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:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we investigated the signaling pathways involved in bradykinin (BK)-induced NF-kappaB activation and cyclooxygenase-2 (COX-2) expression in human airway epithelial cells (A549). BK caused concentration- and time-dependent increase in COX-2 expression, which was attenuated by a selective B2 BK receptor antagonist (HOE140), a Ras inhibitor (manumycin A), a Raf-1 inhibitor (GW 5074), a MEK inhibitor (PD 098059), an NF-kappaB inhibitor (pyrrolidine dithiocarbate), and an IkappaB protease inhibitor (L-1-tosylamido-2-phenylethyl chloromethyl ketone). The B1 BK receptor antagonist (Lys-(Leu8)des-Arg9-BK) had no effect on COX-2 induction by BK. BK-induced increase in COX-2-luciferase activity was inhibited by cells transfected with the kappaB site deletion of COX-2 construct. BK-induced Ras activation was inhibited by manumycin A. Raf-1 phosphorylation at Ser338 by BK was inhibited by manumycin A and GW 5074. BK-induced ERK activation was inhibited by HOE140, manumycin A, GW 5074, and PD 098059. Stimulation of cells with BK activated IkappaB kinase alphabeta (IKKalphabeta), IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 and p50 translocation from the cytosol to the nucleus, the formation of an NF-kappaB-specific DNA-protein complex, and kappaB-luciferase activity. BK-mediated increase in IKKalphabeta activity and formation of the NF-kappaB-specific DNA-protein complex were inhibited by HOE140, a Ras dominant-negative mutant (RasN17), manumycin A, GW 5074, and PD 098059. Our results demonstrated for the first time that BK, acting through B2 BK receptor, induces activation of the Ras/Raf-1/ERK pathway, which in turn initiates IKKalphabeta and NF-kappaB activation, and ultimately induces COX-2 expression in human airway epithelial cell line (A549).
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PMID:Bradykinin B2 receptor mediates NF-kappaB activation and cyclooxygenase-2 expression via the Ras/Raf-1/ERK pathway in human airway epithelial cells. 1547 67

In this study, we showed that plasminogen (Plg) and plasmin (Pla) bind to lysine-binding sites on cell surface and trigger a signaling pathway that activates the mitogen-activated protein kinase (MAPK) MEK and ERK1/2, which in turn leads to the expression of the primary response genes c-fos and early growth response gene egr-1. Our data show that the Plg/Pla-stimulated steady-state mRNA levels of both genes reached a maximum by 30 min and then returned to basal levels by 1h. The gene induction was sensitive to both pharmacological and genetic inhibition of MEK. Leupeptin, a serine protease inhibitor, suppressed Pla but not Plg-induced c-fos and egr-1 expression, emphasizing the role played by the serine protease activity associated with Pla. Pre-incubation with cholera toxin completely blocked the Plg/Pla-induced gene expression, suggesting that another signaling pathway, which recruits G protein-coupled receptors, may also be involved. Furthermore, Plg/Pla also stimulated AP-1 and EGR-1 DNA-binding activities, which were abrogated by pharmacological inhibition of MEK. Altogether, these results suggest that Plg/Pla stimulates c-fos and egr-1 expression via activation of the MEK/ERK pathway.
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PMID:Plasminogen/plasmin regulates c-fos and egr-1 expression via the MEK/ERK pathway. 1572 Dec 99

Epigenetic histone modifications contribute to the regulation of eukaryotic gene transcription. The role of epigenetic regulation in immunity to intracellular pathogens is poorly understood. We tested the hypothesis that epigenetic histone modifications influence cytokine expression by intracellular bacteria. Intracellular Listeria monocytogenes, but not noninvasive Listeria innocua, induced release of distinct CC and CXC chemokines, as well as Th1 and Th2 cytokines and growth factors by endothelial cells. Cytokine expression was in part dependent on p38 MAPK and MEK1. We analyzed global histone modification and modifications in detail at the gene promoter of IL-8, which depended on both kinase pathways, and of IFN-gamma, which was not blocked by kinase inhibition. Intracellular Listeria induced time-dependent acetylation (lysine 8) of histone H4 and phosphorylation/acetylation (serine 10/lysine 14) of histone H3 globally and at the il8 promoter in HUVEC, as well as recruitment of the histone acetylase CREB-binding protein. Inhibitors of p38 MAPK and MEK1 reduced lysine 8 acetylation of histone H4 and serine 10/lysine 14 phosphorylation/acetylation of histone H3 in Listeria-infected endothelial cells and disappearance of histone deacetylase 1 at the il8 promoter in HUVEC. In contrast, IFN-gamma gene transcription was activated by Listeria monocytogenes independent of p38 MAPK and MEK1, and histone phosphorylation/acetylation remained unchanged in infected cells at the IFN-gamma promoter. Specific inhibition of histone deacetylases by trichostatin A increased Listeria-induced expression of IL-8, but not of IFN-gamma, underlining the specific physiological impact of histone acetylation. In conclusion, MAPK-dependent epigenetic modifications differentially contributed to L. monocytogenes-induced cytokine expression by human endothelial cells.
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PMID:Intracellular bacteria differentially regulated endothelial cytokine release by MAPK-dependent histone modification. 1611 70

Skeletal disorders and neural tube closure defects represent clinically significant human malformations. The signaling networks regulating normal skeletal patterning and neurulation are largely unknown. Targeted mutation of the active site lysine of MEK kinase 4 (MEKK4) produces a kinase-inactive MEKK4 protein (MEKK4(K1361R)). Embryos homozygous for this mutation die at birth as a result of skeletal malformations and neural tube defects. Hindbrains of exencephalic MEKK4(K1361R) embryos show a striking increase in neuroepithelial cell apoptosis and a dramatic loss of phosphorylation of MKK3 and -6, mitogen-activated protein kinase kinases (MKKs) regulated by MEKK4 in the p38 pathway. Phosphorylation of MAPK-activated protein kinase 2, a p38 substrate, is also inhibited, demonstrating a loss of p38 activity in MEKK4(K1361R) embryos. In contrast, the MEK1/2-extracellular signal-regulated kinase 1 (ERK1)/ERK2 and MKK4-Jun N-terminal protein kinase pathways were unaffected. The p38 pathway has been shown to regulate the phosphorylation and expression of the small heat shock protein HSP27. Compared to the wild type, MEKK4(K1361R) fibroblasts showed significantly reduced phosphorylation of p38 and HSP27, with a corresponding heat shock-induced instability of the actin cytoskeleton. Together, these data demonstrate MEKK4 regulation of p38 and that substrates downstream of p38 control cellular homeostasis. The findings are the first demonstration that MEKK4-regulated p38 activity is critical for neurulation.
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PMID:Ablation of MEKK4 kinase activity causes neurulation and skeletal patterning defects in the mouse embryo. 1619 73

In studies of gene regulation of keratin 16, we reported previously that simian virus 40 promoter factor 1 shows a functional cooperation with c-Jun and coactivators p300/CBP in driving the transcriptional regulation of epidermal growth factor (EGF)-induced keratin 16 gene expression. In the present study, we found that the stimulated expression of keratin 16 by EGF was mediated mainly through the mitogen-activated protein kinase kinase-extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling pathway. Ser63 and Ser73 on the c-Jun NH(2)-terminal transactivation domain could be phosphorylated in cells treated with EGF; nevertheless, we found that the c-Jun COOH terminus played a pivotal role in EGF-induced expression of keratin 16. The activation of keratin 16 by EGF treatment could not be enhanced by the overexpression of myc-c-JunK3R, in which three putative acetylation lysine residues on the c-Jun COOH terminus were all mutated into arginines, suggesting that c-Jun acetylation on the COOH terminus might partially play a functional role in this system. In addition, by using a chromatin immunoprecipitation assay and a DNA affinity precipitation assay, EGF treatment up-regulated the p300 recruitment through ERK signaling to the promoter region in regulating keratin 16 transcriptional activity. Furthermore, the enhancement of acetyl-histone H3 to the keratin 16 chromatin promoter induced by EGF was also mediated via ERK activation. In conclusion, these results strongly suggest that both c-Jun induction and p300 recruitment to gene promoter, mediated through ERK activation, played an essential role in regulating keratin 16 gene expression by EGF. p300 mediated and regulated EGF-induced keratin 16 gene expression, at least in part, through multiple mechanisms, including a selective acetylation of c-Jun and histone H3.
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PMID:Activation of extracellular signal-regulated kinase signaling by epidermal growth factor mediates c-Jun activation and p300 recruitment in keratin 16 gene expression. 1621 53

The EGFR/Ras/Raf/MEK/ERK pathway is a major pathway involved in the control of growth signals, cell survival and differentiation. Mutations of signaling components, such as EGFR (c-erbB1), Ras, and B-Raf, have been shown to play roles in the genesis of human cancer, while point mutation of ERK has not been reported. In this study, we present evidence for a mutation in an oral squamous cell carcinoma cell line, HSC6. PCR-amplification of cDNA, cloning and sequencing resulted in the identification of glutamic acid to lysine substitution at codon 322 (E322K) that occurred in the common docking (CD) domain of ERK2. The mutant protein contributed towards faster-migration in SDS-PAGE, and constitutive phosphorylation in a MEK-dependent manner. The transient transfection of the mutant ERK2 in 293T cells resulted in the expression of the same faster-migrating band in SDS-PAGE as was detected in HSC6 cells, which was preferentially phosphorylated relative to endogenous wild-type ERK2. The present study is the first to report ERK2 substitution mutation in a human cancer cell line which resulted in constitutive phosphorylation.
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PMID:A mutation in the common docking domain of ERK2 in a human cancer cell line, which was associated with its constitutive phosphorylation. 1627 4

Human T-cell leukemia virus type 1 (HTLV-1) Tax-induced activation of nuclear factor-kappaB (NFkappaB) is thought to play a critical role in T-cell transformation and onset of adult T-cell leukemia. However, the molecular mechanism of the Tax-induced NFkappaB activation remains unknown. One of the mitogen-activated protein kinase kinase kinses (MAP3Ks) members, TAK1, plays a critical role in cytokine-induced activation of NFkappaB, which involves lysine 63-linked (K63) polyubiquitination of NEMO, a noncatalytic subunit of the IkappaB kinase complex. Here we show that Tax induces K63 polyubiquitination of NEMO. However, TAK1 is dispensable for Tax-induced NFkappaB activation, and deubiquitination of the K63 polyubiquitin chain failed to block Tax-induced NFkappaB activation. In addition, silencing of other MAP3Ks, including MEKK1, MEKK3, NIK, and TPL-2, did not affect Tax-induced NFkappaB activation. These results strongly suggest that unlike cytokine signaling, Tax-induced NFkappaB activation does not involve K63 polyubiquitination-mediated MAP3K activation.
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PMID:HTLV-1 Tax-induced NFkappaB activation is independent of Lys-63-linked-type polyubiquitination. 1741

Since the signal transduction mechanisms responsible for liver regeneration mediated by the plasminogen/plasmin system remain largely undetermined, we have investigated whether plasmin regulates the pro-apoptotic protein Bim(EL) in primary hepatocytes. Plasmin bound to hepatocytes in part via its lysine binding sites (LBS). Plasmin also triggered phosphorylation of ERK1/2 without cell detachment. The plasmin-induced phosphorylation of ERK1/2 was inhibited by the LBS inhibitor epsilon-aminocaproic acid (EACA), the serine protease inhibitor aprotinin, and the MEK inhibitor PD98059. DFP-inactivated plasmin failed to phosphorylate ERK1/2. Plasmin temporally decreased the starvation-induced expression of Bim(EL) and activation of caspase-3 via the ERK1/2 signaling pathway, resulting in an enhancement of cell survival. The amount of mRNA for Bim increased 1 day after the injection of CCl(4) in livers of plasminogen knockout (Plg-KO) and the wild-type (WT) mice. The increase in Bim(EL) protein persisted for at least 7 days post-injection in livers of Plg-KO mice, whereas WT mice showed an increase in Bim(EL) protein 1 day after the injection. Plg-KO and WT mice showed notable phosphorylation of ERK1/2 7 and 3 days after the injection of CCl(4), respectively. Our data suggest that the plasminogen/plasmin system could decrease Bim(EL) expression via the ERK1/2 signaling pathway during liver regeneration.
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PMID:Plasmin decreases the BH3-only protein BimEL via the ERK1/2 signaling pathway in hepatocytes. 1748 86

Matrix metalloproteinases (MMPs) contribute to the matrix-degrading phenotype of mycobacterial diseases. Considering that MMPs could contribute to the mutual exacerbation of both Mycobacterium avium and HIV in coinfections, it is of importance to understand the mechanisms of M. avium-induced MMP induction. Focusing on MMP-9, our work demonstrates that a cyclooxygenase-2 (COX-2)-dependent signalling loop is critical for activation of MMP-9 transcription in RAW264.7 cells and murine bone marrow-derived macrophages. M. avium-stimulated MMP-9 induction involves the p65 and p50 subunits of NF-kappaB and the c-Fos and c-jun subunits of AP-1. The c-Fos gene is upregulated in a MEK1-dependent manner in M. avium-challenged macrophages. M. avium-induced MMP-9 gene induction requires the histone acetyltransferase p300 and chromatin modifications involving phosphorylation of p65 at serine 276 and its acetylation at lysines 221 and 310. At the same time, histone H3 modified by mitogen and stress-activated protein kinase 1 (MSK1)-dependent phosphorylation on serine 10 and by acetylation on lysine 14, typical signatures linked to transcriptional activation, also associates with the MMP-9 promoter following M. avium challenge. Taken together, our results show that co-ordinated post-translational modifications of p65 and histone H3 involving phosphorylation and acetylation drive COX-2-dependent transcriptional activation of the MMP-9 gene in response to challenge of macrophages with M. avium.
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PMID:Mycobacterium avium-induced matrix metalloproteinase-9 expression occurs in a cyclooxygenase-2-dependent manner and involves phosphorylation- and acetylation-dependent chromatin modification. 1759 Jan 63

Proteins containing the PB1 domain, a protein interaction module conserved in animals, fungi, amoebas, and plants, participate in diverse biological processes. The PB1 domains adopt a ubiquitin-like beta-grasp fold, containing two alpha helices and a mixed five-stranded beta sheet, and are classified into groups harboring an acidic OPCA motif (type I), the invariant lysine residue on the first beta strand (type II), or both (type I/II). The OPCA motif of a type I PB1 domain forms salt bridges with basic residues, especially the conserved lysine, of a type II PB1 domain, thereby mediating a specific PB1-PB1 heterodimerization, whereas additional contacts contribute to high affinity and specificity of the modular interaction. The canonical PB1 dimerization is required for the formation of complexes between p40(phox) and p67(phox) (for activation of the NADPH oxidase crucial for mammalian host defense), between the scaffold Bem1 and the guanine nucleotide exchange factor Cdc24 (for polarity establishment in yeasts), and between the polarity protein Par6 and atypical protein kinase C (for cell polarization in animal cells), as well as for the interaction between the mitogen-activated protein kinase kinase kinases MEKK2 or MEKK3 and the downstream target mitogen-activated protein kinase kinase MEK5 (for early cardiovascular development in mammals). PB1 domains can also mediate interactions with other protein domains. For example, an intramolecular interaction between the PB1 and PX domains of p40(phox) regulates phagosomal targeting of the microbicidal NADPH oxidase; the PB1 domain of MEK5 is likely responsible for binding to the downstream kinase ERK5, which lacks a PB1 domain; and the scaffold protein Nbr1 associates through a PB1-containing region with titin, a sarcomere protein without a PB1 domain. This Review describes various aspects of PB1 domains at the molecular and cellular levels.
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PMID:Structure and function of the PB1 domain, a protein interaction module conserved in animals, fungi, amoebas, and plants. 1772 78


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