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)

Mitogen-activated protein (MAP) kinase phosphatases (MKPs) are dual-specificity phosphatases that dephosphorylate phosphothreonine and phosphotyrosine residues within MAP kinases. Here, we describe a novel posttranslational mechanism for regulating MKP-3/Pyst1/DUSP6, a member of the MKP family that is highly specific for extracellular signal-regulated kinase 1 and 2 (ERK1/2) inactivation. Using a fibroblast model in which the expression of either MKP-3 or a more stable MKP-3-green fluorescent protein (GFP) chimera was induced by tetracycline, we found that serum induces the phosphorylation of MKP-3 and its subsequent degradation by the proteasome in a MEK1 and MEK2 (MEK1/2)-ERK1/2-dependent manner. In vitro phosphorylation assays using glutathione S-transferase (GST)-MKP-3 fusion proteins indicated that ERK2 could phosphorylate MKP-3 on serines 159 and 197. Tetracycline-inducible cell clones expressing either single or double serine mutants of MKP-3 or MKP-3-GFP confirmed that these two sites are targeted by the MEK1/2-ERK1/2 module in vivo. Double serine mutants of MKP-3 or MKP-3-GFP were more efficiently protected from degradation than single mutants or wild-type MKP-3, indicating that phosphorylation of either serine by ERK1/2 enhances proteasomal degradation of MKP-3. Hence, double mutation caused a threefold increase in the half-life of MKP-3. Finally, we show that the phosphorylation of MKP-3 has no effect on its catalytic activity. Thus, ERK1/2 exert a positive feedback loop on their own activity by promoting the degradation of MKP-3, one of their major inactivators in the cytosol, a situation opposite to that described for the nuclear phosphatase MKP-1.
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PMID:Extracellular signal-regulated kinases phosphorylate mitogen-activated protein kinase phosphatase 3/DUSP6 at serines 159 and 197, two sites critical for its proteasomal degradation. 1563 84

The MEK1-ERK1/2 signaling pathway has been implicated in the regulation of renal epithelial cell proliferation, epithelial-to-mesenchymal transition and the induction of an invasive cell phenotype. Much less information is available about the MEK5-ERK5 module and its role in renal epithelial cell proliferation and differentiation. In the present study we have investigated the regulation of these two families of extracellular signal-regulated kinases in epidermal growth factor (EGF)-stimulated human kidney-2 (HK-2) cells and a possible interaction between ERK1/2 and ERK5. Here we report that 5 ng/ml EGF led to a strong stimulation of HK-2 cell proliferation, which was largely U0126-sensitive. Both synthetic MEK1/2 inhibitors U0126 and Cl-1040, when used at 10 and 1 microM, respectively, inhibited basal and EGF-induced ERK1/2 phosphorylation but not ERK5 phosphorylation. Long-term inhibition of MEK1/2-ERK1/2 signaling and/or vanadate-sensitive protein phosphatases enhanced and prolonged EGF-induced ERK5 phosphorylation, while transient expression of an adenoviral constitutively active MEK1 (Ad-caMEK1) construct completely blocked EGF-induced ERK5 phosphorylation. Expression of Ad-caMEK1 in HK-2 cells resulted in the upregulation of the dual-specificity phosphatases MKP-3/DUSP6, MKP-1/DUSP1, and DUSP5. The EGF-mediated time-dependent induction of MKP-3, MKP-1 and DUSP5 mRNA levels was U0126-sensitive at a concentration, which blocked EGF-mediated ERK1/2 phosphorylation but not ERK5 phosphorylation. Furthermore, U0126 inhibited EGF-induced MKP-3 and MKP-1 protein expression. Both MKP-3 and MKP-1 co-immunoprecipitated with ERK5 in unstimulated as well as in EGF-stimulated HK-2 cells. These results suggest the existence of an ERK1/2-driven negative feed-back regulation of ERK5 signaling in EGF-stimulated HK-2 cells, which is mediated by MKP-3, DUSP5 and/or MKP-1.
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PMID:ERK1/2-driven and MKP-mediated inhibition of EGF-induced ERK5 signaling in human proximal tubular cells. 1713 84

MAP kinases phosphatases (MKPs) belong to the dual-specificity phosphatase family (DUSP) and dephosphorylate phosphothreonine and phosphotyrosine within MAP kinases. We had previously shown that DUSP6/MKP-3 was phosphorylated and degraded upon growth factor stimulation, in a MEK-dependent manner. Here we show that another pathway involved in growth factor signaling, the PI3K/mTOR signaling pathway, accounts for a part of the phosphorylation and degradation of DUSP6 induced by serum growth factors, as evidenced by experiments using pharmacological inhibitors of PI3 kinase and mammalian target of rapamycin (mTOR). Moreover, specific agonists of the mTOR pathway, such as amino acids or insulin/IGF-1, which do not activate extracellular signal regulated kinases (ERKs) in our cellular model, were also able to induce the phosphorylation and degradation of DUSP6. However, a basal activity of MEK was required for the mTOR pathway-mediated phosphorylation to occur. Mutagenesis studies identified serine 159 within DUSP6 as the target of the mTOR pathway. The ERK phosphatase DUSP6 may thus constitute a novel branch-point of the crosstalk between two major signaling pathways induced by growth factors, the MEK/ERK pathway and the PI3K/mTOR pathway.
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PMID:Post-translational regulation of the ERK phosphatase DUSP6/MKP3 by the mTOR pathway. 1822 77

Extracellular signal-regulated kinase-1 and -2 (ERK1/2) are activated by dual threonine and tyrosine phosphorylation of a TEY motif. The highly related kinase ERK5 is also activated by phosphorylation at a TEY motif. Inactivation of ERK1/2 is achieved by distinct members of the dual-specificity protein phosphatase (DUSP) family, which are responsible for the specific, regulated de-phosphorylation of the TEY motif. These include both nuclear (DUSP5) and cytoplasmic (DUSP6) enzymes. DUSP6, a candidate tumour suppressor gene, is thought to be highly specific for inactivation of ERK1/2 but several reports have suggested that it may also inactivate ERK5. Here we have compared the ability of DUSP6 to regulate the ERK1/2 and ERK5 protein kinases. We find that DUSP6 binds to ERK1/2 in both yeast and human cells but fails to bind to ERK5. Recombinant ERK2 can induce catalytic activation of DUSP6 whereas ERK5 cannot. Ectopic expression of DUSP6 can de-phosphorylate a co-expressed ERK2 construct but does not de-phosphorylate ERK5. Finally, expression of DUSP6 blocks the MEK1-driven activation of GAL4-ELK1, an ERK1/2-regulated transcription factor, but fails to block the MEK5-driven activation of GAL4-MEF2D, an ERK5-regulated transcription factor. These results demonstrate that even upon over-expression DUSP6 fails to inactivate ERK5, confirming that it is indeed an ERK1/2-specific DUSP.
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PMID:DUSP6/MKP-3 inactivates ERK1/2 but fails to bind and inactivate ERK5. 1828 Jan 12

DUSP6/MKP-3 is a cytoplasmic dual-specificity phosphatase specific for the MAP kinases ERK1/2. Previous data have shown that the MEK/ERK axis exerts a retro-control on its own signaling through transcriptional and post-translational regulation of DUSP6. We first confirm the key role of MEK/ERK in maintaining the levels of dusp6 mRNA, while PI3K/mTOR, p38 MAPK, and JNK signaling pathways had no significant effects. We further show that regulation of dusp6 mRNA stability plays a critical role in ERK-dependent regulation of dusp6 expression. Luciferase reporter constructs indicated that MEK/ERK signaling increased the half-life of dusp6 mRNA in a 3'untranslated region (3'UTR)-dependent manner. In addition, hypoxia, a hallmark of tumor growth, was found to increase both endogenous levels of dusp6 mRNA and the stability of the luciferase reporter constructs containing its 3'UTR, in a HIF-1-dependent manner. Nevertheless, a basal ERK activity was required for the response to hypoxia. Finally, Tristetraprolin (TTP), a member of the TIS11 CCCH zinc finger protein family, and PUM2, an homolog of drosophila pumilio, two proteins regulating mRNA stability reduced the levels of endogenous dusp6 mRNA and the activity of the dusp6/3'UTR luciferase reporter constructs. This study shows that post-transcriptional regulation is a key process in the control of DUSP6 expression.
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PMID:Post-transcriptional regulation of the DUSP6/MKP-3 phosphatase by MEK/ERK signaling and hypoxia. 2066 74

The incidence of malignant melanoma is growing rapidly worldwide and there is still no effective therapy for metastatic disease. Melanoma is the second most common cancer among young adults in the UK, where incidence rates have more than quadrupled since the 1970s. Increased expression of a number of DNA repair genes has been reported in melanoma and this likely contributes to its extreme resistance to conventional DNA-damaging chemotherapeutics. One such chemotherapeutic that is effective against a range of other cancers, but not melanoma, is cisplatin. The DNA repair proteins ERCC1 and XPF are needed to remove cisplatin-induced DNA damage and we have investigated the response of these proteins to cisplatin in melanoma. The expression of both genes is induced by cisplatin. Use of a MEK inhibitor showed that ERCC1, but not XPF induction was regulated by the mitogen-activated protein kinase (MAPK) pathway, with reduction in expression of DUSP6, the phosphatase that inactivates the extracellular signal-regulated kinase (ERK), being particularly important. DUSP6 overexpression prevented cisplatin induction of both ERCC1 and XPF, resulting in increased sensitivity to cisplatin. A novel ERCC1 mRNA was found that initiated upstream of the normal transcription initiation site, and was strongly regulated by both cisplatin and the MAPK pathway and its role in cisplatin resistance merits further study. The cisplatin induction of ERCC1 and XPF provides important insights into the resistance of melanoma to DNA-damaging chemotherapeutics, which is one of the major obstacles to melanoma treatment.
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PMID:Cisplatin regulates the MAPK kinase pathway to induce increased expression of DNA repair gene ERCC1 and increase melanoma chemoresistance. 2199 34

The MEK1 and MEK2 inhibitor GSK1120212 is currently in phase II/III clinical development. To identify predictive biomarkers, sensitivity to GSK1120212 was profiled for 218 solid tumor cell lines and 81 hematologic malignancy cell lines. For solid tumors, RAF/RAS mutation was a strong predictor of sensitivity. Among RAF/RAS mutant lines, co-occurring PIK3CA/PTEN mutations conferred a cytostatic response instead of a cytotoxic response for colon cancer cells that have the biggest representation of the comutations. Among KRAS mutant cell lines, transcriptomics analysis showed that cell lines with an expression pattern suggestive of epithelial-to-mesenchymal transition were less sensitive to GSK1120212. In addition, a proportion of cell lines from certain tissue types not known to carry frequent RAF/RAS mutations also seemed to be sensitive to GSK1120212. Among these were breast cancer cell lines, with triple negative breast cancer cell lines being more sensitive than cell lines from other breast cancer subtypes. We identified a single gene DUSP6, whose expression was associated with sensitivity to GSK1120212 and lack of expression associated with resistance irrelevant of RAF/RAS status. Among hematologic cell lines, acute myeloid leukemia and chronic myeloid leukemia cell lines were particularly sensitive. Overall, this comprehensive predictive biomarker analysis identified additional efficacy biomarkers for GSK1120212 in RAF/RAS mutant solid tumors and expanded the indication for GSK1120212 to patients who could benefit from this therapy despite the RAF/RAS wild-type status of their tumors.
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PMID:Comprehensive predictive biomarker analysis for MEK inhibitor GSK1120212. 2216 69

As dual-specificity phosphatase (DUSP) expression has been correlated to sensitivity to MEK inhibitors, DUSP expression levels may indicate activation of the mitogen-activated protein kinase (MAPK) pathway in many tumor types. In this study, we investigate if DUSP levels can indicate different levels of MAPK activation within colorectal cancer (CRC) patients. In three different CRC patient microarray datasets, we analyzed the expression of DUSP1. DUSP4 and DUSP6 according to mutational status, their correlation with survival and their association with different clinical characteristics. DUSP4 was significantly differentially expressed between all mutational subgroups with the highest expression in BRAF mutated tumors. Moreover, high DUSP4 expression was associated with a worse overall survival and with clinical characteristics typical for BRAF mutant patients. The use of DUSP expression as a predictive biomarker towards MAPK targeted therapy in CRC patients needs further investigation.
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PMID:DUSP 4 expression identifies a subset of colorectal cancer tumors that differ in MAPK activation, regardless of the genotype. 2387 12

Deregulated pro-survival signalling plays a role in ovarian carcinoma drug resistance. Here, we show that cisplatin or oxaliplatin in combination with the MEK1/2 inhibitor CI-1040 resulted in a synergistic effect associated with enhanced apoptotic response in platinum-sensitive cells. The drug combinations were additive in platinum-resistant cells exhibiting increased phospho-ERK1/2, down-regulation of apoptosis-related factors (BAX, PUMA, FOXO1) and of phosphatases inhibiting ERK1/2 (DUSP5, DUSP6). Consistently, FOXO1 knockdown in sensitive cells reduced the efficacy of the combination treatment. Pharmacological targeting of ERK1/2 pathway increases cell sensitivity to platinum compounds by interfering with multiple events, ultimately favouring apoptosis induction in selected molecular backgrounds.
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PMID:Differential outcome of MEK1/2 inhibitor-platinum combinations in platinum-sensitive and -resistant ovarian carcinoma cells. 2457 22

The Met receptor tyrosine kinase is activated or genetically amplified in some gastric cancers, but resistance to small-molecule inhibitors of Met often emerges in patients. We found that Met abundance correlated with a proliferation marker in patient gastric tumor sections, and gastric cancer cell lines that have MET amplifications depended on Met for proliferation and anchorage-independent growth in culture. Inhibition of Met induced temporal changes in gene expression in the cell lines, initiated by a rapid decrease in the expression of genes encoding transcription factors, followed by those encoding proteins involved in epithelial-mesenchymal transition, and finally those encoding cell cycle-related proteins. In the gastric cancer cell lines, microarray and chromatin immunoprecipitation analysis revealed considerable overlap between genes regulated in response to Met stimulation and those regulated by signal transducer and activator of transcription 3 (STAT3). The activity of STAT3, extracellular signal-regulated kinase (ERK), and the kinase Akt was decreased by Met inhibition, but only inhibitors of STAT3 were as effective as the Met inhibitor in decreasing tumor cell proliferation in culture and in xenografts, suggesting that STAT3 mediates the pro-proliferative program induced by Met. However, the phosphorylation of ERK increased after prolonged Met inhibition in culture, correlating with decreased abundance of the phosphatases DUSP4 and DUSP6, which inhibit ERK. Combined inhibition of Met and the mitogen-activated protein kinase kinase (MEK)-ERK pathway induced greater cell death in cultured gastric cancer cells than did either inhibitor alone. These findings indicate combination therapies that may counteract resistance to Met inhibitors.
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PMID:Dynamic reprogramming of signaling upon met inhibition reveals a mechanism of drug resistance in gastric cancer. 2475 78


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