Gene interactions and pathways from curated databases and text-mining
Mol Cell Biol 1999, PMID: 10022928

Shp-2 tyrosine phosphatase functions as a negative regulator of the interferon-stimulated Jak/STAT pathway.

You, M; Yu, D H; Feng, G S

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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Text Mining Data

IFN-gamma ⊣ caspase: " Furthermore, IFN-gamma induced a higher level of caspase 1 expression in Shp-2 ( -/- ) cells than in wild-type cells "

Manually curated Databases

  • IRef Hprd Interaction: PTPN11 — IFNGR1 (in vitro)
  • NCI Pathway Database IFN-gamma pathway: IFN-gamma/IFN-gammaR/JAK1/JAK1/JAK2/JAK2 complex (IFNGR1-JAK1-JAK2-IFNG) → IFN-gammaR/JAK1/JAK1/JAK2/JAK2 complex (IFNGR1-JAK1-JAK2) (modification, collaborate)
    Evidence: mutant phenotype, physical interaction, other species
  • NCI Pathway Database IFN-gamma pathway: IFN-gamma/IFN-gammaR/JAK1/JAK1/JAK2/JAK2 complex (IFNGR1-JAK1-JAK2-IFNG) → IFN-gamma (dimer) complex (IFNG) (modification, collaborate)
    Evidence: mutant phenotype, physical interaction, other species
  • NCI Pathway Database IFN-gamma pathway: IFN-gammaR/JAK1/JAK1/JAK2/JAK2 complex (IFNGR1-JAK1-JAK2) → IFN-gamma (dimer) complex (IFNG) (modification, collaborate)
    Evidence: mutant phenotype, physical interaction, other species
  • NCI Pathway Database IFN-gamma pathway: IFN-gammaR/JAK1/JAK1/JAK2/JAK2 complex (IFNGR1-JAK1-JAK2) → SHP2 (PTPN11) (modification, collaborate)
    Evidence: mutant phenotype, physical interaction, other species
  • NCI Pathway Database IFN-gamma pathway: IFN-gamma (dimer) complex (IFNG) → SHP2 (PTPN11) (modification, collaborate)
    Evidence: mutant phenotype, physical interaction, other species
  • NCI Pathway Database IFN-gamma pathway: SHP2 (PTPN11) → STAT1 (dimer)/SHP2 complex (STAT1-PTPN11) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database IFN-gamma pathway: SHP2 (PTPN11) → STAT1 (dimer) complex (STAT1) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database IFN-gamma pathway: STAT1 (dimer)/SHP2 complex (STAT1-PTPN11) → STAT1 (dimer) complex (STAT1) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database SHP2 signaling: SHP2 (PTPN11) → STAT1 (dimer)/SHP2 complex (STAT1-PTPN11) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database SHP2 signaling: SHP2 (PTPN11) → STAT1 (dimer) complex (STAT1) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database SHP2 signaling: STAT1 (dimer)/SHP2 complex (STAT1-PTPN11) → STAT1 (dimer) complex (STAT1) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • Reactome Reaction: IFNA2 → JAK1 (indirect_complex)
  • Reactome Reaction: IFNA2 → TYK2 (indirect_complex)
  • Reactome Reaction: IFNA21 → STAT2 (indirect_complex)
  • Reactome Reaction: IFNB1 → IFNAR1 (indirect_complex)
  • Reactome Reaction: IFNA4 → IFNAR2 (indirect_complex)
  • Reactome Reaction: IFNB1 → JAK1 (indirect_complex)
  • Reactome Reaction: IFNA2 → IFNAR1 (indirect_complex)
  • Reactome Reaction: IFNA5 → PTPN11 (reaction)
  • Reactome Reaction: IFNA1 → IFNAR2 (indirect_complex)
  • Reactome Reaction: IFNA21 → TYK2 (indirect_complex)
  • Reactome Reaction: IFNA1 → STAT1 (indirect_complex)
  • Reactome Reaction: IFNB1 → PTPN11 (reaction)
  • Reactome Reaction: IFNA6 → IFNAR1 (indirect_complex)
  • Reactome Reaction: IFNA17 → JAK1 (indirect_complex)
  • Reactome Reaction: IFNAR1 → PTPN11 (reaction)
  • Reactome Reaction: IFNA2 → PTPN11 (reaction)
  • Reactome Reaction: IFNA5 → STAT1 (indirect_complex)
  • Reactome Reaction: STAT2 → TYK2 (indirect_complex)
  • Reactome Reaction: IFNA5 → TYK2 (indirect_complex)
  • Reactome Reaction: IFNA5 → JAK1 (indirect_complex)
  • Reactome Reaction: IFNA10 → IFNAR1 (indirect_complex)
  • Reactome Reaction: IFNA16 → TYK2 (indirect_complex)
  • Reactome Reaction: IFNA14 → PTPN11 (reaction)
  • Reactome Reaction: IFNA1 → IFNAR1 (indirect_complex)
  • Reactome Reaction: IFNAR2 → STAT1 (indirect_complex)
  • Reactome Reaction: IFNA5 → IFNAR2 (indirect_complex)
  • Reactome Reaction: IFNA8 → TYK2 (indirect_complex)
  • Reactome Reaction: IFNA21 → PTPN11 (reaction)
  • Reactome Reaction: IFNA16 → PTPN11 (reaction)
  • Reactome Reaction: IFNA4 → PTPN11 (reaction)
  • Reactome Reaction: IFNA17 → STAT1 (indirect_complex)
  • Reactome Reaction: IFNA14 → TYK2 (indirect_complex)
  • Reactome Reaction: IFNA4 → STAT2 (indirect_complex)
  • Reactome Reaction: IFNAR1 → JAK1 (indirect_complex)
  • Reactome Reaction: IFNB1 → IFNAR2 (indirect_complex)
  • Reactome Reaction: IFNA17 → PTPN11 (reaction)
  • Reactome Reaction: IFNA8 → IFNAR2 (indirect_complex)
  • Reactome Reaction: IFNA6 → TYK2 (indirect_complex)
  • Reactome Reaction: PTPN11 → STAT2 (reaction)
  • Reactome Reaction: IFNB1 → TYK2 (indirect_complex)
  • Reactome Reaction: STAT1 → STAT2 (indirect_complex)
  • Reactome Reaction: IFNA5 → STAT2 (indirect_complex)
  • Reactome Reaction: JAK1 → TYK2 (indirect_complex)
  • Reactome Reaction: IFNA2 → STAT1 (indirect_complex)
  • Reactome Reaction: IFNA6 → IFNAR2 (indirect_complex)
  • Reactome Reaction: IFNA7 → TYK2 (indirect_complex)
  • Reactome Reaction: JAK1 → STAT2 (indirect_complex)
  • Reactome Reaction: IFNA17 → TYK2 (indirect_complex)
  • Reactome Reaction: IFNA7 → JAK1 (indirect_complex)
  • Reactome Reaction: IFNA7 → IFNAR2 (indirect_complex)
  • Reactome Reaction: IFNA10 → TYK2 (indirect_complex)
  • Reactome Reaction: IFNA10 → JAK1 (indirect_complex)
  • Reactome Reaction: JAK1 → STAT1 (indirect_complex)
  • Reactome Reaction: IFNA4 → JAK1 (indirect_complex)
  • Reactome Reaction: IFNA14 → STAT1 (indirect_complex)
  • Reactome Reaction: IFNA2 → IFNAR2 (indirect_complex)
  • Reactome Reaction: IFNAR1 → IFNAR2 (indirect_complex)
  • Reactome Reaction: PTPN11 → IFNAR2 (reaction)
  • Reactome Reaction: JAK1 → PTPN11 (reaction)
  • Reactome Reaction: STAT2 → STAT1 (indirect_complex)
  • Reactome Reaction: IFNA8 → STAT1 (indirect_complex)
  • Reactome Reaction: IFNA21 → IFNAR1 (indirect_complex)
  • Reactome Reaction: IFNA4 → TYK2 (indirect_complex)
  • Reactome Reaction: IFNA1 → STAT2 (indirect_complex)
  • Reactome Reaction: STAT2 → IFNAR2 (indirect_complex)
  • Reactome Reaction: IFNA17 → IFNAR1 (indirect_complex)
  • Reactome Reaction: IFNB1 → STAT2 (indirect_complex)
  • Reactome Reaction: TYK2 → IFNAR2 (indirect_complex)
  • Reactome Reaction: IFNAR1 → STAT2 (indirect_complex)
  • Reactome Reaction: IFNA1 → JAK1 (indirect_complex)
  • Reactome Reaction: IFNA6 → STAT2 (indirect_complex)
  • Reactome Reaction: IFNA7 → STAT1 (indirect_complex)
  • Reactome Reaction: IFNA7 → PTPN11 (reaction)
  • Reactome Reaction: IFNA14 → STAT2 (indirect_complex)
  • Reactome Reaction: IFNA1 → PTPN11 (reaction)
  • Reactome Reaction: IFNA6 → PTPN11 (reaction)
  • Reactome Reaction: IFNA4 → IFNAR1 (indirect_complex)
  • Reactome Reaction: STAT1 → IFNAR2 (indirect_complex)
  • Reactome Reaction: IFNA10 → IFNAR2 (indirect_complex)
  • Reactome Reaction: IFNA5 → IFNAR1 (indirect_complex)
  • Reactome Reaction: IFNA1 → TYK2 (indirect_complex)
  • Reactome Reaction: IFNA8 → PTPN11 (reaction)
  • Reactome Reaction: IFNA6 → STAT1 (indirect_complex)
  • Reactome Reaction: IFNA8 → STAT2 (indirect_complex)
  • Reactome Reaction: IFNA16 → STAT2 (indirect_complex)
  • Reactome Reaction: IFNA14 → JAK1 (indirect_complex)
  • Reactome Reaction: IFNA16 → IFNAR1 (indirect_complex)
  • Reactome Reaction: IFNA17 → IFNAR2 (indirect_complex)
  • Reactome Reaction: IFNA16 → STAT1 (indirect_complex)
  • Reactome Reaction: IFNA21 → JAK1 (indirect_complex)
  • Reactome Reaction: IFNA21 → STAT1 (indirect_complex)
  • Reactome Reaction: IFNB1 → STAT1 (indirect_complex)
  • Reactome Reaction: IFNA8 → IFNAR1 (indirect_complex)
  • Reactome Reaction: IFNA10 → PTPN11 (reaction)
  • Reactome Reaction: IFNA14 → IFNAR1 (indirect_complex)
  • Reactome Reaction: IFNA7 → IFNAR1 (indirect_complex)
  • Reactome Reaction: IFNA21 → IFNAR2 (indirect_complex)
  • Reactome Reaction: IFNA8 → JAK1 (indirect_complex)
  • Reactome Reaction: IFNA17 → STAT2 (indirect_complex)
  • Reactome Reaction: IFNA14 → IFNAR2 (indirect_complex)
  • Reactome Reaction: IFNA6 → JAK1 (indirect_complex)
  • Reactome Reaction: PTPN11 → TYK2 (reaction)
  • Reactome Reaction: IFNA2 → STAT2 (indirect_complex)
  • Reactome Reaction: IFNA4 → STAT1 (indirect_complex)
  • Reactome Reaction: IFNA16 → IFNAR2 (indirect_complex)
  • Reactome Reaction: PTPN11 → STAT1 (reaction)
  • Reactome Reaction: IFNA7 → STAT2 (indirect_complex)
  • Reactome Reaction: IFNA10 → STAT1 (indirect_complex)
  • Reactome Reaction: IFNA16 → JAK1 (indirect_complex)
  • Reactome Reaction: IFNA10 → STAT2 (indirect_complex)
In total, 123 gene pairs are associated to this article in curated databases