Mutational analyses of the SOCS proteins suggest a dual domain requirement but distinct mechanisms for inhibition of LIF and IL‐6 signal transduction
Open accessAbstract
SOCS-1 (suppressor of cytokine signaling-1) is a representative of a family of negative regulators of cytokine signaling (SOCS-1 to SOCS-7 and CIS) characterized by a highly conserved C-terminal SOCS box preceded by an SH2 domain. This study comprehensively examined the ability of several SOCS family members to negatively regulate the gp130 signaling pathway. SOCS-1 and SOCS-3 inhibited both interleukin-6 (IL-6)- and leukemia inhibitory factor (LIF)-induced macrophage differentiation of murine monocytic leukemic M1 cells and LIF induction of a Stat3-responsive reporter construct in 293T fibroblasts. Deletion of amino acids 51-78 in the N-terminal region of SOCS-1 prevented inhibition of LIF signaling. The SOCS-1 and SOCS-3 N-terminal regions were functionally interchangeable, but this did not extend to other SOCS family members. Mutation of SH2 domains abrogated the ability of both SOCS-1 and SOCS-3 to inhibit LIF signal transduction. Unlike SOCS-1, SOCS-3 was unable to inhibit JAK kinase activity in vitro, suggesting that SOCS-1 and SOCS-3 act on the JAK-STAT pathway in different ways. Thus, although inhibition of signaling by SOCS-1 and SOCS-3 requires both the SH2 and N-terminal domains, their mechanisms of action appear to be biochemically different.
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SOCS1 and SOCS3 proteins can both inhibit JAK phosphorylation of STAT, creating a negative feedback loop that attenuates cytokine signal transduction.
“SOCS1 and SOCS3 proteins can both inhibit JAK phosphorylation of STAT, thus creating a negative feedback loop that attenuates cytokine signal transduction, although the mechanisms by which they act appear to differ.”
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 [20]
The section on STAT3 tyrosine phosphorylation reports that both SOCS-1 and SOCS-3 inhibit LIF-induced STAT3 phosphorylation in M1 cells. The Introduction describes a negative feedback loop for SOCS-1 only, not SOCS-3; the discussion (p. 382) also says SOCS-3 did not directly inhibit JAK kinase activity in the assay. Thus the shared reduction in STAT3 phosphorylation is supported, but a negative feedback loop for both proteins—and direct JAK inhibition by both—is not established. (LLM, conf=0.84)
Experimental — accuracy not yet measuredSOCS3 inhibits signaling by binding to phosphorylated tyrosine sites on the cytoplasmic domain of the receptor.
“Whereas SOCS1 functions by binding directly to JAK proteins, SOCS3 inhibits signaling by binding to phosphorylated tyrosine sites on the cytoplasmic domain of the receptor (19,20).”
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 [20]
The discussion (p. 382) says SOCS-3 inhibits IL-6 and LIF signaling, but presents binding to receptor phosphotyrosine residues as one possible mechanism, not an established one. The citing sentence states that mechanism as fact. (LLM, conf=0.90)
Experimental — accuracy not yet measuredSOCS1 functions by binding directly to JAK proteins.
“Whereas SOCS1 functions by binding directly to JAK proteins, SOCS3 inhibits signaling by binding to phosphorylated tyrosine sites on the cytoplasmic domain of the receptor (19,20).”
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 [20]
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Research works printed but not linked: 4
- Chen,M. et al. (1997) The amino terminus of JAK3 is necessary and sufficient for binding to the common γ chain and confers the ability to transmit interleukin 2-mediated signals. Proc. Natl Acad. Sci. USA, 94, 6910-6915.
- Hilton,D.J. et al. (1998) Twenty proteins containing a C-terminal SOCS box form five structural classes. Proc. Natl Acad. Sci. USA, 95, 114-119.
- MacGregor,G.R., Nolan,G.P., Fiering,S., Roederer,M. and Herzenberg,L.A. (1991) Use of E.coli lacZ (β-galactosidase) as a reporter gene. In Murray,E.J. (ed.), Methods in Molecular Biology: Gene Transfer and Expression Protocols. The Humana Press Inc., Clifton, NJ, pp. 217-235.
- Metcalf,D. (1984) Hemopoietic Colony-stimulating Factors. Elsevier, Amsterdam.
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- Authors
- Nicholson, S. E., Willson, T. A., Farley, A., Starr, R., Zhang, J., Baca, M., Alexander, W. S., Metcalf, D., Hilton, D. J., & Nicola, N. A.
- Affiliations
- Walter and Eliza Hall Institute of Medical Research (AU)
- Corresponding author
- Nicholson, Sandra E.
- Venue
- The EMBO Journal
- Published
- 1999-01-15
- Volume
- 18
- Issue
- 2
- Pages
- 375-385
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1171132
- OpenAlex
- W1967486091
- Cited by
- 407
- References
- 0
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 4 · 2023: 6 · 2022: 3 · 2021: 3 · 2020: 2 · 2019: 6 · 2018: 5 · 2017: 9 · 2016: 4 · 2015: 7 · 2014: 8 · 2013: 12 · 2012: 22
- FWCI
- 16.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Australian Government
- National Institutes of Health
- Medical Research Council
- National Health and Medical Research Council
- 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 › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- SOCS1, SOCS3, suppressor of cytokine signaling, SOCS box, SH2 domain, LIF signaling, IL-6 signaling, gp130, JAK/STAT signaling, macrophage differentiation, STAT3, negative regulation of cytokine signaling, N-terminal domain
- MeSH terms
- Suppressor of Cytokine Signaling 1 Protein, Suppressor of Cytokine Signaling 3 Protein, Animals, Carrier Proteins, Cell Differentiation, Cell Line, DNA-Binding Proteins, Growth Inhibitors, Lymphokines, Mutation, Phosphorylation, Proteins, Repressor Proteins, Transcription Factors, Transfection, Tyrosine, Signal Transduction, Trans-Activators, Interleukin-6, Cytokines, Calcium-Calmodulin-Dependent Protein Kinases, src Homology Domains, Mitogen-Activated Protein Kinases, JNK Mitogen-Activated Protein Kinases, Suppressor of Cytokine Signaling Proteins, Mice, Leukemia Inhibitory Factor
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