Inhibitors of Cytokine Signal Transduction
Open accessAbstract
Cytokines are secreted proteins that regulate diverse biological functions by binding to receptors at the cell surface to activate complex signal transduction pathways including the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. Stringent mechanisms of signal attenuation are essential for ensuring an appropriate, controlled cellular response. Three families of proteins, the SH2-containing phosphatases (SHP), the protein inhibitors of activated STATs (PIAS), and the suppressors of cytokine signaling (SOCS), inhibit specific and distinct aspects of cytokine signal transduction. The analysis of mice lacking genes for members of the SHP and SOCS families has shed much light on the roles of these proteins in vivo. In recent in vitro studies, the protein modifiers ubiquitin and SUMO (small ubiquitin-like modifier) have emerged as key players in the strategies employed by SOCS and PIAS to repress signaling.
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Signaling by IFNγ and IL-6 is fundamentally similar, and activity of SOCS3 is required to sculpt the cellular response to IL-6 and thereby discriminate it from that of IFNγ.
“This indicates that signaling by IFN␥ and IL-6 is fundamentally similar, and that the activity of SOCS3 is required to sculpt the cellular response to IL-6 and thereby discriminate it from that of IFN␥.”
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 [16]
The SOCS section (page not supplied) reports that IL-6 induced IFNγ-associated genes in cells lacking SOCS3 and says SOCS3 plays an important role in sculpting the IL-6 response. It does not establish that IFNγ and IL-6 signaling are fundamentally similar or that SOCS3 is required to distinguish their responses; it says the exact nature of SOCS3’s role remains undetermined. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPhosphorylated 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 [16]
The Fig. 1 caption (Conclusions; page unavailable) says phosphorylated STATs dimerize, enter the nucleus, and induce transcription of cytokine-regulated genes. The SOCS section suggests STAT3-mediated induction of SOCS3, and the PIAS section describes STAT association with DNA. Our copy does not specifically say that STATs bind promoter sequences or activate transcription of SOCS1. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIL-6 signaling in the absence of SOCS3 resulted in prolonged phosphorylation of STAT1 and a qualitative shift in the transcriptional response of IL-6 toward that typical of IFNγ.
“Surprisingly, IL-6 signaling in the absence of SOCS3 resulted in the prolonged phosphorylation of STAT1 and a qualitative shift in the transcriptional response of IL-6 toward that typical of IFN␥ (16,24,25).”
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 [16]
Despite the physiologically distinct functions of IFNγ and IL-6, the signaling mechanisms by which they elicit cellular responses are similar, and in the case of IL-6 are distinguished at least in part through the activity of SOCS3.
“Despite the physiologically distinct functions of IFN␥ and IL-6, the signaling mechanisms by which they elicit their cellular responses are similar, and in the case of IL-6 are distinguished at least in part through the activity of SOCS3 (16,24,25).”
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 [16]
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Cites
Specific Inhibition of Stat3 Signal Transduction by PIAS3
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Wormald, S., Zhang, J.-G., Krebs, D. L., Mielke, L. A., Silver, J., Alexander, W. S., Speed, T. P., Nicola, N. A., & Hilton, D. J. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m509595200 · Cited by 123 · see citing works
Self-citationRegis, G., Icardi, L., Conti, L., Chiarle, R., Piva, R., Giovarelli, M., Poli, V, & Novelli, F. (2009) · Leukemia · doi:10.1038/leu.2009.139 · Cited by 47 · see citing works
- Authors
- Wormald, S., & Hilton, D. J.
- Affiliations
- Walter and Eliza Hall Institute of Medical Research (AU)
- Corresponding author
- Wormald, Samuel
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-01
- Volume
- 279
- Issue
- 2
- Pages
- 821-824
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2014420892
- Cited by
- 440
- References
- 3
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 5 · 2023: 9 · 2022: 10 · 2021: 14 · 2020: 9 · 2019: 8 · 2018: 11 · 2017: 8 · 2016: 21 · 2015: 10 · 2014: 26 · 2013: 23 · 2012: 18
- FWCI
- 4.78
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (CA22556)
- Medical Research Council
- National Health and Medical Research Council (257500)
- National Cancer Institute (CA22556)
- 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 › Cancer Research › NF-κB Signaling Pathways
- Keywords
- cytokine signaling, JAK/STAT signaling, PIAS, suppressor of cytokine signaling, signal attenuation, ubiquitination, SUMOylation, knockout mice, cytokine receptors
- MeSH terms
- Animals, DNA-Binding Proteins, Fungal Proteins, Humans, Models, Biological, Protein-Tyrosine Kinases, Signal Transduction, Trans-Activators, Cytokines, SUMO-1 Protein
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