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Shp-2 Tyrosine Phosphatase Functions as a Negative Regulator of the Interferon-Stimulated Jak/STAT Pathway
Open accessAbstract
Shp-2 is an SH2 domain-containing protein tyrosine phosphatase. Although the mechanism remains to be defined, substantial experimental data suggest that Shp-2 is primarily a positive regulator in cell growth and development. We present evidence here that Shp-2, while acting to promote mitogenic signals, also functions as a negative effector in interferon (IFN)-induced growth-inhibitory and apoptotic pathways. Treatment of mouse fibroblast cells lacking a functional Shp-2 with IFN-alpha or IFN-gamma resulted in an augmented suppression of cell viability compared to that of wild-type cells. To dissect the molecular mechanism, we examined IFN-induced activation of signal transducers and activators of transcription (STATs) by electrophoretic mobility shift assay, using a specific DNA probe (hSIE). The amounts of STAT proteins bound to hSIE upon IFN-alpha or IFN-gamma stimulation were significantly increased in Shp-2(-/-) cells. Consistently, tyrosine phosphorylation levels of Stat1 upon IFN-gamma treatment and, to a lesser extent, upon IFN-alpha stimulation were markedly elevated in mutant cells. Furthermore, IFN-gamma induced a higher level of caspase 1 expression in Shp-2(-/-) cells than in wild-type cells. Reintroduction of wild-type Shp-2 protein reversed the hypersensitivity of Shp-2(-/-) fibroblasts to the cytotoxic effect of IFN-alpha and IFN-gamma. Excessive activation of STATs by IFNs was also diminished in mutant cells in which Shp-2 had been reintroduced. Together, these results establish that Shp-2 functions as a negative regulator of the Jak/STAT pathway. We propose that Shp-2 acts to promote cell growth and survival through two mechanisms, i.e., the stimulation of growth factor-initiated mitogenic pathways and the suppression of cytotoxic effect elicited by cytokines, such as IFNs.
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“probably a result of the activity of the phosphatase SHP-2 (36).”
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 [36]
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Cites
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A new protein containing an SH2 domain that inhibits JAK kinases
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The JAK/STAT signaling pathway: from bench to clinic
Hu, X., li, J., Fu, M., Zhao, X., & Wang, W. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00791-1 · Cited by 2,633
Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome
Tartaglia, M., Mehler, E. L., Goldberg, R. B., Zampino, G., Brunner, H. G., Kremer, H., van der Burgt, I., Crosby, A. H., Ion, A., Jeffery, S., et al. (2001) · Nature Genetics · doi:10.1038/ng772 · Cited by 1,736
Metadata
- Authors
- You, M., Yu, D.-H., & Feng, G.-S.
- Affiliations
- Indiana University Indianapolis (US)
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 1999-03
- Volume
- 19
- Issue
- 3
- Pages
- 2416-2424
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC84034
- OpenAlex
- W2114990619
- Cited by
- 364
- References
- 50
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 8 · 2023: 5 · 2022: 7 · 2021: 12 · 2020: 11 · 2019: 10 · 2018: 8 · 2017: 13 · 2016: 13 · 2015: 12 · 2014: 11 · 2013: 18 · 2012: 14
- FWCI
- 7.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- National Institutes of Health
- National Institute of General Medical Sciences (R29GM53660, R29GM053660)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- SHP2, protein tyrosine phosphatase, JAK/STAT signaling, interferon-alpha, interferon-gamma, STAT1 tyrosine phosphorylation, caspase-1, apoptosis, cell growth inhibition, negative regulation, SH2 domain, fibroblasts
- MeSH terms
- Interferon gamma Receptor, Animals, Cell Line, DNA-Binding Proteins, Enzyme Induction, Fibroblasts, Humans, Interferon-gamma, Membrane Proteins, Phenotype, Phosphorylation, Protein-Tyrosine Kinases, Signal Transduction, Trans-Activators, Mutagenesis, Interferon-alpha, Protein Tyrosine Phosphatases, Receptors, Interferon, Caspase 1, Intracellular Signaling Peptides and Proteins, STAT1 Transcription Factor, STAT2 Transcription Factor, Mice, Janus Kinase 1, Receptor, Interferon alpha-beta, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatase, Non-Receptor Type 11, SH2 Domain-Containing Protein Tyrosine Phosphatases
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