SOCS3 binds specific receptor–JAK complexes to control cytokine signaling by direct kinase inhibition
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The inhibitory protein SOCS3 plays a key part in the immune and hematopoietic systems by regulating signaling induced by specific cytokines. SOCS3 functions by inhibiting the catalytic activity of Janus kinases (JAKs) that initiate signaling within the cell. We determined the crystal structure of a ternary complex between mouse SOCS3, JAK2 (kinase domain) and a fragment of the interleukin-6 receptor β-chain. The structure shows that SOCS3 binds JAK2 and receptor simultaneously, using two opposing surfaces. While the phosphotyrosine-binding groove on the SOCS3 SH2 domain is occupied by receptor, JAK2 binds in a phosphoindependent manner to a noncanonical surface. The kinase-inhibitory region of SOCS3 occludes the substrate-binding groove on JAK2, and biochemical studies show that it blocks substrate association. These studies reveal that SOCS3 targets specific JAK-cytokine receptor pairs and explains the mechanism and specificity of SOCS action.
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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 Kershaw et al., 2013
The Results section identifies the gp130 pYSTV-containing binding site and shows the gp130 fragment in SOCS3’s SH2-domain binding groove. The Introduction describes direct JAK inhibition by SOCS3’s kinase-inhibitory region, supporting the proposed restraint on JAK/STAT signaling. Our copy does not establish that activated STAT3 and STAT1 rapidly induce SOCS3 mRNA, or specifically demonstrate reduced further STAT3 activation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAvailable peptide co-structures for SOCS3 show an expanded hydrophobic pocket that may be more amenable to targeting.
“the available peptide co-structures for SOCS3 (refs 107,108,109 ) show an expanded hydrophobic pocket that may be more amenable to targeting”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [108]
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- Authors
- Kershaw, N. J., Murphy, J. M., Liau, N. P. D., Varghese, L. N., Laktyushin, A., Whitlock, E. L., Lucet, I. S., Nicola, N. A., & Babon, J. J.
- Affiliations
- Walter and Eliza Hall Institute of Medical Research (AU)
- The University of Melbourne (AU)
- Monash University (AU)
- Corresponding author
- Nicola, Nicos A
- Babon, Jeffrey J
- ORCID
- Venue
- Nature Structural & Molecular Biology
- Published
- 2013-03-03
- Volume
- 20
- Issue
- 4
- Pages
- 469-476
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC3618588
- OpenAlex
- W2043162503
- Cited by
- 301
- References
- 55
- Citations by year
- 2026: 29 · 2025: 14 · 2024: 27 · 2023: 18 · 2022: 24 · 2021: 26 · 2020: 18 · 2019: 21 · 2018: 25 · 2017: 29 · 2016: 14 · 2015: 21 · 2014: 25 · 2013: 10
- FWCI
- 12.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Funders
- National Cancer Institute (R37CA022556, CA22556, R01CA022556)
- 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, JAK2, IL-6 receptor, cytokine signaling, Janus kinase inhibition, crystal structure, ternary complex, SH2 domain, substrate-binding groove, hematopoiesis
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Amino Acid Sequence, Binding Sites, Humans, Models, Molecular, Molecular Sequence Data, Protein Binding, Signal Transduction, Cytokines, Sequence Homology, Amino Acid, Suppressor of Cytokine Signaling Proteins, Janus Kinase 2
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