SHP2 and SOCS3 Contribute to Tyr-759-dependent Attenuation of Interleukin-6 Signaling through gp130
Open accessAbstract
Interleukin-6 (IL-6) activates the Jak/STAT pathway as well as the mitogen-activated protein kinase cascade. Tyrosine 759 of the IL-6 signal-transducing receptor subunit gp130 has been identified as being involved in negative regulation of IL-6-induced gene induction and activation of the Jak/STAT pathway. Because this site is known to be a recruitment motif for the protein-tyrosine phosphatase SHP2, it has been suggested that SHP2 is the mediator of tyrosine 759-dependent signal attenuation. We recently observed that the suppressor of cytokine-signaling SOCS3 also acts through the tyrosine motif 759 of gp130. However, the relative contributions of SHP2 and SOCS3 to the repression of IL-6 signaling are not understood. Therefore, we designed experiments allowing the independent recruitment of each of these proteins to the IL-6-receptor complex. We show that receptor- and membrane-targeted SHP2 counteracts IL-6 signaling independent of SOCS3 binding to gp130. On the other hand, SOCS3 inhibits signaling in cells expressing a truncated SHP2 protein, which is not recruited to gp130. These data suggest, that there are two, largely distinct modes of negative regulation of gp130 activity, despite the fact that both SOCS3 and SHP2 are recruited to the same site within gp130.
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?
Hy-IL-6-induced STAT3-Y705 phosphorylation is increased in MEF SHP2 ΔEx3 cells compared to MEF wildtype (wt) cells.
“In accordance with previously published results [13], Hy-IL-6-induced STAT3-Y705 phosphorylation is increased in MEF SHP2 ΔEx3 cells compared to MEF wildtype (wt) cells (Fig. 1a).”
From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [13]
In “SHP2 Contributes to the Attenuation of Interleukin-6 Signal” (Fig. 1B; page unavailable), the paper reports enhanced STAT3 DNA-binding activity in exon-3-mutant murine fibroblasts versus wild-type cells after stimulation with IL-6 and soluble IL-6R. It does not report STAT3-Y705 phosphorylation for that fibroblast comparison. Its Y705-phosphorylation experiment (Fig. 2B; page unavailable) instead uses IL-5-stimulated COS-7 cells expressing catalytically inactive SHP2 mutants. (LLM, conf=0.87)
Experimental — accuracy not yet measuredMutation of SHP2 to prevent recruitment to gp130 or to block phosphatase activity increases basal and IL-6-induced STAT3 activation and STAT3-induced gene expression.
“Mutation of SHP2 to prevent recruitment to gp130 or to block phosphatase activity increases basal and IL-6-induced STAT3 activation and STAT3-induced gene expression [13].”
From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [13]
In “SHP2 Contributes to the Attenuation of Interleukin-6 Signal” (page unavailable), the recruitment-defective SHP2 mutant shows enhanced stimulated STAT3 DNA binding and STAT3-responsive reporter activity. The same section reports increased basal and induced STAT3 activation, plus greater reporter activity, for catalytically inactive SHP2. It does not report increased basal STAT3 activation for the recruitment-defective mutant. (LLM, conf=0.83)
Experimental — accuracy not yet measuredF759/F757-dependent negative regulation is mainly dependent on the recruitment of SOCS3.
“However, this site is also a recruitment motif for SOCS3, and it was found that the F759/F757-dependent negative regulation is mainly dependent on the recruitment of SOCS3 (116, 117).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [116]
The opening summary and Results report that SOCS3 acts through gp130 Tyr-759 and that its inhibitory activity depends on that site. But the paper also finds an independent inhibitory role for SHP2 and describes two largely distinct modes of negative regulation; it does not establish that SOCS3 recruitment accounts for most of the site-dependent effect. Our copy addresses Tyr-759, not the cited F757 counterpart. (LLM, conf=0.84)
Experimental — accuracy not yet measuredSHP2 is a repressor of basal cytokine-independent STAT3 phosphorylation.
“Additionally, SHP2 is a repressor of basal cytokine-independent STAT3 phosphorylation [12, 13].”
From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [13]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 63 · Cited by 236
Research works printed but not linked: 6
- Gauldie, J., Richards, C., Harnish, D., Lansdorp, P., and Baumann, H. (1987) Proc. Natl. Acad. Sci. U. S. A. 84, 7251-7255
- Narazaki, M., Fujimoto, M., Matsumoto, T., Morita, Y., Saito, H., Kajita, T., Yoshizaki, K., Naka, T., and Kishimoto, T. (1998) Proc. Natl. Acad. Sci.
- Hilton, D. J., Richardson, R. T., Alexander, W. S., Viney, E. M., Willson, T. A., Sprigg, N. S., Starr, R., Nicholson, S. E., Metcalf, D., and Nicola, N. A. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 114 -119
- Zhang, J. G., Farley, A., Nicholson, S. E., Willson, T. A., Zugaro, L. M., Simpson, R. J., Moritz, R. L., Cary, D., Richardson, R., Hausmann, G., Kile, B. J., Kent, S. B., Alexander, W. S., Metcalf, D., Hilton, D. J., Nicola, N. A., and Baca, M. (1999) Proc. Natl. Acad. Sci. U. S. A. 96, 2071-2076
- Nicholson, S. E., De Souza, D., Fabri, L. J., Corbin, J., Willson, T. A., Zhang, J. G., Silva, A., Asimakis, M., Farley, A., Nash, A. D., Metcalf, D., Hilton, D. J., Nicola, N. A., and Baca, M. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 6493-6498
- Payne, G., Shoelson, S. E., Gish, G. D., Pawson, T., and Walsh, C. T. (1993) Proc. Natl. Acad. Sci. U. S. A. 90, 4902-4906
- Authors
- Lehmann, U., Schmitz, J., Weissenbach, M., Sobota, R. M., Hörtner, M., Friederichs, K., Behrmann, I., Tsiaris, W., Sasaki, A., Schneider-Mergener, J., Yoshimura, A., Neel, B. G., Heinrich, P. C., & Schaper, F.
- Affiliations
- RWTH Aachen University (DE)
- Bayer (Germany) (DE)
- Beth Israel Deaconess Medical Center (US)
- Kyushu University (JP)
- Corresponding author
- Heinrich, Peter C.
- Schaper, Fred
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-01
- Volume
- 278
- Issue
- 1
- Pages
- 661-671
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2164967233
- Cited by
- 236
- References
- 63
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 5 · 2023: 1 · 2022: 4 · 2021: 9 · 2020: 5 · 2019: 8 · 2018: 5 · 2017: 7 · 2016: 5 · 2015: 9 · 2014: 10 · 2013: 16 · 2012: 30
- FWCI
- 6.33
- 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)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Health Sciences › Medicine › Oncology › 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
- SHP2, SOCS3, IL-6 signaling, gp130, signal attenuation, negative regulation of cytokine signaling, JAK/STAT signaling, protein tyrosine phosphatase, suppressor of cytokine signaling
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Amino Acid Sequence, Animals, Cell Line, Cell Nucleus, Enzyme Activation, Fibroblasts, Humans, Membrane Glycoproteins, Molecular Sequence Data, Protein Binding, Protein-Tyrosine Kinases, Proteins, Recombinant Fusion Proteins, Repressor Proteins, Transcription Factors, Tyrosine, Biosensing Techniques, Signal Transduction, Antigens, CD, Interleukin-6, Protein Tyrosine Phosphatases, Receptors, Erythropoietin, Genes, Reporter, src Homology Domains, Mitogen-Activated Protein Kinases, Macromolecular Substances, Intracellular Signaling Peptides and Proteins, Cytokine Receptor gp130, Suppressor of Cytokine Signaling Proteins, Mice, Janus Kinase 1, Protein Tyrosine Phosphatase, Non-Receptor Type 11, SH2 Domain-Containing Protein Tyrosine Phosphatases
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
