Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
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Drug
Enzyme
Compound
Query: EC:4.2.3.23 (
GAS
)
957
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
SHP-1
(also known as PTP1C, SHPTP-1, SHP, and HCP) is an SH2 domain-containing protein-tyrosine phosphatase. We have stably overexpressed the native form and a catalytically inactive cysteine to serine mutant of the enzyme,
SHP-1
-(Cys --> Ser), in human cervical carcinoma HeLa cells. Following stimulation of the cells with epidermal growth factor (EGF) and interferon-gamma (INF-gamma), signal transducers and activators of transcription (STAT) activity was analyzed by using two 32P-labeled DNA probes, namely hSIE which is derived from a high affinity mutant form of the serum-inducible element in the c-fos promotor and
GAS
which resembles the INF-gamma activation site. EGF induced hSIE binding activity only, and the activity was suppressed by approximately 70% when the inactive mutant form of
SHP-1
was expressed but was essentially unaffected by expression of the native enzyme. INF-gamma treatment resulted in appearance of both hSIE and
GAS
binding activities. While expression of the inactive mutant reduced the activities by 30-50%, the native enzyme caused a 20-30% increase. Consistent with effects on STAT activation, altered
SHP-1
expression also affected EGF-induced activation of the mitogen-activated protein kinase pathway; expression of
SHP-1
-(Cys --> Ser) inhibited activity of MEK by approximately 25%, whereas expression of
SHP-1
resulted in a approximately 25% increase. Further studies revealed that overexpression of
SHP-1
caused decreased tyrosine phosphorylation of the EGF receptor and that EGF induced phosphorylation and recruitment of
SHP-1
. Together, the data suggest that
SHP-1
is positively involved in EGF- and INF-gamma-induced STAT activation in non-hematopoietic HeLa cells and that, in the EGF signaling system,
SHP-1
functions at least partly by modulating tyrosine phosphorylation of EGF receptor.
...
PMID:Positive effects of SH2 domain-containing tyrosine phosphatase SHP-1 on epidermal growth factor- and interferon-gamma-stimulated activation of STAT transcription factors in HeLa cells. 928 52
Expression of
SHP-1
phosphatase, a key negative regulator of cell signaling, is lost in T cell lymphomas and other malignancies due to DNA methylation of the
SHP-1
promoter by a currently undefined mechanism. We demonstrate that malignant T cells express DNA methyltransferase (DNMT) 1 and that constantly activated signal transducer and activator of transcription (STAT) 3 is capable of binding in vitro to DNA oligonucleotides corresponding to four STAT3 SIE/
GAS
binding sites identified in the
SHP-1
promoter. STAT3, DNMT1, and histone deacetylase 1 form complexes and bind to the
SHP-1
promoter in vivo. Treatment with pharmacologic grade DNMT1 anti-sense oligonucleotides and STAT3 small-interfering RNA induces in the malignant T cells DNA demethylation and expression of
SHP-1
gene. These data indicate that STAT3 may, in part, transform cells by inducing epigenetic silencing of
SHP-1
in cooperation with DNMT1 and, apparently, histone deacetylase 1. Reversal of such gene silencing represents an attractive aim for novel anticancer therapies.
...
PMID:STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes. 1587 Jan 98
