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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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“It is known that SOCS-3 interacts with several tyrosine-phosphorylated receptors, such as gp130 in IL-6 signaling (30, 31), the EPO receptor (32), and the IGF-I receptor (33).”
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The Role of Suppressors of Cytokine Signalling in Human Neoplasms
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“SOCS3, therefore, in contrast to SOCS1, has to be recruited to the receptor complex in order to inhibit IL-6 signal transduction [114].”
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“This interaction did not depend on the presence of SHP2 (48).”
BackgroundSelf-citationSOCS1 is a critical checkpoint in immune homeostasis, inflammation and tumor immunity
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SOCS proteins in infectious diseases of mammals
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“SOCS3 exerts its inhibitory function on interleukin-6 signal transduction through the SHP2 recruitment site of gp130.”
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“193 Two other STAT3-dependent mechanisms for suppression of the IL-6 signaling pathway involve the suppressors of cytokine signaling SOCS1 and SOCS3, 199 which act by binding to and blocking the activity of phosphorylated JAK 200 and gp130, 201 respectively.”
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Regulation of pancreatic β-cell mass and proliferation by SOCS-3
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“However, several studies also suggest that crosstalk between different cytokine-induced signaling pathways can be mediated by the SOCS proteins (Magrangeas et al. 2001, Schmitz et al. 2000, Wu et al. 2003).”
BackgroundSOCS proteins and caveolin-1 as negative regulators of endocrine signaling
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Synthetic cytokine receptors transmit biological signals using artificial ligands
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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].”
BackgroundSelf-citationc‐myc as a mediator of accelerated apoptosis and involution in mammary glands lacking Socs3
Sutherland, K. D., Vaillant, F., Alexander, W. S., Wintermantel, T. M., Forrest, N. C., Holroyd, S. L., McManus, E. J., Schütz, G., Watson, C. J., Chodosh, L. A., et al. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601455 · Cited by 54
“The current model suggests that Socs3 binds with high affinity to the phosphory- lated Y757 residue of the gp130 receptor chain, thus dimin- ishing Stat3 activation (Nicholson et al, 2000; Schmitz et al, 2000).”
BackgroundWoolson, H. D., Thomson, V. S., Rutherford, C. L., Yarwood, S. J., & Palmer, T. M. (2009) · Cellular Signalling · doi:10.1016/j.cellsig.2009.07.009 · Cited by 52
Updating interleukin‐6 classic‐ and trans‐signaling
Scheller, J., Grötzinger, J., & Rose‐John, S. (2006) · Signal Transduction · doi:10.1002/sita.200600086 · Cited by 53
Regulatory Effect of SOCS on NF- κ B Activity in Murine Monocytes/Macrophages
Park, S.-H., Kim, K.-E., Hwang, H.-Y., & Kim, T. Y. (2003) · DNA and Cell Biology · doi:10.1089/104454903321515931 · Cited by 52
Furcht, C. M., Buonato, J. M., Skuli, N., Mathew, L. K., Muñoz-Rojas, A. R., Simon, M. C., & Lazzara, M. J. (2014) · Journal of Cell Science · doi:10.1242/jcs.150862 · Cited by 51
“SHP2 can also negatively regulate STAT3 activation downstream of the interleukin-6 receptor (Schmitz et al., 2000), and one recent study even described a ‘tumorsuppressor’ role for SHP2 in hepatocellular carcinoma through its regulation of STAT3 (Bard-Chapeau et al., 2011).”
BackgroundDittrich, A., Khouri, C., Sackett, S. D., Ehlting, C., Böhmer, O., Albrecht, U., Bode, J. G., Trautwein, C., & Schaper, F. (2012) · Hepatology · doi:10.1002/hep.24655 · Cited by 51
“In a second approach, hepatocytes isolated from mice that express a mutant form of the IL-6 coreceptor gp130 (Y757F) (which lack the SOCS3 recruiting motif and are thus resistant to SOCS3-dependent feedback inhibition) were analyzed.(30) Similar to what was observed in WT primary hepatocytes (Fig.”
ResultSelf-citationKnight, D. A., Ernst, M., Anderson, G. P., Moodley, Y. P., & Mutsaers, S. E. (2003) · Pharmacology & Therapeutics · doi:10.1016/s0163-7258(03)00095-0 · Cited by 50
Trinath, J., Holla, S., Mahadik, K., Prakhar, P., Singh, V., & Balaji, K. N. (2014) · Molecular and Cellular Biology · doi:10.1128/mcb.00641-14 · Cited by 50
“The SOCS family of genes is known to bring about ubiquitination-mediated degradation of target proteins such as STAT, thus downregulating IFN- response (51, 52).”
Backgroundvan de Geijn, G. J. M., Aarts, L. H. J., Erkeland, S. J., Prasher, J. M., & Touw, L. P. (2003) · Reviews of physiology, biochemistry and pharmacology · doi:10.1007/s10254-003-0014-0 · Cited by 50
Albrecht, U., Yang, X., Asselta, R., Keitel, V., Tenchini, M. L., Ludwig, S., Heinrich, P. C., Häussinger, D., Schaper, F., & Bode, J. G. (2007) · Cellular Signalling · doi:10.1016/j.cellsig.2007.04.007 · Cited by 50
Self-citationTron, K., Samoylenko, A., Musikowski, G., Kobe, F., Immenschuh, S., Schaper, F., Ramadori, G. P., & Kietzmann, T. (2006) · Journal of Hepatology · doi:10.1016/j.jhep.2005.12.019 · Cited by 51
“We determined whether the gp130 tyrosines 767, 814, 905, 915, necessary for STAT recruitment [19], or tyrosyine 759, known to be crucial for MAPK [23] and SH2-domain-containing tyrosine phosphatase-2 (SHP2) activation [24] as well as SOCS3 recruitment [25], initiate HO-1 induction in HepG2 cells (Fig.”
BackgroundSelf-citationLi, L., Modi, H., McDonald, T., Rossi, J., Yee, J., & Bhatia, R. (2011) · Blood · doi:10.1182/blood-2010-06-288910 · Cited by 49
Hamanaka, I., Saito, Y., Yasukawa, H., Kishimoto, I., Kuwahara, K., Miyamoto, Y., Harada, M., Ogawa, E., Kajiyama, N., Takahashi, N., et al. (2001) · Circulation Research · doi:10.1161/hh0701.088512 · Cited by 49
Bode, J. G., Schweigart, J., Kehrmann, J., Ehlting, C., Schaper, F., Heinrich, P. C., & Häussinger, D. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.1.257 · Cited by 48
“Recruitment of SHP2 and SOCS3 to the gp130 receptor subunit depends on the phosphorylation of the tyrosine residue 759 of gp130 (15, 39, 41).”
BackgroundMethodSelf-citationHebenstreit, D., Luft, P., Schmiedlechner, A., Duschl, A., & Horejs‐Hoeck, J. (2004) · Molecular Immunology · doi:10.1016/j.molimm.2004.09.004 · Cited by 48
Babon, J. J., Yao, S., DeSouza, D. P., Harrison, C. F., Fabri, L., Liepinsh, E., Scrofani, S. D. B., Baca, M., & Norton, R. S. (2005) · FEBS Journal · doi:10.1111/j.1742-4658.2005.05010.x · Cited by 48
Uto-Konomi, A., Miyauchi, K., Ozaki, N., Motomura, Y., Suzuki, Y., Yoshimura, A., Suzuki, S., Cua, D., & Kubo, M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0040343 · Cited by 48
“components of the IL-6 receptor, gp130 [25,26].”
Magrangeas, F., Boisteau, O., DENIS, S., Jacques, Y., & Minvielle, S. (2001) · Biochemical Journal · doi:10.1042/0264-6021:3530223 · Cited by 48
Hunter, M. G., Jacob, A., O’Donnell, L. C., Agler, A., Druhan, L. J., Coggeshall, K. M., & Avalos, B. R. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.8.5036 · Cited by 46
A Conserved IFN-α Receptor Tyrosine Motif Directs the Biological Response to Type I IFNs
Zhao, W., Lee, C., Piganis, R., Plumlee, C. R., de Weerd, N. A., Hertzog, P. J., & Schindler, C. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.8.5483 · Cited by 47
Suppressor of cytokine signaling proteins as regulators of innate immune signaling
Strebovsky, J. (2011) · Frontiers in bioscience · doi:10.2741/4008 · Cited by 46
“In contrast SOCS3 gets access to JAKs via binding to the cytokine receptor as exemplified by binding to the IL-6 receptor/gp130 (37,38), erythropoietin receptor (32), G-CSF receptor (39), leptin receptor (40,41) or growth hormone receptor (42).”
BackgroundJessica, P., Bongartz, H., Klepsch, O., Wundrack, N., Poli, V., Schaper, F., & Dittrich, A. (2016) · Cellular Signalling · doi:10.1016/j.cellsig.2016.04.004 · Cited by 50
“In accordance with the timespan needed to reduce REDD1 expression maximal IL-6induced SOCS3 expression occurs within 30 to 60 min [31].”
BackgroundSelf-citationForcina, L., Miano, C., & Musarò, A. (2018) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2018.05.001 · Cited by 46
Zhu, P., Hata, R., Cao, F., Gu, F., Hanakawa, Y., Hashimoto, K., & Sakanaka, M. (2008) · The FASEB Journal · doi:10.1096/fj.08-105908 · Cited by 46
“SOCS3 has been shown to interact with gp130 and Jak, and this interaction results in relatively specific inhibition of gp130 signaling (15).”
BackgroundJAK-STAT3 and somatic cell reprogramming
Tang, Y., & Tian, X. (2013) · JAK-STAT · doi:10.4161/jkst.24935 · Cited by 44
Poussin, K., Pilati, C., Couchy, G., Caldéraro, J., Bioulac‐Sage, P., Bacq, Y., Paradis, V., Leteurtre, E., Stürm, N., Ramos, J., et al. (2013) · OncoImmunology · doi:10.4161/onci.27090 · Cited by 48
“The activity of IHCA-associated gp130 mutants is attenuated by SOCS3 SOCS3 is induced as a direct target of STAT3 and modulates JAK signaling upon interaction with gp130 Y759.”
BackgroundSle1ab Mediates the Aberrant Activation of STAT3 and Ras-ERK Signaling Pathways in B Lymphocytes
Liu, K., Liang, C., Liang, Z., Tus, K., & Wakeland, E. K. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.3.1630 · Cited by 44
“Since SOCS3 is a suppressor of IL-6 signaling, its elevated expression under normal circumstances would be predicted to down-regulate IL-6 signaling in B lymphocytes and subsequently extinguish STAT3 activation (11, 16, 19, 32, 33).”
BackgroundShouda, T., Hiraoka, K., Komiya, S., Hamada, T., Zenmyo, M., Iwasaki, H., Isayama, T., Fukushima, N., Nagata, K., & Yoshimura, A. (2005) · Cancer Letters · doi:10.1016/j.canlet.2005.01.042 · Cited by 44
“SOCS3 has been shown to interact with gp130 and JAKs, and this interaction results in the relatively specific inhibition of gp130 signaling [13–15].”
BackgroundSp3 is involved in the regulation of SOCS3 gene expression
Ehlting, C., Häussinger, D., & Bode, J. G. (2005) · Biochemical Journal · doi:10.1042/bj20041101 · Cited by 44
Proteolytic control of Interleukin-11 and Interleukin-6 biology
Lokau, J., Agthe, M., Flynn, C. M., & Garbers, C. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2017.06.008 · Cited by 43
IL-6 Mediates the Susceptibility of Glycoprotein 130 Hypermorphs to Toxoplasma gondii
Silver, J. S., Stumhofer, J. S., Passos, S., Ernst, M., & Hunter, C. A. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1004144 · Cited by 42
Negative regulation of cytokine signaling and inflammatory diseases
Inagaki-Ohara, K. (2003) · Current Opinion in Pharmacology · doi:10.1016/s1471-4892(03)00070-5 · Cited by 41
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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