ArticleMolecular and cellular biology1999
Shp-2 tyrosine phosphatase functions as a negative regulator of the interferon-stimulated Jak/STAT pathway.
Article in Molecular and cellular biology, 1999. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 119 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
119 citing papers in PubMed, 1 synthesis or guideline pooled it, 359 citations in OpenAlex.
- Pooled it
- JAK-STAT signaling pathway in cancer: from molecular mechanisms to clinical intervention.Molecular cancer · 2026Review
- EGFR activation disrupts immunotherapy response via SHP2-mediated suppression of tumor-intrinsic response to IFN-γ.The Journal of clinical investigation · 2026Article
- SFX-01 is therapeutic against myeloproliferative disorders caused by activating mutations in Shp2.EMBO molecular medicine · 2025Article
- Targeting Shp2 as a therapeutic strategy for neurodegenerative diseases.Translational psychiatry · 2025Review
- Phosphopeptide binding to the N-SH2 domain of tyrosine phosphatase SHP2 correlates with the unzipping of its central β-sheet.Computational and structural biotechnology journal · 2024Article
- Respiratory syncytial virus NS1 inhibits anti-viral Interferon-α-induced JAK/STAT signaling, by limiting the nuclear translocation of STAT1.Frontiers in immunology · 2024Article
- Review
- Article
- Setting sail: Maneuvering SHP2 activity and its effects in cancer.Advances in cancer research · 2023Review
- A comprehensive review of SHP2 and its role in cancer.Cellular oncology (Dordrecht, Netherlands) · 2022Review
- Role of Glycogen Synthase Kinase-3 in Interferon-γ-Mediated Immune Hepatitis.International journal of molecular sciences · 2022Review
- MicroRNA Regulation of T-Cell Exhaustion in Cutaneous T Cell Lymphoma.The Journal of investigative dermatology · 2022Article
- Pathogenic signaling in multiple myeloma.Seminars in oncology · 2022Article
- Impact of circ-0000221 in the Pathogenesis of Hepatocellular via Modulation of miR-661-PTPN11 mRNA Axis.Pharmaceutics · 2022Article
- Therapeutic Targets of KRAS in Colorectal Cancer.Cancers · 2021Review
- Determining folding and binding properties of the C-terminal SH2 domain of SHP2.Protein science : a publication of the Protein Society · 2021Article
- The JAK/STAT signaling pathway: from bench to clinic.Signal transduction and targeted therapy · 2021Review
- SHP2 blockade enhances anti-tumor immunity via tumor cell intrinsic and extrinsic mechanisms.Scientific reports · 2021Article
- UFMylation inhibits the proinflammatory capacity of interferon-γ-activated macrophages.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
59 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
3 authors at 1 institution in 1 country.
Funding
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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