Mol Cell Biol 1999,
PMID: 10022928
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