Model-driven experimental analysis of the function of SHP-2 in IL-6-induced Jak/STAT signaling
Abstract
Misregulated interleukin-6 (IL-6)-induced Jak/STAT signaling contributes to many diseases. Under non-pathological conditions Jak/STAT signaling is tightly regulated by a complex network of regulators. One of these regulators is the protein tyrosine phosphatase SH2-containing phosphatase 2 (SHP2). Although SHP2 is known to be a negative regulator of IL-6-induced Jak/STAT signaling, its exact molecular function is not entirely understood. To elucidate the function of SHP2 in IL-6 signaling we followed a systems biology approach, in which modeling, stepwise model refinement, and experimental analysis are closely linked. We come up with an identifiable model of early Jak/STAT signaling that describes the data and proves to be predictive. The model-based analysis implies that (1) the stepwise association of IL-6 with gp80 and gp130 and (2) STAT3 dimerization at the receptor are essential for the dynamics of early pathway activation, and (3) phosphorylation of SHP2 is nonlinear. Furthermore, the modeling results indicate that SHP2 does not act as a feedback inhibitor in an early phase of IL-6-induced Jak/STAT signaling. However, experimental data reveal that SHP2 exhibits a basal repressory function.
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SHP2 is a repressor of basal cytokine-independent STAT3 phosphorylation.
“Additionally, SHP2 is a repressor of basal cytokine-independent STAT3 phosphorylation [12, 13].”
From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [12]
In cell populations, the mean amount of SHP2 correlates negatively with the strength of STAT3 activation.
“Interestingly, in cell populations the mean amount of SHP2 correlates negatively with the strength of STAT3 activation [12].”
From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [12]
Knock down of SHP2 increases basal STAT3 activation.
“Knock down of SHP2 increases basal STAT3 activation [12].”
From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [12]
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Self-citation
- Authors
- Dittrich, A., Quaiser, T., Khouri, C., Görtz, D., Mönnigmann, M., & Schaper, F.
- Affiliations
- RWTH Aachen University (DE)
- Ruhr University Bochum (DE)
- Corresponding author
- Mönnigmann, Martin
- Schaper, Fred
- Venue
- Molecular BioSystems
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-06-19
- Volume
- 8
- Issue
- 8
- Pages
- 2119-2134
- ISSN
- 1742-2051 (ISSN-L)
- 1742-206X
- OpenAlex
- W1967804453
- Cited by
- 32
- References
- 0
- Citations by year
- 2026: 2 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 6 · 2020: 1 · 2019: 5 · 2018: 3 · 2017: 1 · 2016: 2 · 2015: 3 · 2014: 2 · 2013: 3
- FWCI
- 1.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular BioSystems (publishedVersion)
- PubMed (publishedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- 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 › Gene Regulatory Network Analysis
- Keywords
- SHP2, IL-6 signaling, JAK/STAT signaling, STAT3 dimerization, gp130, gp80, protein tyrosine phosphatase, product inhibition, signaling pathway modeling
- MeSH terms
- Cell Line, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Humans, Phosphorylation, Blotting, Western, Signal Transduction, Interleukin-6, Receptors, Interleukin-6, STAT Transcription Factors, STAT3 Transcription Factor, Cytokine Receptor gp130, Janus Kinases, Protein Tyrosine Phosphatase, Non-Receptor Type 11
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