pathology · doi:10.1016/j.ajpath.2011.12.022 · Cited by 127 · see citing works
SOCS3 and its role in associated diseases
Yin, Y., Liu, W., & Dai, Y. (2015) · Human Immunology · doi:10.1016/j.humimm.2015.09.037 · Cited by 113 · see citing works
Suppressors of cytokine signaling: Potential immune checkpoint molecules for cancer immunotherapy
Chikuma, S., Kanamori, M., Mise‐Omata, S., & Yoshimura, A. (2017) · Cancer Science · doi:10.1111/cas.13194 · Cited by 112 · see citing works
The tale of transforming growth factor‐beta (TGFβ) signaling: A soigné enigma
Chaudhury, A., & Howe, P. H. (2009) · IUBMB Life · doi:10.1002/iub.239 · Cited by 105 · see citing works
Yu, L., Wu, D., Gao, H., Balic, J. J., Tsykin, A., Han, T.-S., Liu, Y. D., Kennedy, C. L., Li, J. K., Mao, J. Q., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-2485 · Cited by 50 · see citing works
“Gastric tumorigenesis in gp130F/Fmice is driven by hyperactivation of the oncogenic latent transcription factor STAT3 via the IL6 cytokine family member, IL11 (15).”
BackgroundInfluentialSelf-citation
- Authors
- Jenkins, B. J., Grail, D., Nheu, T., Najdovska, M., Wang, B., Waring, P., Inglese, M., McLoughlin, R. M., Jones, S. A., Topley, N., Baumann, H., Judd, L. M., Giraud, A. S., Boussioutas, A., Zhu, H.-J., & Ernst, M.
- Affiliations
- Ludwig Cancer Research (AU)
- Peter MacCallum Cancer Centre (AU)
- Cardiff University (GB)
- Roswell Park Comprehensive Cancer Center (US)
- The University of Melbourne (AU)
- Corresponding author
- Zhu, Hong-Jian
- Ernst, Matthias
- ORCID
- Venue
- Nature Medicine
- Published
- 2005-07-24
- Volume
- 11
- Issue
- 8
- Pages
- 845-852
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2115970547
- Cited by
- 308
- References
- 5
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 8 · 2023: 17 · 2022: 14 · 2021: 21 · 2020: 10 · 2019: 12 · 2018: 15 · 2017: 18 · 2016: 14 · 2015: 13 · 2014: 22 · 2013: 18 · 2012: 19
- FWCI
- 8.12
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- STAT3, gp130, IL-6 receptor, gastric adenoma, TGF-beta signaling, Smad7, SMAD4, negative feedback regulation, gastric polyps, aging, lifespan, splenomegaly, acute phase response, lymphocyte migration
- MeSH terms
- Adenoma, Animals, Histological Techniques, Mice, Mutant Strains, Stomach Neoplasms, Immunoblotting, Signal Transduction, Transcriptional Activation, Transforming Growth Factor beta, Reverse Transcriptase Polymerase Chain Reaction, STAT3 Transcription Factor, Cytokine Receptor gp130, Mice, Smad7 Protein
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