The cytoplasmic tyrosine motifs in full-length glycoprotein 130 have different roles in IL-6 signal transduction
Open accessAbstract
The function of the signal-transducing receptor subunit glycoprotein 130 (gp130) in the IL-6-receptor complex has previously been studied using carboxyl-terminal deletion mutants or a truncated molecule of ∼60 membrane-proximal amino acids (containing box 1 and box 2) linked to the individual gp130 tyrosine motifs. However, the redundancy of the tyrosine motifs within the cytoplasmic part of gp130 has been neglected. Here we describe the analysis of the function of the individual cytoplasmic tyrosine residues of gp130 in the context of the full-length receptor protein in IL-6 signaling as measured by STAT activation, acute phase protein induction, and stimulation of proliferation. Add-back receptor mutants containing only one cytoplasmic tyrosine have been generated and tested for their efficiency in IL-6 signal transduction. Our studies revealed that tyrosine motifs which have been described to recruit STAT proteins are not equivalent with respect to their potential to activate STAT factors and acute phase protein gene promoters: the two distal tyrosines, Tyr905 and Tyr915, of gp130 were more potent than Tyr767 and Tyr814. Surprisingly, Tyr905 and Tyr915 mediate acute phase protein gene promoter activation stronger than the wild-type receptor containing all six cytoplasmic tyrosine residues. In contrast, Ba/F3 cells stably transfected with add-back receptors containing Tyr767 or Tyr905 were more sensitive to IL-6-induced proliferation than cells expressing the other add-back receptor mutants. Thus, the tyrosine residues in the cytoplasmic part of gp130 were found to contribute differentially to IL-6 signal transduction in the full- length gp130 protein.
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Canonical STAT3 signaling is regulated by several feedback-inhibitory loops.
“Canonical STAT3 signaling is regulated by several feedback-inhibitory loops (Schmitz et al., 2000).”
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 Schmitz et al., 2000
The Discussion (page unavailable) says that SHP2 binds gp130 Tyr 759 and negatively regulates STAT activation; it also reports that MAPK activation reduces STAT phosphorylation. This supports inhibitory regulation in the IL-6/gp130 pathway, but the paper does not establish several feedback-inhibitory loops governing canonical STAT3 signaling generally. (LLM, conf=0.82)
Experimental — accuracy not yet measuredSHP-2 is recruited to the pYSTV motif of gp130 and phosphorylated on tyrosine residues by JAKs, which increases its tyrosine phosphatase activity for STAT3 and reduces pY-STAT3 levels.
“The phosphatase tyrosine–protein phosphatase nonreceptor type 11, also known as protein–tyrosine phosphatase 1D or Src homology protein tyrosine phosphatase (SHP)-2, is recruited to the pYSTV motif of gp130 and phosphorylated on tyrosine residues by JAKs, which increases its tyrosine phosphatase activity for STAT3, which reduces pY-STAT3 levels (Schmitz et al., 2000).”
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 Schmitz et al., 2000
The Discussion (page unavailable) says SHP2 binds gp130 Tyr759, is phosphorylated after IL-6 stimulation, and negatively regulates STAT activation. It does not establish that JAKs directly phosphorylate SHP2 or that phosphorylation increases SHP2’s phosphatase activity toward STAT3. Instead, it discusses MAPK pathway activation as a possible route to reduced STAT phosphorylation. (LLM, conf=0.87)
Experimental — accuracy not yet measured
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Cites
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“(gp130)/Janus kinase (Jak)/STAT pathway (5, 6).”
BackgroundSelf-citationSCHAPER, F., GENDO, C., ECK, M., SCHMITZ, J., GRIMM, C., ANHUF, D., KERR, I. M., & HEINRICH, P. C. (1998) · Biochemical Journal · doi:10.1042/bj3350557 · Cited by 178 · see citing works
Self-citationKim, H., Hawley, T. S., Hawley, R. G., & Baumann, H. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.3.1525 · Cited by 119 · see citing works
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Principles of interleukin (IL)-6-type cytokine signalling and its regulation
HEINRICH, P. C., BEHRMANN, I., HAAN, S., HERMANNS, H. M., MÜLLER-NEWEN, G., & SCHAPER, F. (2003) · Biochemical Journal · doi:10.1042/bj20030407 · Cited by 3,272 · see citing works
Self-citationBharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
“for STAT3, which reduces pY-STAT3 levels (Schmitz et al., 2000).”
BackgroundInfluentialReeh, H., Rudolph, N., Billing, U., Christen, H., Streif, S., Bullinger, E., Schliemann-Bullinger, M., Findeisen, R., Schaper, F., Huber, H. J., et al. (2019) · Cell Communication and Signaling · doi:10.1186/s12964-019-0356-0 · Cited by 180 · see citing works
Self-citationInterleukin-6 signalling: More than Jaks and STATs
Eulenfeld, R., Dittrich, A., Khouri, C., Müller, P. J., Mütze, B., Wolf, A., & Schaper, F. (2012) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2011.09.010 · Cited by 171 · see citing works
Self-citationIL-6-STAT3 signaling and premature senescence
Kojima, H., Inoue, T., Kunimoto, H., & Nakajima, K. (2013) · JAK-STAT · doi:10.4161/jkst.25763 · Cited by 170 · see citing works
- Authors
- Schmitz, J., Dahmen, H., Grimm, C., Gendo, C., Müller-Newen, G., Heinrich, P. C., & Schaper, F.
- Affiliations
- RWTH Aachen University (DE)
- Institut für Biochemie Rheinisch-Westfälische Technische Hochschule \E (RWTH) , Aachen ,
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2000-01
- Volume
- 164
- Issue
- 2
- Pages
- 848-854
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1571617103
- Cited by
- 92
- References
- 3
- Citations by year
- 2026: 2 · 2024: 2 · 2022: 3 · 2021: 2 · 2020: 3 · 2019: 4 · 2018: 1 · 2017: 1 · 2016: 2 · 2015: 2 · 2014: 4 · 2013: 1 · 2012: 7
- FWCI
- 3.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- gp130, IL-6 signaling, STAT activation, receptor tyrosine phosphorylation, cytokine receptor signaling
- MeSH terms
- Cell Division, Cell Membrane, Cytoplasm, DNA-Binding Proteins, Gene Expression Regulation, Genetic Vectors, Humans, Kinetics, Membrane Glycoproteins, Peptide Fragments, Phosphorylation, Recombinant Fusion Proteins, Tyrosine, Signal Transduction, Trans-Activators, Antigens, CD, Interleukin-6, Mutagenesis, Site-Directed, Genes, Reporter, Amino Acid Motifs, STAT3 Transcription Factor, Cytokine Receptor gp130
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