Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously reported that MAPK phosphatase-1 (MKP-1/CL100) is a thrombin-responsive gene in endothelial cells (ECs). We now show that VEGF is another efficacious activator of MKP-1 expression in human umbilical vein ECs. VEGF-A and VEGF-E maximally induced MKP-1 expression in ECs; however, the other VEGF subtypes had no effect. Using specific neutralizing antibodies, we determined that VEGF induced MKP-1 specifically through VEGF receptor 2 (VEGFR-2), leading to the downstream activation of JNK. The VEGF-A(165) isoform stimulated MKP-1 expression, whereas the VEGF-A(162) isoform induced the gene to a lesser extent, and the VEGF-A(121) isoform had no effect. Furthermore, specific blocking antibodies against neuropilins, VEGFR-2 coreceptors, blocked MKP-1 induction. A Src kinase inhibitor (PP1) completely blocked both VEGF- and thrombin-induced MKP-1 expression. A dominant negative approach revealed that Src kinase was required for VEGF-induced MKP-1 expression, whereas Fyn kinase was critical for thrombin-induced MKP-1 expression. Moreover, VEGF-induced MKP-1 expression required JNK, whereas ERK was critical for thrombin-induced MKP-1 expression. In ECs treated with short interfering (si)RNA targeting MKP-1, JNK, ERK, and p38 phosphorylation were prolonged following VEGF stimulation. An ex vivo aortic angiogenesis assay revealed a reduction in VEGF- and thrombin-induced sprout outgrowth in segments from MKP-1-null mice versus wild-type controls. MKP-1 siRNA also significantly reduced VEGF-induced EC migration using a transwell assay system. Overall, these results demonstrate distinct MAPK signaling pathways for thrombin versus VEGF induction of MKP-1 in ECs and point to the importance of MKP-1 induction in VEGF-stimulated EC migration.
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PMID:VEGF and thrombin induce MKP-1 through distinct signaling pathways: role for MKP-1 in endothelial cell migration. 1800 51

Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) is the MAPK phosphatase family member that negatively regulates MAPK signaling. Our previous study showed that MKP-1 is involved in cisplatin resistance, but the mechanism underlying its resistance is not understood. Here, we show that ERK2-mediated MKP-1 expression is critical for cisplatin resistance. Specifically, we showed that in the human ovarian cancer cell lines, cisplatin induces MKP-1 through phosphorylation. We also showed that inhibition of ERK2 activity by the MEK1/2 inhibitor U0126 or by small interfering RNA silencing decreases MKP-1 induction, leading to an increase in cisplatin-induced cell death, which mimicked the results obtained with cells in which MKP-1 is down-regulated. Importantly, down-regulation of ERK2 decreased cisplatin-induced MKP-1 phosphorylation, suggesting that MKP-1 phosphorylation depends on ERK2 activity. Furthermore, down-regulation of ERK2 or MKP-1 enhanced cisplatin-induced apoptosis. In addition, we showed that down-regulation of ERK2 or MKP-1 decreases the basal level of Bcl-2 protein and that inhibition of Bcl-2 activity sensitizes ovarian cancer cells to cisplatin. Collectively, our results indicate that induction of MKP-1 by cisplatin is through phosphorylation involving ERK signaling and that MKP-1 plays a critical role in ERK-mediated cisplatin resistance. Thus, our results suggest that targeting ERK-MKP-1 signaling could overcome cisplatin resistance in human ovarian cancer.
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PMID:ERK-dependent MKP-1-mediated cisplatin resistance in human ovarian cancer cells. 1808 24

Representation of intracellular signaling networks as directed graphs allows for the identification of regulatory motifs. Regulatory motifs are groups of nodes with the same connectivity structure, capable of processing information. The bifan motif, made of two source nodes directly crossregulating two target nodes, is an overrepresented motif in a mammalian cell signaling network and in transcriptional networks. One example of a bifan is the two MAP-kinases, p38, and JNK that phosphorylate and activate the two transcription factors ATF2 and Elk-1. We have used a system of coupled ordinary differential equations to analyze the regulatory capability of this bifan motif by itself, and when it interacts with other motifs such as positive and negative feedback loops. Our results indicate that bifans provide temporal regulation of signal propagation and act as signal sorters, filters, and synchronizers. Bifans that have OR gate configurations show rapid responses whereas AND gate bifans can introduce delays and allow prolongation of signal outputs. Bifans that have AND gates can filter noisy signal inputs. The p38/JNK-ATF2/Elk-1bifan synchronizes the output of activated transcription factors. Synchronization is a robust property of bifans and is exhibited even when the bifan is adjacent to a positive feedback loop. The presence of the bifan promotes the transcription and translation of the dual specificity protein phosphatase MKP-1 that inhibits p38 and JNK thus enabling a negative feedback loop. These results indicate that bifan motifs in cell signaling networks can contribute to signal processing capability both intrinsically and by enabling the functions of other regulatory motifs.
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PMID:Functions of bifans in context of multiple regulatory motifs in signaling networks. 1817 48

There are ten mitogen-activated protein kinase (MAPK) phosphatases (MKPs) that act as negative regulators of MAPK activity in mammalian cells and these can be subdivided into three groups. The first comprises DUSP1/MKP-1, DUSP2/PAC1, DUSP4/MKP-2 and DUSP5/hVH-3, which are inducible nuclear phosphatases. With the exception of DUSP5, these MKPs display a rather broad specificity for inactivation of the ERK, p38 and JNK MAP kinases. The second group contains three closely related ERK-specific and cytoplasmic MKPs encoded by DUSP6/MKP-3, DUSP7/MKP-X and DUSP9/MKP-4. The final group consists of three MKPs DUSP8/hVH-5, DUSP10/MKP-5 and DUSP16/MKP-7 all of which preferentially inactivate the stress-activated p38 and JNK MAP kinases. Abnormal MAPK signalling will have important consequences for processes critical to the development and progression of human cancer. In addition, MAPK signalling also plays a key role in determining the response of tumour cells to conventional cancer therapies. The emerging roles of the dual-specificity MKPs in the regulation of MAPK activities in normal tissues has highlighted the possible pathophysiological consequences of either loss (or gain) of function of these enzymes as part of the oncogenic process. This review summarises the current evidence implicating the dual-specificity MKPs in the initiation and development of cancer and also on the outcome of treatment.
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PMID:Dual-specificity MAP kinase phosphatases (MKPs) and cancer. 1833 Jun 78

Hyperplasia of airway smooth muscle (ASM) within the bronchial wall of asthmatic patients has been well documented and is likely due to increased muscle proliferation. We have shown that ASM cells obtained from asthmatic patients proliferate faster than those obtained from non-asthmatic patients. In ASM from non-asthmatics, mitogens act via dual signaling pathways (both ERK- and PI 3-kinase-dependent) to control growth. In this study we are the first to examine whether dual pathways control the enhanced proliferation of ASM from asthmatics. When cells were incubated with 0.1% or 1% FBS, ERK activation was significantly greater in cells from asthmatic subjects (P < 0.05). In contrast, when cells were stimulated with 10% FBS, ERK activity was significantly greater in the non-asthmatic cells. However, cell proliferation in asthmatic cells was still significantly higher in cells stimulated by both 1% and 10% FBS. Pharmacological inhibition revealed that although dual proliferative pathways control ASM growth in cells from non-asthmatics stimulated with 10% FBS to an equal extent ([(3)H]-thymidine incorporation reduced to 57.2 +/- 6.9% by the PI 3-kinase inhibitor LY294002 and 57.8 +/- 1.1% by the ERK-pathway inhibitor U0126); in asthmatics, the presence of a strong proliferative stimulus (10% FBS) reduces ERK activation resulting in a shift to the PI 3-kinase pathway. The underlying mechanism appears to be upregulation of an endogenous MAPK inhibitor--MKP-1--that constrains ERK signaling in asthmatic cells under strong mitogenic stimulation. This study suggests that the PI 3-kinase pathway may be an attractive target for reversing hyperplasia in asthma.
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PMID:Dual ERK and phosphatidylinositol 3-kinase pathways control airway smooth muscle proliferation: differences in asthma. 1833 17

We have recently identified the MAPK phosphatase (MKP)-1 as a novel mediator of the antiinflammatory properties of glucocorticoids (dexamethasone) in the human endothelium. However, nothing is as yet known about the signaling pathways responsible for the up-regulation of MKP-1 by dexamethasone in endothelial cells. Knowledge of the molecular basis of this new alternative way of glucocorticoid action could facilitate the identification of new antiinflammatory drug targets. Thus, the aim of our study was to elucidate the underlying molecular mechanisms. Using Western blot analysis, we found that dexamethasone rapidly activates ERK, c-jun N-terminal kinase (JNK), and p38 MAPK in human umbilical vein endothelial cells. By applying the kinase inhibitors PD98059 (MAPK kinase-1) and SP600125 (JNK), ERK and JNK were shown to be crucial for the induction of MKP-1. Using EMSA and a decoy oligonucleotide approach, the transcription factors activator protein-1 (activated by ERK and JNK) and cAMP response element-binding protein (activated by ERK) were found to be involved in the up-regulation of MKP-1 by dexamethasone. Interestingly, dexamethasone induces the generation of reactive oxygen species (measured by dihydrofluorescein assay), which participate in the signaling process by triggering JNK activation. Our work elucidates a novel alternative mechanism for transducing antiinflammatory effects of glucocorticoids in the human endothelium. Thus, our study adds valuable information to the efforts made to find new antiinflammatory principles utilized by glucocorticoids. This might help to gain new therapeutic options to limit glucocorticoid side effects and to overcome resistance.
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PMID:Dexamethasone-induced expression of endothelial mitogen-activated protein kinase phosphatase-1 involves activation of the transcription factors activator protein-1 and 3',5'-cyclic adenosine 5'-monophosphate response element-binding protein and the generation of reactive oxygen species. 1840 84

Although mutations in intermediate filament proteins cause many human disorders, the detailed pathogenic mechanisms and the way these mutations affect cell metabolism are unclear. In this study, selected keratin mutations were analysed for their effect on the epidermal stress response. Expression profiles of two keratin-mutant cell lines from epidermolysis bullosa simplex patients (one severe and one mild) were compared to a control keratinocyte line before and after challenge with hypo-osmotic shock, a common physiological stress that transiently distorts cell shape. Fewer changes in gene expression were found in cells with the severely disruptive mutation (55 genes altered) than with the mild mutation (174 genes) or the wild type cells (261 genes) possibly due to stress response pre-activation in these cells. We identified 16 immediate-early genes contributing to a general cell response to hypo-osmotic shock, and 20 genes with an altered expression pattern in the mutant keratin lines only. A number of dual-specificity phosphatases (MKP-1, MKP-2, MKP-3, MKP-5 and hVH3) are differentially regulated in these cells, and their downstream targets p-ERK and p-p38 are significantly up-regulated in the mutant keratin lines. Our findings strengthen the case for the expression of mutant keratin proteins inducing physiological stress, and this intrinsic stress may affect the cell responses to secondary stresses in patients' skin.
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PMID:Dual-specificity phosphatases in the hypo-osmotic stress response of keratin-defective epithelial cell lines. 1841 Sep 23

The enzymatic activity of CD38, ADP-ribosyl cyclase, synthesizes the calcium mobilizing molecule cyclic ADP-ribose from beta-NAD. In human airway smooth muscle (HASM) cells, CD38 expression is augmented by the inflammatory cytokine, TNF-alpha, causing increased intracellular calcium response to agonists. The transcriptional and posttranscriptional regulation of CD38 expression involves signaling through MAPKs and requires activation of NF-kappaB and activator protein-1 (AP-1). The cytokine-augmented CD38 expression is decreased by anti-inflammatory glucocorticoids due to inhibition of NF-kappaB activation and other mechanisms. In this study, we investigated glucocorticoid regulation of CD38 expression in HASM cells through the MKP-1. In HASM cells, dexamethasone and TNF-alpha induced MKP-1 expression (both mRNA and protein) rapidly. Dexamethasone decreased TNF-alpha-induced phosphorylation of the major MAPKs, i.e., ERK, p38, and JNK, and decreased the activation of NF-kappaB and AP-1. Dexamethasone also decreased CD38 expression induced by TNF-alpha, and part of this effect was attributable to decreased transcript stability. In cells transfected with MKP-1-specific small interfering RNAs (siRNAs), there was significant attenuation of MKP-1 expression and partial, but nonsignificant, reversal of dexamethasone inhibition of CD38 expression. These results indicate that regulation of CD38 expression in HASM cells by glucocorticoids involves decreased signaling through MAPKs and activation of transcription factors. The glucocorticoid effects on decreased CD38 expression and function result from regulation through transcription and transcript stability.
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PMID:Glucocorticoid regulation of CD38 expression in human airway smooth muscle cells: role of dual specificity phosphatase 1. 1844 Oct 94

The mechanism regulating radiation-induced anti-apoptotic response, a limiting factor in improving cell radiosensitivity, remains elusive. Mitogen-activated protein kinase (MAPK) phosphatase (MKP)-1 is the major member of MKPs that dephosphorylates and inactivates MAPK. Here we provide the evidence that MKP-1 was negatively bridging between NF-kappaB-mediated prosurvival pathway and c-Jun N-terminal kinase (JNK)-mediated proapoptotic response. MKP-1 was induced by gamma-radiation and repressed radiation-induced pro-apoptotic status. NF-kappaB RelA/p50 heterodimer was recruited to MKP-1 gene promoter to induce MKP-1 transcription. Deletion of the NF-kappaB-binding site or inactivation of NF-kappaB by its small interfering RNA significantly decreased the radiation-induced MKP-1 promoter activity. In addition, MKP-1-deficient mouse embryonic fibroblasts exhibited a prolonged activation of JNK but not p38 or extracellular signal-regulated kinase subfamilies of MAPKs. The prolonged activation of JNK was not induced by treatment with tumor necrosis factor alpha or interleukin-6, and inactivation of JNK but not p38 or ERK abolished radiation-induced proapoptotic status, indicating that JNK is specifically inhibited by radiation-induced MKP-1. Three MKP-1 wild type human tumor cell lines treated with MKP-1 small interfering RNA showed an increased proapoptotic response that can be rescued by overexpression of wild type mouse MKP-1. Together, these results suggest that MKP-1 is a NF-kappaB-mediated prosurvival effector in attenuating JNK-mediated pro-apoptotic response; NF-kappaB/MKP-1-mediated negative JNK regulation represents a potential therapeutic target for adjusting cell radiosensitivity.
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PMID:Mitogen-activated protein kinase phosphatase-1 represses c-Jun NH2-terminal kinase-mediated apoptosis via NF-kappaB regulation. 1850 59

Ginsenosides have been reported to release nitric oxide (NO) and decrease intracellular free Ca(2+) in cardiovascular system, which play important roles in antihypertrophic effect. This study investigated the potential inhibitory effect of total ginsenosides (TG) on right ventricular hypertrophy induced by monocrotaline (MCT, 60 mg/kg/d) and examined the possible antihypertrophic mechanism in male Sprague Dawley rats. MCT-intoxicated animals were treated with TG (20, 40, 60 mg/kg/d) for 18 d. TG treatment ameliorated MCT-induced elevations in right ventricular peak systolic pressure, right ventricular hypertrophy and the expression of atrial natriuretic peptide; N(G)-nitro-L-arginine-methyl ester (L-NAME), an NO synthase (NOS) inhibitor, had no influence on these inhibitory effects of TG 40 mg/kg/d, and TG at this dose had no any effect on the eNOS mRNA expression, suggesting the limited rule of NO in TG's effects. To further examine the mechanisms of the protection, the expression of calcineurin and its catalytic subunit CnA, as well as extracellular signal-regulated kinase-1 (ERK-1) and mitogen-activated protein kinase (MAPK) Phosphatase-1 (MKP-1) was examined. TG treatment significantly suppressed MCT-induced elevations of these signaling pathways in a dose-dependent manner. In summary, TG is effective in protecting against MCT-induced right ventricle hypertrophy, possibly through lowering pulmonary hypertension. Multiple molecular mechanisms appeared to be involved in this protection, such as the suppression of MCT-activated calcineurin and ERK signaling pathways.
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PMID:Total ginsenosides inhibit the right ventricular hypertrophy induced by monocrotaline in rats. 1867 84


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