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Cited by 456Cytokine Signaling Pathways and InteractionsProtein Tyrosine PhosphatasesReceptor Mechanisms and Signaling

Suppressor of cytokine signaling-3 preferentially binds to the SHP-2-binding site on the shared cytokine receptor subunit gp130

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Nicholson, Sandra E., De Souza, David, Fabri, Louis J., Corbin, Jason, Willson, Tracy A., Zhang, Jian-Guo, Silva, Anabel, Asimakis, Maria +6 more·2000·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.100135197PMC PMC18633
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Abstract

Suppressor of cytokine signaling-3 (SOCS-3) is one member of a family of intracellular inhibitors of signaling pathways initiated by cytokines that use, among others, the common receptor subunit gp130. The SH2 domain of SOCS-3 has been shown to be essential for this inhibitory activity, and we have used a quantitative binding analysis of SOCS-3 to synthetic phosphopeptides to map the potential sites of interaction of SOCS-3 with different components of the gp130 signaling pathway. The only high-affinity ligand found corresponded to the region of gp130 centered around phosphotyrosine-757 (pY757), previously shown to be a docking site for the tyrosine phosphatase SHP-2. By contrast, phosphopeptides corresponding to other regions within gp130, Janus kinase, or signal transducer and activator of transcription proteins bound to SOCS-3 with weak or undetectable affinity. The significance of pY757 in gp130 as a biologically relevant SOCS-3 docking site was investigated by using transfected 293T fibroblasts. Although SOCS-3 inhibited signaling in cells transfected with a chimeric receptor containing the wild-type gp130 intracellular domain, inhibition was considerably impaired for a receptor carrying a Y→F point mutation at residue 757. Taken together, these data suggest that the mechanism by which SOCS-3 inhibits the gp130 signaling pathway depends on recruitment to the phosphorylated gp130 receptor, and that some of the negative regulatory roles previously attributed to the phosphatase SHP-2 might in fact be caused by the action of SOCS-3.

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  • Nascent SOCS-3 blocks the activation of STAT-3 by binding to the receptor complex via gp130 at tyrosine 759 and/or by binding and inhibiting Jak2 activity.

    “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 [35]

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Authors
Nicholson, S. E., De Souza, D., Fabri, L. J., Corbin, J., Willson, T. A., Zhang, J.-G., Silva, A., Asimakis, M., Farley, A., Nash, A. D., Metcalf, D., Hilton, D. J., Nicola, N. A., & Baca, M.
Affiliations
  • Walter and Eliza Hall Institute of Medical Research (AU)
  • The Walter and Eliza Hall Institute of Medical Research and The Cooperative Research Centre for Cellular Growth Factors, Parkville, Victoria 3050, Australia; and AMRAD Operations, Richmond, Victoria 3121, Australia
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2000-05-30
Volume
97
Issue
12
Pages
6493-6498
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.100135197
PMC
PMC18633
OpenAlex
W2119733834
Cited by
456
References
3
Citations by year
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FWCI
15.95
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Australian Government
  • National Institutes of Health (CA22556)
  • Medical Research Council
  • Australian Research Council
  • National Health and Medical Research Council
  • 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, gp130, SHP2, SH2 domain, phosphopeptide binding, tyrosine phosphorylation, cytokine signaling inhibition, Janus kinase, signal transducer and activator of transcription, receptor tyrosine phosphatase, negative regulation of signaling
MeSH terms
Suppressor of Cytokine Signaling 3 Protein, Amino Acid Sequence, Binding Sites, Membrane Glycoproteins, Molecular Sequence Data, Protein-Tyrosine Kinases, Proteins, Repressor Proteins, Transcription Factors, Signal Transduction, Antigens, CD, Protein Tyrosine Phosphatases, Intracellular Signaling Peptides and Proteins, Cytokine Receptor gp130, Suppressor of Cytokine Signaling Proteins, Janus Kinase 1, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatase, Non-Receptor Type 11, SH2 Domain-Containing Protein Tyrosine Phosphatases

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