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)

Morphine sulfate causes immunomodulatory and immunosuppressive effects in human. In this study, the signaling pathway involved in these morphine effects was studied. Addition of morphine sulfate to human CEMx174 lymphocytic cells resulted in increased expression of mitogen-activated protein kinase cascade proteins. Morphine enhanced the cellular levels of ERK1 (44 kDa), ERK2 (42 kDa), a 54-kDa ERK, MEK1 (45 kDa), and MEKK (78 kDa). A time-dependent increase in the activated (Thr and Tyr dually phosphorylated) state of ERK1 and ERK2 was also observed. Naloxone, a morphine antagonist, reversed the observed morphine effects, implicating a micro opioid receptor-mediated process. These findings suggest that mitogen-activated protein kinases are important intermediates in signal transduction pathways initiated by morphine receptors in immune cells.
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PMID:Induction and activation of mitogen-activated protein kinases of human lymphocytes as one of the signaling pathways of the immunomodulatory effects of morphine sulfate. 934 Nov 10

Receptors coupled to pertussis toxin (PTX)-sensitive Gi proteins regulate T lymphocyte cytokine secretion, proliferation, and chemotaxis, yet little is known about the molecular mechanisms of Gi protein signaling in mammalian lymphocytes. Using the Jurkat T lymphocyte cell line, we found that a stably expressed Gi protein-coupled receptor (the delta-opioid receptor (DOR1)) stimulates MEK-1 and extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2) and transcriptional activity by an ERK target, Elk-1, via a mechanism requiring a PTX-sensitive Gi protein. Levels of beta-adrenergic receptor kinase-1 C-terminal fragment that inhibited signaling by Gi protein beta gamma subunits in these cells had no effect on DOR1 stimulation of either MEK-1- or Elk-1-dependent transcription, indicating that this pathway is independent of beta gamma. Analysis of this betagamma-independent pathway indicates a role for a herbimycin A-sensitive tyrosine kinase. Unlike beta gamma-mediated pathways, the beta gamma-independent pathway was insensitive to RasN17, inhibitors of phosphatidylinositol 3-kinase (PI 3-kinase), and constitutive PI 3-kinase activity. The beta gamma-independent pathway regulates downstream events, since blocking it abrogated both Elk-1-dependent transcription and mobilization of the mitogenic transcription factor, AP-1, in response to DOR1 signaling. These results characterize a novel, Ras- and PI 3kinase-independent pathway for ERK activation by Gi protein signaling that is distinct from ERK activation by beta gamma and may therefore be mediated by the alphai subunit.
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PMID:Gi proteins use a novel beta gamma- and Ras-independent pathway to activate extracellular signal-regulated kinase and mobilize AP-1 transcription factors in Jurkat T lymphocytes. 1039 49

Stimulation of the delta(1)-opioid receptor has been shown to trigger ischemic preconditioning (IPC). Additionally, myocardial ischemia/reperfusion induces the activation of extracellular signal-regulated kinase (ERK). Therefore, we examined the role of ERK in acute cardioprotection induced by delta(1)-opioid receptor stimulation or IPC. Infarct size (IS) was expressed as a percentage of the area at risk (AAR). Control animals had an IS/AAR of 60.6 +/- 1.8. IPC and delta(1)-opioid receptor stimulation with TAN-67 reduced IS/AAR (8.2 +/- 1.3 and 30.2 +/- 2.4). Inhibition of ERK with the selective MEK-1 antagonist, PD 098059 during IPC or TAN-67 administration significantly reduced cardioprotection (41.5 +/- 6.4 and 63.0 +/- 4.8). Western Blot analysis and subsequent densitometry corroborated these observations. Control, TAN-67-, or IPC-treated hearts were harvested after 0, 5, 15, and 30 min of ischemia or 5, 30, and 60 min of reperfusion and separated into cytosolic and nuclear fractions. Both isoforms of ERK (p44 and p42) rapidly increased to greater levels throughout reperfusion in the nuclear fraction of IPC- and opioid-treated versus control rats, however, this increase was not attenuated by PD 098059. Conversely, the rapid activation of the 44-kDa isoform of ERK after 5 min of reperfusion in the cytosolic fraction was significantly increased in IPC- and opioid-treated hearts versus control, and this increase was abolished by pretreatment with PD 098059. Additionally, p42 was activated in the cytosolic fraction of IPC-treated animals. These results suggest a key role for the 44-kDa isoform of ERK in the cytoplasm during cardioprotection induced by either IPC or stimulation of the delta(1)-opioid receptor.
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PMID:Differential activation of extracellular signal regulated kinase isoforms in preconditioning and opioid-induced cardioprotection. 1116 Jun 53

Opioids have been previously shown to confer acute and delayed cardioprotection against a prolonged ischemic insult. We have extensively characterized the signal transduction pathway mediating acute cardioprotection and have suggested a role for extracellular signal regulated kinase (ERK) in this cardioprotection. Therefore, we attempted to determine a role for ERK and the stress activated MAP kinase, p38, in opioid-induced delayed cardioprotection by using selective inhibitors of these pathways. All rats were subjected to 30 min of ischemia and 2 h of reperfusion (I/R). Control animals, injected with saline 48 h prior to I/R, had an infarct size/area at risk (IS/AAR) of 61.6 +/- 1.6.48-h pretreatment with TAN-67 (30 mg/kg), a delta1-opioid receptor agonist, maximally reduced IS/AAR (31.2 +/- 6.5). The involvement of ERK was examined with PD 098059, a selective pharmacological antagonist which inhibits the upstream kinase, MEK-1, that phosphorylates and activates ERK. PD 098059 (0.3 mg/kg) did not alter IS/AAR when administered alone (60.7 +/- 4.9). However, PD 098059 (0.3 mg/kg) administration 30 min prior to TAN-67 (30 mg/kg) completely abolished cardioprotection (61.0 +/- 7.6). The selective p38 inhibitor, SB 203580 (1.0 mg/kg), had no effect on IS/AAR in the absence of TAN-67 (53.1 +/- 2.3). Additionally, SB 203580 (1.0 mg/kg) when administered prior to TAN-67 (30 mg/kg) partially abolished cardioprotection (51.3 +/- 6.4). These results suggest that both ERK and p38 are integral components of opioid-induced delayed cardioprotection and may act via parallel pathways.
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PMID:ERK and p38 MAP kinase activation are components of opioid-induced delayed cardioprotection. 1132 31

The mu-opioid receptor stimulates the activity of extracellular signal-regulated protein kinase 1/2 (ERK1/2) in recombinant human embryonic kidney (HEK) 293 cells but this stimulatory response is abolished by prolonged opioid treatment. Chronic opioid treatment of the same cells has also been shown to induce adenylyl cyclase (AC) superactivation. This study examined the role of ERK1/2 activity in opioid-induced AC superactivation. Acute opioid treatment of HEK 293 cells expressing mu-opioid receptors resulted in the activation of ERK1/2, and this response was abolished in the presence of U0126, a MEK1/2 inhibitor. Despite a complete blockade of ERK1/2 phosphorylation, U0126 did not affect opioid-induced AC superactivation, indicating that ERK1/2 activity was not required for opioid-induced AC superactivation in HEK 293 cells.
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PMID:Role of extracellular signal-regulated kinases in opioid-induced adenylyl cyclase superactivation in human embryonic kidney 293 cells. 1172 Jul 67

Various mechanisms have been proposed for opioid receptor down regulation in different experimental preparations. The present study was aimed to test whether distinct mechanisms can mediate opioid receptor down regulation within the same cell. For this purpose we transfected HEK-293 cells with rat delta-opioid receptor (DOR). We exposed the cells to the opioid agonist etorphine in the absence or presence of various pharmacological agents and measured the binding of the opioid ligand [(3)H]diprenorphine to either isolated cell membranes or whole cells. We found that internalization of the receptors into the cell was mediated by clathrin coated pits and that the internalized receptors were degraded either in lysosomes or by proteosomes. Down regulation involved phosphorylation and at least two different kinases, a tyrosine kinase (TK) and MAPK kinase (MEK), mediated DOR down regulation in parallel routes. G-protein-coupled receptor kinase (GRK) was found to have only a minor role in DOR down regulation in HEK-293 cells. On the other hand, in N18TG2 cells that endogenously express delta-opioid receptors, GRK was the predominant kinase mediating DOR down regulation, with only a minor role for TK and MEK. We conclude that down regulation can take place via divers pathways within the same cell, and that in different cells down regulation is mediated by different mechanisms, depending on the kinase profile of the cells and the compartmentalization of the receptors within the cells.
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PMID:Divers pathways mediate delta-opioid receptor down regulation within the same cell. 1173 Oct 19

Mapping inducible transcription factors has shown that the Edinger-Westphal nucleus is preferentially sensitive to alcohol intoxication. Herein, we characterize the pharmacological and signal transduction mechanisms related to alcohol-induced c-Fos expression in Edinger-Westphal neurons. Using immunohistochemistry, we show that pretreatment with gamma-aminobutyric acid (GABA)-ergic antagonists (4 mg/kg bicuculline and 45 mg/kg pentylenetetrazole) attenuates induction of c-Fos expression by alcohol (2.4 g/kg, intraperitoneal). In addition, 10 mg/kg 2-(2,3-dihydro-2-methoxy-1,4-benzodioxin-2-yl)4,5-dihydro-1H-imidazole (RX 821002), an alpha(2A/D)-adrenoceptor antagonist, and 20 mg/kg haloperidol, a dopamine antagonist, also block alcohol-induced c-Fos expression in Edinger-Westphal neurons. No effects were seen in alcohol-induced c-Fos after the pretreatment of 20 mg/kg propranolol (beta-adrenoceptor antagonist), 10 mg/kg 2-(2-(4-(2-methoxyphenyl)piperazin-1-yl) ethy)-4,4-dimethyl-1,3-(2H,4H)-isoquinolindione dihydrochloride (ARC 239) (alpha(2B/C)-adrenoceptor antagonist), or 30 mg/kg naltrexone (opioid antagonist). Although positive modulators for the GABA(A) receptor (20 mg/kg 3alpha-hydroxy-5alpha-pregnan-20-one and 10-30 mg/kg chlordiazepoxide) and opioid receptor (10 mg/kg morphine) produced significant elevations, agonists for alpha(2)-adrenoceptors (clonidine) and dopamine receptors (apomorphine) had no effect on Edinger-Westphal c-Fos expression. These findings suggest that alcohol-induced c-Fos expression in Edinger-Westphal results from direct interactions with GABA(A) receptors, which are modified by alpha(2A/D)-adrenoceptors and dopamine receptors. Also using immunohistochemistry to identify potential intracellular mechanisms associated with alcohol-induced c-Fos expression in Edinger-Westphal, we show time-dependent increases in serine 727 phospho-signal transducer and activator of transcription 3 (Stat3) but no changes in phospho-cAMP response element-binding protein and phospho-Elk1. Time-dependent increases in phospho-extracellular signal-regulated kinase (ERK) 1/2 were found to occur simultaneously with increases in serine 727 phospho-Stat3. Finally, blockade of ERK 1/2 phosphorylation with the mitogen-activated protein kinase (MEK) 1/2 inhibitor SL327 blocked alcohol-induced c-Fos expression, suggesting that alcohol induces c-Fos in Edinger-Westphal neurons through activation of the MEK1/2-ERK1/2-Stat3 pathway.
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PMID:Alcohol-induced c-Fos expression in the Edinger-Westphal nucleus: pharmacological and signal transduction mechanisms. 1213 Jul 10

The mouse kappa-opioid receptor (KOR) gene is expressed in mouse embryonal carcinoma P19 cells and induced by retinoic acid (RA) within 24 h. An RA-responsive cis-acting element is identified within promoter I of the KOR gene. This element contains a GC box, a putative binding site for transcription factor Sp1. Enhanced binding of Sp1 to this GC box correlates with RA induction of KOR gene. Phosphatase inhibitor (sodium pyrophosphate) decreases RA induction of this promoter, whereas hypophosphorylation of Sp1 results in an increase in its DNA binding affinity to this promoter as demonstrated by in vitro gel retardation and in vivo chromatin immunoprecipitation assays. Consistently, the inhibitor of MEK, PD98058, dose-dependently enhances RA induction of this promoter, suggesting that the ERK signaling pathway is negatively involved in the RA induction of mouse KOR gene activities. Collectively, enhanced binding of Sp1 to promoter I of the KOR gene as a result of inhibiting the ERK pathway contributes to RA induction of this gene in P19.
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PMID:Induction of the mouse kappa-opioid receptor gene by retinoic acid in P19 cells. 1217 13

The hematopoietic-specific Galpha14 links a variety of G protein-coupled receptors to phospholipase Cbeta (PLCbeta) stimulation. Recent studies reveal that several Galpha subunits are capable of activating signal transducer and activator of transcription (STAT) proteins. In the present study, we investigated the mechanism by which Galpha14 mediates receptor-induced stimulation of STAT3. In human embryonic kidney 293 cells, coexpression of Galpha14 with delta-opioid receptor supported [D-Pen2, D-Pen5]enkephalin (DPDPE)-induced STAT3 phosphorylations at both Tyr705 and Ser727 in a pertussis toxin-insensitive manner. The constitutively active Galpha4QL mutant also induced STAT3 phosphorylations at these sites and promoted STAT3-dependent luciferase activity. Requirements for PLCbeta, protein kinase C (PKC), and calmodulin-dependent kinase II (CaMKII) in Galpha14QL-induced STAT3 activation were demonstrated by their respective inhibitors as well as by coexpression of their dominant-negative mutants. Inhibition of c-Src and Janus kinase 2 and 3 activities abolished STAT3 activation induced by Galpha14QL, but no physical association between Galpha14QL and c-Src could be detected by coimmunoprecipitation. Various intermediates along the extracellular signal-regulated kinase signaling cascade were apparently required for Galpha14QL-induced STAT3 activation; they included Ras/Rac1, Raf-1, and mitogen-activated protein kinase kinase-1/2. In contrast, functional blockade of c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, and phosphatidylinositol-3 kinase had no effect on Galpha14QL-induced responses. PLCbeta, PKC, and CaMKII were shown to be involved in Galpha14QL-mediated c-Src phosphorylation. Similar results were obtained with human erythro-leukemia cells upon DPDPE treatment. These results demonstrate for the first time that Galpha14 activation can lead to STAT3 stimulation via a complex signaling network involving multiple intermediates.
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PMID:Signal transducer and activator of transcription 3 activation by the delta-opioid receptor via Galpha14 involves multiple intermediates. 1515 36

Acetylcholine (ACh) and opioid receptor agonists trigger the preconditioned phenotype through sequential activation of the epidermal growth factor (EGF) receptor, phosphatidylinositol 3-kinase (PI3-K), Akt, and nitric oxide synthase (NOS), and opening of mitochondrial (mito) K(ATP) channels with the generation of reactive oxygen species (ROS). Although extracellular signal-regulated kinase (ERK) has recently been reported to be part of this pathway, its location has not been determined. To address this issue, we administered a 5-min pulse of ACh (550 microM) prior to 30 min of ischemia in isolated rabbit hearts. It reduced infarction from 30.4 +/- 2.2% of the risk zone in control hearts to 12.3 +/- 2.8% and co-administration of the MEK, and, therefore, downstream ERK inhibitor U0126 abolished protection (29.1 +/- 4.6% infarction) con.rming ERK's involvement. MitoK(ATP) opening was monitored in adult rabbit cardiomyocytes by measuring ROS production with MitoTracker Red. ROS production was increased by each of three G protein-coupled agonists: ACh (250 microM), bradykinin (BK) (500 nM), and the delta-opioid agonist DADLE (20 nM). Co-incubation with the MEK inhibitors U0126 (500 nM) or PD 98059 (10 microM) blocked the increased ROS production seen with all three agonists. Direct activation of its receptor by EGF increased ROS production and PD 98059 blocked that increase, thus placing ERK downstream of the EGF receptor. Desferoxamine (DFO) which opens mitoK(ATP) through direct activation of NOS also increased ROS. PD 98059 could not block DFO-induced ROS production, placing ERK upstream of NOS. In isolated hearts, ACh caused phosphorylation of both Akt and ERK. U0126 blocked phosphorylation of ERK but not of Akt. The PI3-K inhibitor wortmannin blocked both. Together these data indicate that ERK is located between Akt and NOS.
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PMID:Localizing extracellular signal-regulated kinase (ERK) in pharmacological preconditioning's trigger pathway. 1628 91


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