A family of cytokine-inducible inhibitors of signalling
Abstract
Cytokines are secreted proteins that regulate important cellular responses such as proliferation and differentiation. Key events in cytokine signal transduction are well defined: cytokines induce receptor aggregation, leading to activation of members of the JAK family of cytoplasmic tyrosine kinases. In turn, members of the STAT family of transcription factors are phosphorylated, dimerize and increase the transcription of genes with STAT recognition sites in their promoters. Less is known of how cytokine signal transduction is switched off. We have cloned a complementary DNA encoding a protein SOCS-1, containing an SH2-domain, by its ability to inhibit the macrophage differentiation of M1 cells in response to interleukin-6. Expression of SOCS-1 inhibited both interleukin-6-induced receptor phosphorylation and STAT activation. We have also cloned two relatives of SOCS-1, named SOCS-2 and SOCS-3, which together with the previously described CIS form a new family of proteins. Transcription of all four SOCS genes is increased rapidly in response to interleukin-6, in vitro and in vivo, suggesting they may act in a classic negative feedback loop to regulate cytokine signal transduction.
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In addition to SOCS-3, injection of IL-6 induces CIS, SOCS-1, and SOCS-2 mRNA in the liver.
“In addition to SOCS-3, injection of IL-6 induces CIS, SOCS-1, and SOCS-2 mRNA (Figure 6) in the liver, an observation reported by other laboratories (20).”
From Expression of suppressors of cytokine signaling during liver regeneration (2001) · cites this paper as [20]
Phosphorylated STATs dimerize and are transported to the nucleus, where they bind promoter sequences and activate transcription of genes including SOCS1 and SOCS3.
“The phosphorylated STATs (P-STATs) then dimerize and are transported to the nucleus, where they bind to promoter sequences, and activate the transcription of a suite of genes, among which are those encoding the suppressor of cytokine signaling-1 (SOCS1) and SOCS3 proteins (15,16).”
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 [15]
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 [4]
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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].”
BackgroundCytokine signaling: Inhibitors keep cytokines in check
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The impact of <i>SOCS1</i> mutations in diffuse large B‐cell lymphoma
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- Authors
- Starr, R., Willson, T. A., Viney, E. M., Murray, L. J. L., Rayner, J. R., Jenkins, B. J., Gonda, T. J., Alexander, W. S., Metcalf, D., Nicola, N. A., & Hilton, D. J.
- Affiliations
- Walter and Eliza Hall Institute of Medical Research (AU)
- Hanson Institute (AU)
- Corresponding author
- Hilton, Douglas J.
- ORCID
- Venue
- Nature
- Published
- 1997-06-26
- Volume
- 387
- Issue
- 6636
- Pages
- 917-921
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1668039320
- Cited by
- 2,066
- References
- 1
- Citations by year
- 2026: 23 · 2025: 29 · 2024: 24 · 2023: 34 · 2022: 36 · 2021: 50 · 2020: 42 · 2019: 49 · 2018: 50 · 2017: 51 · 2016: 69 · 2015: 54 · 2014: 64 · 2013: 72 · 2012: 75
- FWCI
- 52.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Funders
- National Science Foundation
- National Institutes of Health
- 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
- SOCS1, SOCS2, SOCS3, CIS, cytokine signaling, negative feedback regulation, interleukin-6, JAK/STAT signaling, STAT phosphorylation, SH2 domain, macrophage differentiation, transcriptional regulation
- MeSH terms
- Suppressor of Cytokine Signaling 1 Protein, Suppressor of Cytokine Signaling 3 Protein, Interleukin-6 Inhibitors, Amino Acid Sequence, Animals, Carrier Proteins, Cell Differentiation, Cloning, Molecular, DNA-Binding Proteins, Enzyme Inhibitors, Feedback, Gene Expression Regulation, Humans, Macrophages, Membrane Glycoproteins, Mice, Inbred C57BL, Molecular Sequence Data, Protein-Tyrosine Kinases, Proteins, Proto-Oncogene Proteins, Repressor Proteins, Transcription Factors, Tumor Cells, Cultured, Signal Transduction, Trans-Activators, Antigens, CD, Interleukin-6, Cytokines, Conserved Sequence, Sequence Homology, Amino Acid, Immediate-Early Proteins, DNA, Complementary, src Homology Domains, Intracellular Signaling Peptides and Proteins, STAT3 Transcription Factor, Cytokine Receptor gp130, Suppressor of Cytokine Signaling Proteins, Mice, Janus Kinase 2
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