Defective gp130-mediated signal transducer and activator of transcription (STAT) signaling results in degenerative joint disease, gastrointestinal ulceration, and failure of uterine implantation
Open accessAbstract
The receptor subunit gp130 transduces multiple cell type–specific activities of the leukemia inhibitory factor (LIF)/interleukin (IL)-6 family of cytokines through the signal transducer and activator of transcription (STAT) and src homology 2 domain–bearing protein tyrosine phosphatase (SHP)-2/ras/Erk pathways. To define STAT-dependent physiological responses, we generated mice with a COOH-terminal gp130ΔSTAT “knock-in” mutation which deleted all STAT-binding sites. gp130ΔSTAT mice phenocopyed mice deficient for IL-6 (impaired humoral and mucosal immune and hepatic acute phase responses) and LIF (failure of blastocyst implantation). However, unlike mice with null mutations in any of the components in the gp130 signaling pathway, gp130ΔSTAT mice also displayed gastrointestinal ulceration and a severe joint disease with features of chronic synovitis, cartilaginous metaplasia, and degradation of the articular cartilage. Mitogenic hyperresponsiveness of synovial cells to the LIF/IL-6 family of cyto-kines was caused by sustained gp130-mediated SHP-2/ras/Erk activation due to impaired STAT-mediated induction of suppressor of cytokine signaling (SOCS) proteins which normally limits gp130 signaling. Therefore, the joint pathology in gp130ΔSTAT mice is likely to arise from the disturbance of the otherwise balanced activation of the SHP-2/ras/Erk and STAT signaling cascades emanating from gp130.
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Defective STAT3 activation enhances SHP-2-ERK-MAPK activation pathways, most likely through an impaired STAT3-mediated induction of SOCS3.
“Similarly, defective STAT3 activation enhances SHP-2–ERK–MAPK activation pathways, most likely through an impaired STAT3-mediated induction of suppressor of cytokine signaling 3 (SOCS3) (111, 112).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [111]
The Results section, “Sustained Activation of the SHP-2/ras/Erk Pathway Results from Impaired Induction of SOCS-1” (page unavailable), links impaired STAT signaling to sustained SHP-2/ras/Erk activation and reports reduced SOCS-3 induction. It does not establish the specific STAT3-to-SOCS3 mechanism claimed: it emphasizes SOCS-1 and describes induction of both SOCS-1 and SOCS-3 as mediated at least in part by STATs. (LLM, conf=0.86)
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Self-citation
- Authors
- Ernst, M., Inglese, M., Waring, P., Campbell, I. K., Bao, S., Clay, F. J., Alexander, W. S., Wicks, I. P., Tarlinton, D. M., Novak, U., Heath, J. K., & Dunn, A. R.
- Affiliations
- The Royal Melbourne Hospital (AU)
- Peter MacCallum Cancer Centre (AU)
- The University of Sydney (AU)
- The University of Melbourne (AU)
- ORCID
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2001-07-16
- Volume
- 194
- Issue
- 2
- Pages
- 189-204
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2193459
- OpenAlex
- W2125415295
- Cited by
- 227
- References
- 51
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 4 · 2023: 3 · 2022: 2 · 2021: 7 · 2020: 4 · 2019: 7 · 2018: 1 · 2017: 8 · 2016: 4 · 2015: 5 · 2014: 8 · 2013: 12 · 2012: 6
- FWCI
- 9.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc-sa)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
- Keywords
- gp130, STAT signaling, interleukin-6, suppressor of cytokine signaling, articular cartilage degeneration, synovitis, gastrointestinal ulceration, embryo implantation, cytokine receptor signaling, knock-in mice
- MeSH terms
- Suppressor of Cytokine Signaling 1 Protein, Animals, Carrier Proteins, DNA-Binding Proteins, Female, Joint Diseases, Male, Membrane Glycoproteins, Mice, Mutant Strains, Embryo Implantation, Peptic Ulcer, Pregnancy, Repressor Proteins, Signal Transduction, Trans-Activators, Antigens, CD, DNA Primers, Mice, Knockout, Mitogen-Activated Protein Kinases, STAT1 Transcription Factor, STAT3 Transcription Factor, Cytokine Receptor gp130, Suppressor of Cytokine Signaling Proteins, Mice
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