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SOCS3 Exerts Its Inhibitory Function on Interleukin-6 Signal Transduction through the SHP2 Recruitment Site of gp130
Open accessAbstract
Interleukin-6 is involved in the regulation of many biological activities such as gene expression, cell proliferation, and differentiation. The control of the termination of cytokine signaling is as important as the regulation of initiation of signal transduction pathways. Three families of proteins involved in the down-regulation of cytokine signaling have been described recently: (i) SH2 domain-containing protein-tyrosine phosphatases (SHP), (ii) suppressors of cytokine signaling (SOCS), and (iii) protein inhibitors of activated STATs (PIAS). We have analyzed the interplay of two inhibitors in the signal transduction pathway of interleukin-6 and demonstrate that the tyrosine phosphatase SHP2 and SOCS3 do not act independently but are functionally linked. The activation of one inhibitor modulates the activity of the other; Inhibition of SHP2 activation leads to increased SOCS3-mRNA levels, whereas increased expression of SOCS3 results in a reduction of SHP2 phosphorylation after activation of the interleukin-6 signal transduction pathway. Furthermore, we show that tyrosine 759 in gp130 is essential for both SHP2 and SOCS3 but not for SOCS1 to exert their inhibitory activities on interleukin-6 signal transduction. Besides SHP2, SOCS3 also interacts with the Tyr(P)-759 peptide of gp130. Taken together, our results suggest differences in the function of SOCS1 and SOCS3 and a link between SHP2 and SOCS3.
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“Inhibition of SOCS3 expression [37] or lack of SOCS3 binding sites in gp130 results in sustained STAT3 activation and altered physiological outcomes in response to IL-6 [38].”
From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [38]
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“In the first mechanism, nascent SOCS-3 blocks the activation of STAT-3 by binding to the receptor complex via gp130 at tyrosine 759 (34,35) and/or by binding and inhibiting Jak2 activity (36).”
From Expression of suppressors of cytokine signaling during liver regeneration (2001) · cites this paper as [34]
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Cited by
Sorted by citations
IL‐6 in inflammation, immunity, and disease
Tanaka, T., Narazaki, M., & Kishimoto, T. (2014) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a016295 · Cited by 5,046
“In this context, SOCS1 binds to tyrosine-phosphorylated JAK (Naka et al. 1997), whereas SOCS3 binds to tyrosine-phosphorylated gp130 (Schmitz et al. 2000) to stop IL-6 signaling by means of a negative feedback loop.”
BackgroundPrinciples 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
Self-citationYing, Q.-L., Nichols, J., Chambers, I., & Smith, A. G. (2003) · Cell · doi:10.1016/s0092-8674(03)00847-x · Cited by 2,114
“…(Schorpp-Kistner et al.,stimulated with LIF plus BMP. Immunoprecipation fol- lowing transfection with FLAG-tagged Smad1 indicated 1999), and SOCS3 functions as a negative feedback regulator of gp130 signaling (Schmitz et al., 2000) thatthat activated STAT3 and Smad1 may colocalize (Figure 3F).”
IL-6 in inflammation, autoimmunity and cancer
Hirano, T. (2021) · International Immunology · doi:10.1093/intimm/dxaa078 · Cited by 1,453
“SOCS3 is induced by STAT3 and considered to regulate a major negative feedback loop of a gp130-mediated signaling pathway (118–120).”
BackgroundThe ‘Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling
Neel, B. G., Gu, H., & Pao, L. (2003) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(03)00091-4 · Cited by 1,249
Metadata
- Authors
- Schmitz, J., Weissenbach, M., Haan, S., Heinrich, P. C., & Schaper, F.
- Affiliations
- RWTH Aachen University (DE)
- Corresponding author
- Heinrich, Peter C.
- ORCID
- Schaper, Fred
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2000-04
- Volume
- 275
- Issue
- 17
- Pages
- 12848-12856
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2038468714
- Cited by
- 388
- References
- 36
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 4 · 2023: 3 · 2022: 9 · 2021: 10 · 2020: 10 · 2019: 7 · 2018: 8 · 2017: 14 · 2016: 10 · 2015: 10 · 2014: 13 · 2013: 10 · 2012: 23
- FWCI
- 15.16
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, cc-by-nc-sa)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- SOCS3, IL-6 signaling, SHP2, gp130, suppressor of cytokine signaling, SOCS1, protein-protein interaction
- MeSH terms
- Suppressor of Cytokine Signaling 1 Protein, Suppressor of Cytokine Signaling 3 Protein, Interleukin-6 Inhibitors, alpha-Macroglobulins, Carrier Proteins, Cell Nucleus, Glutathione Transferase, Humans, Membrane Glycoproteins, Phosphorylation, Precipitin Tests, Promoter Regions, Genetic, Protein Binding, Proteins, Recombinant Fusion Proteins, Repressor Proteins, Transcription Factors, Transfection, Tumor Cells, Cultured, Tyrosine, Immunoblotting, Blotting, Northern, Signal Transduction, Antigens, CD, Interleukin-6, Protein Tyrosine Phosphatases, src Homology Domains, Intracellular Signaling Peptides and Proteins, Cytokine Receptor gp130, Suppressor of Cytokine Signaling Proteins, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatase, Non-Receptor Type 11, SH2 Domain-Containing Protein Tyrosine Phosphatases
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