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)

Angiotensin II (Ang II) is a potent pressor hormone, a stimulus for vascular smooth muscle hypertrophy and an activator of multiple tyrosine kinases. The physiological effects of Ang II are mediated through activation of AT1 and AT2 receptors, receptors that have been coupled to tyrosine kinase(s) and tyrosine phosphatases, respectively. Agonists of G protein-coupled receptors, of which Ang II is one, have recently been shown to stimulate smooth muscle contraction in part via activation tyrosine kinases. We tested the hypothesis that Ang II-induced contraction in the rat aorta was dependent on activation of tyrosine kinase(s) and specifically investigated the role of the tyrosine kinase mitogen-activated protein kinase kinase (MEK), a kinase important to the mitogen activated protein kinase (MAPK) pathway. Rat thoracic aortic strips denuded of endothelium and cultured aortic smooth muscle cells were used in isolated tissue baths for measurement of isometric contractile force and Western analyses of protein tyrosyl-phosphorylation. Ang II (0.1-100 nM)-induced contraction in the aorta was completely blocked by the AT1 receptor antagonist losartan (1 microM) but unaffected by the AT2 receptor antagonist PD123319 (100 nM) or tyrosine phosphatase inhibitor sodium orthovanadate (1 microM), indicating an AT1 receptor mediates aortic contraction to Ang II. Neither the tyrosine kinase inhibitor genistein (5 microM), inactive tyrosine kinase inhibitor daidzein (5 microM) nor MEK inhibitor PD098059 (10 microM) reduced Ang II-induced contraction; the concentrations of inhibitors used maximally reduced contraction stimulated by other agonists of G protein-coupled receptors such as serotonin. Moreover, Ang II-induced contraction was not altered by the combination of PD098059 and PD123319, indicating that it is unlikely AT2 receptor stimulation masks activation of the MAPK pathway through AT1 receptor activation. The nonflavone tyrosine kinase inhibitor tyrphostin B42 (30 microM) reduced Ang II-induced maximal contraction (to 11.2% control) but, unlike the other tyrosine kinase inhibitors, also reduced KCl-induced contraction (to 55.2% control), indicating a probable nonselectivity of tyrphostin B42. Ang IIinduced maximal contraction was reduced by the L-type voltage gated calcium channel antagonist nifedipine (50 nM), consistent with the activation of calcium channels by Ang II. In cultured rat aortic smooth muscle cells, Ang II (0.1-1000 nM) stimulated concentration-dependent tyrosyl-phosphorylation of the extracellular signal regulated kinase (Erk) mitogen activated protein kinases (maximal stimulation, fold basal: Erk-1 = 17-fold, Erk-2 = 3-fold), indicating that Ang II can activate MEK. Losartan (1 microM) abolished Ang II (10 nM)-induced Erk tyrosyl-phosphorylation and PD098059 (10 microM), which did not diminish Ang II-induced aortic contraction, reduced Ang II (10 nM)-stimulated phosphorylation of Erk-2 by 72%. Finally, Ang II (1 microM) increased tyrosyl-phosphorylation of the Erk proteins in isolated aorta exposed to Ang II for 5 min. Thus, while Ang II can stimulate both MEK activation and vascular contraction via interaction with AT1 receptors, stimulation of MEK does not appear to be important for Ang II-induced contraction. These findings dissociate the process of Ang II-stimulated Erk protein tyrosyl-phosphorylation from Ang II-induced contraction in the rat aorta.
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PMID:Dissociation of angiotensin II-stimulated activation of mitogen-activated protein kinase kinase from vascular contraction. 973 8

The presence of GABA and its receptors early in rodent nervous system development has lead to speculation on the role of this transmitter system in neuroblast proliferation, migration and differentiation. We studied the effect of GABA and GABA agonists on immature cerebellar granule cell proliferation and survival. Cerebellar granule cell suspensions were obtained from 6-8-day-old rats and grown in culture for up to 7 days in serum-containing or serum-free medium. The addition of GABA (0.1-100 microM) or muscimol (0.01-10 microM) 2 h after inoculation and harvested 22 h later, lead to an increase in 3H-thymidine incorporation over control samples with the correspondent increase in granule cells number assayed 48 h later. The effect on cell proliferation exerted by GABAA agonists was blocked by MgCl2 and nifedipine, as well as by the chloride channel blocker, picrotoxin (50 microM), and the GABAA receptor specific blocker, bicuculline (50 microM). The increase on cell proliferation induced by GABA also was blocked by PD98059 (75 microM), a specific inhibitor of the mitogen-activated protein kinase kinase (MAPKK). GABAA receptor-mediated proliferation was consistently seen in cells inoculated in serum-containing medium supplemented with 25 mM KCl but not seen in serum-free medium, with 5 mM or 25 mM KCl. The presence of serum did not enhance the survival of cerebellar granule cells grown for 7 days in either 5 mM or 25 mM KCl. Additionally, neither GABA nor muscimol applied from day 2 to day 7 in vitro affected cell survival in any culture condition. We conclude that GABA and GABAA receptor agonists influence granule cell proliferation but not survival and that this effect is mediated by a calcium influx via voltage-dependent calcium channel activation, with a subsequent activation of the MAPK cascade.
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PMID:GABA induces proliferation of immature cerebellar granule cells grown in vitro. 1036 96

Exposure of C6 glioma cells to endothelin-1 (ET-1) caused dose-dependent (10(-11) M to 10(-7) M) increments in intracellular calcium concentration ([Ca2+]i) and c-fos mRNA expression (4.5-fold) that were abolished by the endothelinA receptor antagonist, BQ610, and by inhibition of phospholipase C with U73122. ET-1 stimulated c-fos mRNA expression was also inhibited by protein kinase C inhibition (chelerythrine) and by the MAP kinase kinase inhibitor PD98059, but not by inhibitors of tyrosine kinases, protein kinase A type I or II, calmodulin kinase II, or calcium channel blockade. C6 cells treated with ET-1 demonstrated a significant increase in MAP kinase activity as evidenced by Western blotting. These results indicate a mechanism of long-term signaling by ET-1 involving an ET(A) receptor-mediated, phospholipase C(beta)-linked pathway that is dependent on protein kinase C and MAP kinase activation.
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PMID:Endothelin-1 stimulates c-fos mRNA expression in C6 glioma cells via MAP kinase pathway. 1050 67

Spatial and temporal changes in intracellular calcium concentrations are critical for controlling gene expression in neurons. In many neurons, activity-dependent calcium influx through L-type channels stimulates transcription that depends on the transcription factor CREB by activating a calmodulin-dependent pathway. Here we show that selective influx of calcium through P/Q-type channels is responsible for activating expression of syntaxin-1A, a presynaptic protein that mediates vesicle docking, fusion and neurotransmitter release. The initial P/Q-type calcium signal is amplified by release of calcium from intracellular stores and acts through phosphorylation that is dependent on the calmodulin-dependent kinase CaM K II/IV, protein kinase A and mitogen-activated protein kinase kinase. Initiation of syntaxin-1A expression is rapid and short-lived, with syntaxin-1A ultimately interacting with the P/Q-type calcium channel to decrease channel availability. Our results define an activity-dependent feedback pathway that may regulate synaptic efficacy and function in the nervous system.
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PMID:P/Q-type calcium channels mediate the activity-dependent feedback of syntaxin-1A. 1054 6

Mitogen-activated protein (MAP) kinase or extracellular signal-regulated kinase (ERK) are activated by many extracellular stimuli. In this study, we investigated whether MAP kinase and tyrosine kinases were involved in transducing signals in Toxoplasma gondii. Using anti-phosphotyrosine and anti-active ERK antibodies, we identified several phosphorylated proteins in Toxoplasma. In particular, phosphorylation of a 47 kDa and a 43 kDa protein increased strongly after calcium influx. MAP kinase activity, caused by calcium influx, was determined using either a specific synthetic peptide, or an in gel kinase assay. Conversely, calcium chelators (BAPTA and EGTA) and a calcium channel blocker (nifedipine) inhibited this activation. Also, a specific inhibitor of MAP kinase kinase (PD 098059) blocked MAP kinase activity. Three specific anti-MAP kinase antibodies recognized the 47 kDa and 43 kDa proteins, which were putatively identified as ERK1- and ERK2-homologs, respectively. These findings provide early evidence of signal transduction involving members of the MAP kinase family in T. gondii.
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PMID:Biochemical characterization of mitogen-activated protein (MAP) kinase activity in Toxoplasma gondii. 1093 11

This study was conducted to examine the mechanism(s) of synergistic interaction of histamine- and adrenaline-mediated human platelet aggregation. We found that platelet aggregation mediated by subthreshold concentrations of histamine (1-4 microm) plus adrenaline (0.5-2 microm) is inhibited by both an alpha(2)-adrenoceptor blocker (yohimbine) and a histamine (H1) receptor antagonist (diphenhydramine). In examining the role of the downstream signalling pathway, we found that such an interaction is inhibited by the calcium channel blockers verapamil and diltiazem. However, platelet aggregation by adrenaline plus histamine was inhibited by very low concentrations of the phospholipase C (PLC) inhibitor, U73122 (IC(50)= 1.2 microm), the MEK inhibitor, PD98059 (IC(50)= 1.1 microm) and the cyclo-oxygenase (COX) inhibitor, indomethacin (IC(50)= 7 microm). However the inhibition of receptor tyrosine kinase, protein kinase C and phosphatidylinositol 3-kinase by genistien, chelerythrine and wortmannin, respectively, had no significant effect on aggregation. Similarly the nitric oxide donor (SNAP) had no effect on this synergism. These data suggest that the synergistic effect of histamine and adrenaline during human platelet aggregation is receptor mediated and involves activation of PLC, COX and MAP kinase signalling pathways.
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PMID:Synergistic interaction of adrenaline and histamine in human platelet aggregation is mediated through activation of phospholipase, map kinase and cyclo-oxygenase pathways. 1102 12

The mechanism of alpha(2) adrenoceptor-mediated vasoconstriction is unknown, but may involve activation of voltage-sensitive calcium channels, and/or a protein tyrosine kinase. Recently the extracellular signal-regulated kinase (Erk) cascade, often an event downstream of tyrosine kinase activation, has been shown to mediate vasoconstriction to a variety of agents. The aim of this present study was to determine the involvement of the Erk signal transduction cascade in alpha(2) adrenoceptor-mediated vasoconstriction, and to confirm the involvement of activation of voltage-sensitive calcium channels, and protein tyrosine kinase. Contractions to the alpha(2) adrenoceptor agonist UK14304 in the porcine palmar lateral vein in vitro were reduced 70 - 80% by the MEK inhibitors PD98059 (10 - 50 microM) and U0126 (10 - 50 microM), indicating the involvement of the Erk signal transduction cascade. Immunoblots also demonstrated an increase in the phosphorylated (activated) form of Erk in palmar lateral vein segments after contraction with UK14304, which was inhibited by PD98059 and U0126. The calcium channel blockers nifedipine and verapamil, or removal of extracellular calcium inhibited UK14304-induced contractions and phosphorylation of Erk, demonstrating the importance of an influx of extracellular calcium. UK14304-induced contractions were inhibited by PP2 (1 - 10 microM), a selective inhibitor of Src tyrosine kinases, but not by PP3, an inactive analogue. PP2 also prevented the phosphorylation of Erk by UK14304. These data demonstrate that alpha(2) adrenoceptor-mediated vasoconstriction in the porcine palmar lateral vein is dependent upon activation of the Erk signal transduction cascade, which is downstream of an influx of extracellular calcium, and activation of Src tyrosine kinases.
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PMID:Role of the extracellular signal-regulated kinase (Erk) signal transduction cascade in alpha(2) adrenoceptor-mediated vasoconstriction in porcine palmar lateral vein. 1145 59

Bisphosphonates (BPs) are analogues of pyrophosphate, which are widely used for the treatment of different pathologies associated with imbalances in bone turnover. Recent evidence suggested that cells of the osteoblastic lineage might be targets of the action of BPs. The objective of this work was to determine whether BPs induce proliferation of osteoblasts and whether this action involves activation of the extracellular signal-regulated kinases (ERKs). We have shown that three different BPs (olpadronate, pamidronate, and etidronate) induce proliferation in calvaria-derived osteoblasts and ROS 17/2.8 as measured by cell count and by [3H]thymidine uptake. Osteoblast proliferation induced by all BPs diminished to control levels in the presence of U0126, a specific inhibitor of the upstream kinase MEK 1 responsible for ERK phosphorylation. Consistent with this, BPs induced ERK activation as assessed by in-gel kinase assays. Phosphorylation of ERK1/2 was induced by the BPs olpadronate and pamidronate within 30 s, followed by rapid dephosphorylation, whereas etidronate induced phosphorylation of ERKs only after 90 s of incubation and returned to basal levels within 15-30 minutes. In addition, both BP-induced cell proliferation and ERK phosphorylation were reduced to basal levels in the presence of nifedipine, an L-type voltage-sensitive calcium channel (VSCC) inhibitor. These results show that BP-induced proliferation of osteoblastic cells is mediated by activation of ERKs and suggest that this effect requires influx of Ca2+ from the extracellular space through calcium channels.
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PMID:Extracellular signal-regulated kinases and calcium channels are involved in the proliferative effect of bisphosphonates on osteoblastic cells in vitro. 1169 1

We have investigated mechanisms of nicotine-induced phosphorylation of extracellular signal-regulated protein kinase (p42/44 MAP kinase, ERK) and cAMP response element binding protein (CREB) in PC12h cells. Nicotine transiently induced ERK phosphorylation at more than 1 microM. The maximal level of nicotine-induced ERK phosphorylation was lower than that of the membrane depolarization induced and, to a great extent, the nerve growth factor (NGF)-induced ERK phosphorylation. Nicotinic acetylcholine receptor (nAChR) alpha7 subunit-selective inhibitors had no significant effect on nicotine-induced ERK phosphorylation. L-Type voltage-sensitive calcium channel antagonists inhibited nicotine-induced ERK phosphorylation. Calcium imaging experiments showed that alpha7-containing nAChR subtypes were functional at 1 microM of nicotine in the nicotine-induced calcium influx, and non-alpha7 nAChRs were prominent in the Ca(2+) influx at 50 microM of nicotine. An expression of dominant inhibitory Ras inhibited nicotine-induced ERK phosphorylation. A calmodulin antagonist, a CaM kinase inhibitor, a MAP kinase kinase inhibitor inhibited nicotine-induced ERK and CREB phosphorylation. The time course of the phosphorylation of CREB induced by nicotine was similar to that of ERK induced by nicotine. These results suggest that non-alpha7 nAChRs are involved in nicotine-induced ERK phosphorylation through CaM kinase and the Ras-MAP kinase cascade and most of the nicotine-induced CREB phosphorylation is mediated by the ERK phosphorylation in PC12h cells.
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PMID:Nicotine-induced phosphorylation of extracellular signal-regulated protein kinase and CREB in PC12h cells. 1170 52

GnRH acts on pituitary gonadotropes to stimulate the synthesis and release of LH and FSH. However, the signaling pathways downstream of the GnRH receptor that mediate these effects are not fully understood. In this paper, we demonstrate that GnRH activates ERK, c-Jun N-terminal kinase, and p38MAPK in the LbetaT2 gonadotrope cell line. Phosphorylation of both ERK and p38MAPK are stimulated rapidly, 30- to 50-fold in 5 min, but activation of c-Jun N-terminal kinase has slower kinetics, reaching only 10-fold after 30 min. Activation of ERK by GnRH is blocked by inhibition of MAPK kinase (MEK) and partially blocked by inhibition of PKC and calcium, but not PI3K or p38MAPK signaling. We demonstrate that phosphorylated ERK accumulates in the nucleus in a PKC-dependent manner. We also show that GnRH induces c-fos and LHbeta subunit protein expression in LbetaT2 cells via MEK. Experiments with EGTA or calcium channel antagonists indicated that calcium influx is important for the induction of both genes by GnRH. In conclusion, these results show that GnRH activates all three MAPK subfamilies in LbetaT2 cells and induces c-fos and LHbeta protein expression through calcium and MEK-dependent mechanisms. These results also demonstrate that the nuclear translocation of ERK by GnRH requires PKC signaling.
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PMID:GnRH activates ERK1/2 leading to the induction of c-fos and LHbeta protein expression in LbetaT2 cells. 1187 99


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