Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PTP1C, an SH2 domain-containing protein-tyrosine phosphatase, is predominantly expressed in hematopoietic cells, in which it negatively regulates cellular signaling. However, this enzyme is also expressed in many non-hematopoietic cells. We demonstrate here that in non-hematopoietic 293 cells, overexpression of a catalytically inactive mutant of PTP1C strongly suppressed the stimulatory effects of the epidermal growth factor or serum on cell proliferation, early gene transcription, and DNA synthesis. Similarly, the phosphorylation of the mitogen-activated protein kinase and mitogen-activated protein kinase kinase activity was markedly inhibited by overexpression of mutant PTP1C. The inhibitory effect of mutant PTP1C was overcome by cotransfection with wild-type PTP1C, but not with the structurally related PTP2C. Furthermore, expression of the mutant phosphatase resulted in hyperphosphorylation on tyrosine of a 95-kDa protein that was co-immunoprecipitated with the mutant, but not with the wild-type protein. These results suggest that, unlike in hematopoietic cells, PTP1C in 293 cells plays a positive role in epidermal growth factor- or serum-activated mitogenesis. Thus, PTP1C participates in multiple signaling pathways, where the enzyme, depending on its target molecules, may function as either a positive or negative mediator.
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PMID:Positive effect of overexpressed protein-tyrosine phosphatase PTP1C on mitogen-activated signaling in 293 cells. 862 11

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.
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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

The protein tyrosine phosphatase SHP-1 is predominantly expressed in hemopoietic cell lineages, where its function is relatively well defined. However, its expression profile also extends to certain epithelial cell types. Furthermore, the negative regulatory role of this enzyme in hemopoietic cell signaling may not apply to other systems, where positive effects on particular tyrosine kinase signaling pathways have been described. Expression of SHP-1 was therefore investigated in human breast cancer cell lines and primary breast cancers. Differential expression of SHP-1 mRNA was observed among the 19 breast cancer cell lines examined, and in an analysis of 72 primary breast cancers, SHP-1 mRNA expression was increased 2- to 12-fold relative to normal breast epithelial cells in 58% of the samples. Interestingly, a subset of the cancers also over-expressed GRB2 mRNA by 2- to 7-fold, and a significant (p < 0.01) positive correlation was observed between SHP-1 and GRB2 mRNA expression. Since these proteins can bind to each other and regulate MEK/MAP kinase activation, their co-ordinate up-regulation may amplify tyrosine kinase signaling in breast cancer cells.
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PMID:Up-regulation of the protein tyrosine phosphatase SHP-1 in human breast cancer and correlation with GRB2 expression. 1105 64

We previously isolated dephostatin from Streptomyces as a novel inhibitor of CD45-associated protein-tyrosine phosphatase. We prepared Et-3,4-dephostatin as a stable analogue and found it to inhibit PTP-1B and SHPTP-1 protein-tyrosine phosphatases selectively but not to inhibit CD45 and leukocyte common antigen-related phosphatase ones effectively. Et-3,4-dephostatin increased the tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 with or without insulin in differentiated 3T3-L1 mouse adipocytes. The increase of tyrosine phosphorylation by Et-3,4-dephostatin was more prominent in 6-h than in 30-min incubation. It also increased phosphorylation and activation of Akt with or without insulin. Et-3,4-dephostatin also enhanced translocation of glucose transporter 4 from the cytoplasm to the membrane and 2-deoxy-glucose transport. Et-3,4-dephostatin-induced glucose uptake was inhibited by SB203580, a p38 inhibitor, but not by PD98059, a MEK inhibitor, or by cycloheximide as insulin-induced uptake. Interestingly, although LY294002, a phosphatidylinositol 3-kinase inhibitor, inhibited the insulin-induced glucose uptake completely, it only partially inhibited the Et-3,4-dephostatin-induced uptake. It also blocked insulin-induced glucose transporter 4 translocation but not the Et-3,4-dephostatin-induced one. The increase in c-Cbl tyrosine phosphorylation caused by Et-3,4-dephostatin was stronger than that in insulin receptor phosphorylation. These observations indicate that a phosphatidylinositol 3-kinase-independent pathway involving c-Cbl is more important in Et-3,4-dephostatin-induced glucose uptake than in insulin-induced uptake. Et-3,4-dephostatin showed an in vivo antidiabetic effect in terms of reducing the high blood glucose level in KK-A(y) mice after oral administration. Thus, Et-3,4-dephostatin potentiated insulin-related signal transductions in cultured mouse adipocytes and showed an antidiabetic effect in mice.
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PMID:Potentiation of insulin-related signal transduction by a novel protein-tyrosine phosphatase inhibitor, Et-3,4-dephostatin, on cultured 3T3-L1 adipocytes. 1134 32

Eosinophils are selectively primed and activated by the cytokine IL-5. The aim of this investigation was to study the effects of IL-5 treatment on stimulation-dependent protein phosphorylations, in human peripheral blood eosinophils. After IL-5 treatment, basal phosphorylation patterns showed increases in the phosphorylation of 67, 80 and 93 kDa proteins. Cell stimulations resulted in the following protein phosphorylation increases: 50, 60, 67, 80 and 93 kDa (PMA); 50, 67, 80 and 93 kDa (STZ); and 67, 80 and 93 kDa (IL-5). The phosphorylation of the 50 and 60 kDa proteins was shown to be MEK-independent and dependent on some PKC isoform/s, whereas that of the 67, 80 and 93 kDa proteins was both MEK- and PKC-alpha, beta, delta, gamma, tau and zeta-independent. A phosphoprotein of 50 kDa was identified as p47(phox) and another of 67 kDa protein as the tyrosine phosphatase SHPTP-1. Incubation with IL-5 followed by cell stimulation increased the total phosphorylation of p47(phox). Bidimensional (IEF-SDS/PAGE) analysis showed that the combination of IL-5 treatment followed by stimulation with either PMA or STZ induced the formation of an additional, hyperphosphorylated form of p47(phox). The presence of this form would explain the higher NADPH oxidase activity normally observed after IL-5 priming.
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PMID:The effect of IL-5 treatment on the stimulation-induced phosphorylation of proteins in blood eosinophils. 1547 55