Suppression of Cytokine Signaling by SOCS3: Characterization of the Mode of Inhibition and the Basis of Its Specificity
Open accessAbstract
Janus kinases (JAKs) are key effectors in controlling immune responses and maintaining hematopoiesis. SOCS3 (suppressor of cytokine signaling-3) is a major regulator of JAK signaling and here we investigate the molecular basis of its mechanism of action. We found that SOCS3 bound and directly inhibited the catalytic domains of JAK1, JAK2, and TYK2 but not JAK3 via an evolutionarily conserved motif unique to JAKs. Mutation of this motif led to the formation of an active kinase that could not be inhibited by SOCS3. Surprisingly, we found that SOCS3 simultaneously bound JAK and the cytokine receptor to which it is attached, revealing how specificity is generated in SOCS action and explaining why SOCS3 inhibits only a subset of cytokines. Importantly, SOCS3 inhibited JAKs via a noncompetitive mechanism, making it a template for the development of specific and effective inhibitors to treat JAK-based immune and proliferative diseases.
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SOCS3 mRNA is rapidly induced by activated STAT3 and STAT1; SOCS3 protein interacts with the pYSTV motif of gp130 through its SH2 domain and inhibits JAK activity through its kinase-inhibitory region, restricting further STAT3 activation.
“Another inhibitory loop is mediated by suppressor of cytokine signaling (SOCS)3 (Yoshimura et al., 2007). SOCS3 mRNA is rapidly induced by activated STAT3 and STAT1, and SOCS3 protein interacts with pYSTV motif of gp130 through its SH2 domain and inhibits JAK activity through its kinase-inhibitory region, thereby restricting further STAT3 activation (Babon et al., 2012; Kershaw et al., 2013).”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Babon et al., 2012
The Results describe an SH2-domain ligand containing the gp130 pYSTV sequence, show that the kinase-inhibitory region is required for JAK inhibition, and demonstrate that SOCS3 inhibits JAK2 substrate phosphorylation (page not available in our copy). The Introduction describes SOCS expression as induced by JAK–STAT activation, but does not establish rapid SOCS3 mRNA induction specifically by activated STAT3 and STAT1. (LLM, conf=0.87)
Experimental — accuracy not yet measuredSOCS3 acts as a negative feedback inhibitor of cytokine signalling by inhibition of JAK1, JAK2, and Tyk2.
“SOCS3 acts as a negative feedback inhibitor of cytokine signalling by inhibition of JAK1, JAK2, and Tyk2.”
From Sepsis induces interleukin 6, gp130/JAK2/STAT3, and muscle wasting (2022) · cites this paper as [19]
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Cites
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“, IL-6) will be effectively inhibited by SOCS3 (Wormald et al., 2006), whereas cytokines that signal through receptors that lack such a site (e.”
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“SOCS3 inhibits the signaling pathway by increasing degradation of the receptor complex as well as inhibiting phosphorylation of STAT3 by the fully activated receptor complex (Starr et al., 1997; Babon et al., 2012; Kershaw et al., 2013).”
Background
- Authors
- Babon, J. J., Kershaw, N. J., Murphy, J. M., Varghese, L. N., Laktyushin, A., Young, S. N., Lucet, I. S., Norton, R. S., & Nicola, N. A.
- Affiliations
- The University of Melbourne (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Monash University (AU)
- Corresponding author
- Babon, Jeffrey J.
- Nicola, Nicos A.
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2012-02
- Volume
- 36
- Issue
- 2
- Pages
- 239-250
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC3299805
- OpenAlex
- W1972685619
- Cited by
- 279
- References
- 4
- Citations by year
- 2026: 16 · 2025: 11 · 2024: 14 · 2023: 11 · 2022: 14 · 2021: 25 · 2020: 13 · 2019: 19 · 2018: 22 · 2017: 19 · 2016: 27 · 2015: 22 · 2014: 22 · 2013: 29 · 2012: 15
- FWCI
- 13.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 532 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (CA22556)
- National Health and Medical Research Council (461219, 487922, 1011804, 361646)
- Australian Research Council
- State Government of Victoria
- 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
- SOCS3, suppressor of cytokine signaling, Janus kinase, JAK1, JAK2, TYK2, JAK3, cytokine signaling, kinase inhibition, non-competitive inhibition, cytokine receptor binding, inhibition mechanism, JAK inhibitors
- MeSH terms
- Suppressor of Cytokine Signaling 1 Protein, Suppressor of Cytokine Signaling 3 Protein, Amino Acid Sequence, Animals, Binding Sites, Humans, Models, Molecular, Molecular Sequence Data, Recombinant Fusion Proteins, Signal Transduction, Interleukin-6, Cytokines, Mutagenesis, Site-Directed, Conserved Sequence, Sequence Homology, Amino Acid, Protein Structure, Tertiary, Nuclear Magnetic Resonance, Biomolecular, Amino Acid Motifs, Suppressor of Cytokine Signaling Proteins, Janus Kinases
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