Negative regulation of gp130 signalling mediated through tyrosine-757 is not dependent on the recruitment of SHP2
Open accessAbstract
Cytokines of the interleukin-6 family utilize the shared cytokine receptor gp130 in the formation of active signalling complexes. Tyrosine-757 (Y757) on this receptor is critical for negative regulation of gp130-mediated signalling. Two signalling regulators, suppressor of cytokine signalling 3 (SOCS3) and Src homology 2 domain-containing tyrosine phosphatase-2 (SHP2), are recruited to Y757 following receptor activation; however, the relative contribution made by each of these in down-regulating gp130 signalling is not known. In the present study, we show the design of a mutant gp130 receptor that can recruit SHP2, but not SOCS3. This receptor maintains the critical Y757 residue, but contains mutations in other surrounding residues which are also important for interactions with the Src homology 2 domains of SOCS3 and SHP2. Cells transfected with a chimaeric receptor containing the SHP2-selective gp130 intracellular domain showed an enhanced response to cytokine stimulation, which was similar to that shown by a chimaeric gp130 receptor mutant carrying a Y757F point mutation that failed to recruit either SOCS3 or SHP2. These results demonstrate that the recruitment of SHP2 alone is not sufficient for Y757-dependent negative regulation of gp130 signalling and that this activity must therefore be dependent on SOCS3.
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F759/F757-dependent negative regulation is mainly dependent on the recruitment of SOCS3.
“However, this site is also a recruitment motif for SOCS3, and it was found that the F759/F757-dependent negative regulation is mainly dependent on the recruitment of SOCS3 (116, 117).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [117]
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“However, this site is also a recruitment motif for SOCS3, and it was found that the F759/F757-dependent negative regulation is mainly dependent on the recruitment of SOCS3 (116, 117).”
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“Later studies showed that the same gp130 binding site recruited the JAK inhibitor Suppressor of cytokine signaling 3 (SOCS3), attributing to the latter the antagonism with STAT3, and confounding the role of SHP-2 (113, 114).”
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- Authors
- FAIRLIE, W. D., SOUZA, D. D., NICOLA, N. A., & BACA, M.
- Affiliations
- Walter and Eliza Hall Institute of Medical Research (AU)
- The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia
- Corresponding author
- BACA, Manuel
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2003-06-01
- Volume
- 372
- Issue
- 2
- Pages
- 495-502
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC1223392
- OpenAlex
- W2108033183
- Cited by
- 20
- References
- 0
- Citations by year
- 2020: 1 · 2019: 2 · 2018: 1 · 2016: 1 · 2014: 1 · 2012: 1
- FWCI
- 1.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Australian Government
- Monash University
- National Institutes of Health
- Medical Research Council
- Australian Research Council
- National Health and Medical Research Council
- 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
- gp130, SHP2, SOCS3, interleukin-6 family cytokines, cytokine receptor signalling
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Animals, Cells, Cultured, Fibroblasts, Humans, Ligands, Luciferases, Membrane Glycoproteins, Mutation, Phosphorylation, Plasmids, Precipitin Tests, Promoter Regions, Genetic, Protein Binding, Proteins, Recombinant Fusion Proteins, Repressor Proteins, Transcription Factors, Transfection, Tyrosine, Blotting, Western, Signal Transduction, Antigens, CD, Interleukin-6, Gene Expression, Mutagenesis, Site-Directed, Protein Tyrosine Phosphatases, Receptors, Erythropoietin, src Homology Domains, Intracellular Signaling Peptides and Proteins, Cytokine Receptor gp130, Suppressor of Cytokine Signaling Proteins, Mice, Protein Tyrosine Phosphatase, Non-Receptor Type 11, SH2 Domain-Containing Protein Tyrosine Phosphatases, Protein Phosphatase 2
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