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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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“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).”
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“SOCS-3 can also potentially competitively block receptor recruitment of SHP-2 to Tyr759 of gp130, thus inhibiting ERK activation (43).”
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“The JAKs phosphorylate gp130 tyrosine residues which then serve as docking sites for src homology 2 (SH2) domain-containing signaling molecules such as the signal transducers and activators of transcription 3 and 1 (Stat3, Stat1),(3,4) the SH2-containing phosphatase-2 (SHP-2), and the suppressor of cytokine signaling-…”
BackgroundNarimatsu, M., Maeda, H., Itoh, S., Atsumi, T., Ohtani, T., Nishida, K., Itoh, M., Kamimura, D., Park, S., Mizuno, K., et al. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.19.6615-6625.2001 · Cited by 145
“YSTV motif in gp130, causing negative feedback (27, 34).”
BackgroundIdentification of the Y985 and Y1077 motifs as SOCS3 recruitment sites in the murine leptin receptor
Eyckerman, S., Broekaert, D., Verhee, A., Vandekerckhove, J. S., & Tavernier, J. H. (2000) · FEBS Letters · doi:10.1016/s0014-5793(00)02205-5 · Cited by 143
Inhibition of IL-6 and IL-10 Signaling and Stat Activation by Inflammatory and Stress Pathways
Ahmed, S. T., & Ivashkiv, L. B. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.9.5227 · Cited by 138
“Another key feature of the truncated receptor is that it lacks the Y759 SH2 domain-containing protein-tyrosine phosphatase/SOCS3 docking site (55, 56, 64), lending further support for the SOCSindependent nature of the inhibition seen in our system.”
BackgroundInfluentialThe role of the interleukin‐6 family of cytokines in inflammatory arthritis and bone turnover
Wong, P. K. K., Campbell, I. K., Egan, P. J., Ernst, M., & Wicks, I. P. (2003) · Arthritis & Rheumatism · doi:10.1002/art.10943 · Cited by 139
The Src Family of Tyrosine Kinases Is Important for Embryonic Stem Cell Self-renewal
Annerén, C., Cowan, C. A., & Melton, D. A. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m403547200 · Cited by 140
Pernot, F., Heinrich, C., Barbier, L., Peinnequin, A., Carpentier, P., Dhote, F., Baille, V., Beaup, C., Depaulis, A., & Dorandeu, F. (2011) · Epilepsia · doi:10.1111/j.1528-1167.2011.03273.x · Cited by 137
“More precisely, SOCS3 is induced by a wide range of stimuli including interleukin-6 (IL-6) family and regulates the cytokine signaling via the inhibition of the Janus kinases/ signal transducers and activators of transcription (JAK/ STAT) transduction pathway in a negative feedback loop (Heinrich et al., 1998; Schmitz…”
BackgroundDominant-negative mutations in human IL6ST underlie hyper-IgE syndrome
Béziat, V., Tavernier, S. J., Chen, Y., Ma, C. S., Materna, M., Laurence, A. D. J., Staal, J., Aschenbrenner, D., Roels, L., Worley, L., et al. (2020) · The Journal of Experimental Medicine · doi:10.1084/jem.20191804 · Cited by 133
“Upon phosphorylation, Y759 acts as a docking site for SOCS3, which switches off STAT3 activation (Nicholson et al., 2000; Schmitz et al., 2000).”
The role of the interleukin (IL)-6/IL-6 receptor axis in cancer
Taher, M. Y., Davies, D. M., & Maher, J. F. (2018) · Biochemical Society Transactions · doi:10.1042/bst20180136 · Cited by 138
Ivo, P. T. (2006) · Frontiers in bioscience · doi:10.2741/2103 · Cited by 130
“Because Tyr729 is also a docking site for the protein tyrosine phosphatase SHP-2, which binds to and inactivates STAT5, a model is suggested in which the loss of recruitment of both SOCS3 and SHP-2 to the activated receptor complex determine the increased STAT5/STAT3 activation ratio and the resulting signaling abnorm…”
BackgroundInfluentialKalliolias, G. D., & Ivashkiv, L. B. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.9.6325 · Cited by 136
Yamamoto, K., Yamaguchi, M., Miyasaka, N., & Miura, O. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2003.09.140 · Cited by 131
Hörtner, M., Nielsch, U., Mayr, L. M., Johnston, J. A., Heinrich, P. C., & Haan, S. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.3.1219 · Cited by 128
“We and others have recently reported that SOCS-3 exerts part of its inhibitory action on IL-6 signal transduction by binding to pY759 within the signal transducing receptor subunit gp130 (31, 32).”
Self-citationJiang, M., Chen, J., Zhang, W., Zhang, R., Ye, Y., Liu, P., Yu, W., Wei, F., Ren, X., & Yu, J. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01840 · Cited by 129
Regulation of the immune system by SOCS family adaptor proteins
Ilangumaran, S., Ramanathan, S., & Rottapel, R. K. (2004) · Seminars in Immunology · doi:10.1016/j.smim.2004.08.015 · Cited by 128
The biology and mechanism of action of suppressor of cytokine signaling 3
Babon, J. J., & Nicola, N. A. (2012) · Growth Factors · doi:10.3109/08977194.2012.687375 · Cited by 129
“Of all other SH2 domains, only the SH2 domain of SHP-2 is similar in this regard and SHP-2 is known to target SOCS3 binding sites on several receptors (Nicholson et al. 2000; Schmitz et al. 2000; Fairlie et al. 2003).”
BackgroundProlonged inflammatory gene response following soman-induced seizures in mice
Dhote, F., Peinnequin, A., Carpentier, P., Baille, V., Delacour, C., Foquin, A., Lallement, G., & Dorandeu, F. (2007) · Toxicology · doi:10.1016/j.tox.2007.05.032 · Cited by 129
Jak-Stat Signaling Induced by Interleukin-6 Family Cytokines in Hepatocellular Carcinoma
Lokau, J., Schoeder, V., Haybaeck, J., & Garbers, C. (2019) · Cancers · doi:10.3390/cancers11111704 · Cited by 127
“Cancers 2019, 11, 1704 5 of 17 Cancers 2019, 11, 1704 5 of 17 Of note, SHP2 does not only act as negative regulator for STATs, but is also phosphorylated upon gp130 activation and subsequently, activates the PI3K and MAPK signaling cascades [43].”
BackgroundInfluentialMolecular basis of the cell specificity of cytokine action
Ishihara, K., & Hirano, T. (2002) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/s0167-4889(02)00321-x · Cited by 122
Emerging roles for the IL-6 family of cytokines in pancreatic cancer
van Duijneveldt, G., Griffin, M. D. W., & Putoczki, T. L. (2020) · Clinical Science · doi:10.1042/cs20191211 · Cited by 126
Chen, H., Ördög, T., Chen, J., Young, D. L., Bardsley, M. R., Redelman, D. D., Ward, S. M., & Sanders, K. M. (2007) · Physiological Genomics · doi:10.1152/physiolgenomics.00113.2007 · Cited by 119
“Thus, in ICC, Socs3 may be involved not only in feedback regulation of IL-6 signaling but also in signaling from the other receptor tyrosine kinases expressed in these cells.”
BackgroundInfluentialTyrosine Phosphorylation Disrupts Elongin Interaction and Accelerates SOCS3 Degradation
Haan, S., FERGUSON, P. W., Sommer, U., Hiremath, M. M., McVicar, D. W., Heinrich, P. C., Johnston, J. A., & Cacalano, N. A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m303170200 · Cited by 119
Self-citationvan Oosten, A. L., Costa, Y., Smith, A. G., & Silva, J. (2012) · Nature Communications · doi:10.1038/ncomms1822 · Cited by 117
Ehlting, C., Lai, W. S., Schaper, F., Brenndörfer, E. D., Matthes, R.-J., Heinrich, P. C., Ludwig, S., Blackshear, P. J., Gaestel, M., Häussinger, D., et al. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.5.2813 · Cited by 111
“E-mail address: Johannes.Bode@t-online.de 3 Abbreviations used in this paper: SOCS, suppressor of cytokine signaling; ARE, adenosine/uridine-rich element; CT, delta cycle threshold; DIG, digoxygenin; Epo, erythropoietin; HA, hemagglutinin; MEF, mouse embryonic fibroblast; MK2, MAPKactivated protein kinase 2; MKK6, MAP…”
BackgroundMethodInfluentialSelf-citationA Stat3-interacting protein (StIP1) regulates cytokine signal transduction
Collum, R. G., Brutsaert, S., Lee, G., & Schindler, C. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.170192197 · Cited by 114
Cholinergic agonists regulate JAK2/STAT3 signaling to suppress endothelial cell activation
Chatterjee, P. K., Al‐Abed, Y., Sherry, B. A., & Metz, C. N. (2009) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00160.2009 · Cited by 112
“Based on previous reports revealing that 1) SHP2 phosphorylation is impaired by SOCS3 expression; 2) SOCS3 requires SHP2 recruitment site in gp130 to exerts its effect on acute phase proteins, and 3) SHP2 appears to exert part of its effect on the JAK/STAT3 pathway through the recruitment of SOCS3 to the receptor comp…”
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ADAM17 Activity and IL-6 Trans-Signaling in Inflammation and Cancer
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Hypothalamic Regulation of Corticotropin-Releasing Factor under Stress and Stress Resilience
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“more often associated with IL-6 signaling than SOCS2 (35, 36).”
InfluentialOberg, H., Wesch, D., Grüssel, S., Rose‐John, S., & Kabelitz, D. (2006) · International Immunology · doi:10.1093/intimm/dxh396 · Cited by 102
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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