Shp-2 Tyrosine Phosphatase Functions as a Negative Regulator of the Interferon-Stimulated Jak/STAT Pathway

You, Min; Yu, De-Hua; Feng, Gen-Sheng

doi:10.1128/mcb.19.3.2416

Cited by 365Protein Tyrosine PhosphatasesCytokine Signaling Pathways and Interactionsinterferon and immune responses

Shp-2 Tyrosine Phosphatase Functions as a Negative Regulator of the Interferon-Stimulated Jak/STAT Pathway

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You, Min, Yu, De-Hua, Feng, Gen-Sheng·1999·Molecular and Cellular Biology

DOI 10.1128/mcb.19.3.2416PMC PMC84034

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Abstract

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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Desensitization to IFNγ in Socs1-/- Ifnγ-/- macrophages at 240 min is probably a result of SHP-2 activity.
“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]
The Discussion identifies SHP-2 as a negative regulator of IFN-induced STAT signaling, including responses to IFN-γ. But the Results study fibroblasts and measure signaling at 5–60 minutes; they do not establish that SHP-2 causes desensitization at 240 minutes in Socs1-/- Ifnγ-/- macrophages. (LLM, conf=0.87)
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Authors: You, M., Yu, D.-H., & Feng, G.-S.
Affiliations: Indiana University Indianapolis (US)
ORCID: You, Min
Feng, Gen-Sheng
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
DOI: 10.1128/mcb.19.3.2416
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
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
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
Health Sciences › Medicine › Oncology › 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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Shp-2 Tyrosine Phosphatase Functions as a Negative Regulator of the Interferon-Stimulated Jak/STAT Pathway

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