The role of the inhibitors of interleukin-6 signal transduction SHP2 and SOCS3 for desensitization of interleukin-6 signalling
Open accessAbstract
The immediate early response of cells treated with IL-6 (interleukin-6) is the activation of the signal transducer and activator of transcription (STAT)3. The Src homology domain 2 (SH2)-containing protein tyrosine phosphatase SHP2 and the feedback inhibitor SOCS3 (suppressor of cytokine signalling) are potent inhibitors of IL-6 signal transduction. Impaired function of SOCS3 or SHP2 leads to enhanced and prolonged IL-6 signalling. The inhibitory function of both proteins depends on their recruitment to the tyrosine motif 759 within glycoprotein gp130. In contrast to inactivation, desensitization of signal transduction is regarded as impaired responsiveness due to prestimulation. Usually, after activation the sensing receptor becomes inactivated by modifications such as phosphorylation, internalization or degradation. We designed an experimental approach which allows discrimination between desensitization and inactivation of IL-6 signal transduction. We observed that pre-stimulation with IL-6 renders cells less sensitive to further stimulation with IL-6. After several hours, the cells become sensitive again. We show that not only signal transduction through previously activated receptors is affected by desensitization but signalling through receptors which were not targeted by the first stimulation was also attenuated (trans-desensitization). Interestingly, in contrast to inhibition, desensitization does not depend on the presence of functional SHP2. Furthermore, cells lacking SOCS3 show constitutive STAT3 activation which is not affected by pre-stimulation with IL-6. All these observations suggest that desensitization and inhibition of signalling are mechanistically distinct.
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SOCS3 expression is induced in response to STAT3 activation and therefore SOCS3 is only active in late IL-6-induced signalling.
“SOCS3 expression is induced in response to STAT3 activation [4] and therefore SOCS3 is only active in late IL-6-induced signalling [5].”
From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [5]
Citation [5] is attached to the claim that SOCS3 is active only in late IL-6 signalling. In “Kinetics of SOCS1 and SOCS3 induction resemble that of IL-6 desensitization” (page not provided), the paper instead reports that SOCS3 protein was detectable very early and describes SOCS3 as an IL-6-induced immediate-early gene. (LLM, conf=0.88)
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Experimental — accuracy not yet measuredSocs3-deficient primary hepatocytes exhibited signs of basal STAT3 activation, including low level STAT3 tyrosine phosphorylation and induction of IL-6-inducible genes.
“We initially examined IL-6 signaling in Socs3deficient primary hepatocytes, but like Socs3-deficient mouse embryonic fibroblasts (27), these cells exhibited signs of basal STAT3 activation (albeit to a lesser extent), including low level STAT3 tyrosine phosphorylation and induction of IL-6-inducible genes (data not shown).”
From The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling (2006) · cites this paper as [27]
Previous attempts to detect SOCS3-mediated desensitization of cytokine signaling in Socs3-deficient mouse embryonic fibroblasts were hampered by constitutive activation of STAT3 in these cells.
“However, previous attempts to detect SOCS3-mediated desensitization of cytokine signaling in Socs3-deficient mouse embryonic fibroblasts were hampered by the constitutive activation of STAT3 in these cells (27).”
From The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling (2006) · cites this paper as [27]
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Cites
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“SOCS3 expression is induced in response to STAT3 activation [4] and therefore SOCS3 is only active in late IL-6-induced signalling [5].”
BackgroundSelf-citation
- Authors
- FISCHER, P., LEHMANN, U., SOBOTA, R. M., SCHMITZ, J., NIEMAND, C., LINNEMANN, S., HAAN, S., BEHRMANN, I., YOSHIMURA, A., JOHNSTON, J. A., MÜLLER-NEWEN, G., HEINRICH, P. C., & SCHAPER, F.
- Affiliations
- RWTH Aachen University (DE)
- Kyushu University (JP)
- Queen's University Belfast (GB)
- Department of Biochemistry, Faculty of Medicine, RWTH Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany
- Corresponding author
- FISCHER, Patrick
- LEHMANN, Ute
- SCHMITZ, Jochen
- NIEMAND, Claudia
- LINNEMANN, Sonja
- HAAN, Serge
- BEHRMANN, Iris
- SCHAPER, Fred
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2004-03-01
- Volume
- 378
- Issue
- 2
- Pages
- 449-460
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC1223960
- OpenAlex
- W2046256825
- Cited by
- 72
- References
- 8
- Citations by year
- 2026: 2 · 2023: 1 · 2022: 2 · 2021: 2 · 2019: 4 · 2017: 1 · 2016: 3 · 2015: 3 · 2014: 3 · 2013: 5 · 2012: 5
- FWCI
- 4.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, cc-by-nc-sa)
- 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, STAT3 activation, gp130, receptor internalization, receptor degradation, tyrosine phosphorylation, signal transduction inhibition, cytokine signaling
- MeSH terms
- Suppressor of Cytokine Signaling 1 Protein, Suppressor of Cytokine Signaling 3 Protein, Interleukin-6 Inhibitors, Animals, Carrier Proteins, Cell Line, DNA-Binding Proteins, Humans, Kinetics, Membrane Glycoproteins, Protein-Tyrosine Kinases, Repressor Proteins, RNA, Messenger, Transcription Factors, Transcription, Genetic, Tyrosine, Signal Transduction, Trans-Activators, Down-Regulation, Antigens, CD, Interleukin-6, Protein Tyrosine Phosphatases, Mice, Knockout, Receptors, Interleukin-6, Intracellular Signaling Peptides and Proteins, STAT3 Transcription Factor, Cytokine Receptor gp130, Suppressor of Cytokine Signaling Proteins, Mice, Janus Kinase 1, Protein Tyrosine Phosphatase, Non-Receptor Type 11
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