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)

Neurotrophins such as nerve growth factor (NGF) regulate neuronal survival during development and are neuroprotective in certain models of injury to both the peripheral and the central nervous system. Although many effects of neurotrophins involve long-term changes in gene expression, several recent reports have focused on rapid effects of neurotrophins that do not involve synthesis of new gene products. Because enhanced formation of reactive oxygen species (ROS) represents one consequence of many insults that produce neuronal death, we hypothesized that neurotrophins might influence neuronal function and survival through acute alterations in the production of ROS. Using an oxidation-sensitive compound, dihydrorhodamine, we measured ROS formation in a central nervous system-derived neuronal cell line (GT1-1 trk) and in superior cervical ganglion neurons, both of which express the transmembrane NGF receptor tyrosine kinase, trkA. There was enhanced production of ROS in both cell types in the absence of NGF that was rapidly inhibited by application of NGF; complete inhibition of ROS generation in GT1-1 trk cells occurred within 10 min. NGF suppression of ROS formation was prevented by PD 098059, a specific inhibitor of MEK (mitogen/extracellular receptor kinase, which phosphorylates mitogen-activated protein kinase). The observation that NGF acutely blocks ROS formation in neurons through activation of the mitogen-activated protein kinase pathway suggests a novel mechanism for rapid neurotrophin signaling, and has implications for understanding neuroprotective and other effects of neurotrophins.
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PMID:Rapid suppression of free radical formation by nerve growth factor involves the mitogen-activated protein kinase pathway. 910 9

Stimulation of pheochromocytoma (PC12) cells with the mitogen epidermal growth factor (EGF) produced a rapid and robust accumulation of intracellular reactive oxygen species (ROS), an accumulation which, in other systems, has been shown to be essential for mitogenesis. Brief pretreatment of the cells with nerve growth factor (NGF) suppressed the EGF-mediated ROS increase. EGF failed to produce elevations in ROS in a PC12 variant stably expressing a dominant-negative p21(ras) construct (PC12-N17) or in cells pretreated with the MEK inhibitor PD098059. NGF failed to suppress the increase in ROS in the PC12 variant nnr5, which lacks p140(trk) receptors. The suppression of the increase in ROS by NGF was restored in nnr5 cells stably expressing p140(trk) (nnr5-trk), but NGF failed to prevent the increase in ROS in nnr cells expressing mutant p140(trk) receptors that lack binding sites for Shc and phospholipase Cgamma. Among several inhibitors of superoxide-generating enzymes, only the lipoxygenase inhibitor, nordihydroguaiaretic acid reduced EGF-mediated ROS accumulation. The inhibitory action of NGF on ROS production was mimicked by the nitric oxide donor, sodium nitroprusside, and was blocked by an inhibitor of nitric-oxide synthetase, L-nitroarginine methyl ester. These results suggest a novel mechanism for the rapid interruption of mitogenic signaling by the neurotrophin NGF.
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PMID:Nerve growth factor treatment prevents the increase in superoxide produced by epidermal growth factor in PC12 cells. 971 26

The cellular mechanisms that underlie nerve growth factor (NGF) induced increase in Ca(2+)-channel current in adult bullfrog sympathetic B-neurons were examined by whole cell recording techniques. Cells were maintained at low density in neuron-enriched, defined-medium, serum-free tissue culture for 6 days in the presence or absence of NGF (200 ng/ml). The increase in Ba2+ current (IBa) density induced by NGF was attenuated by the RNA synthesis inhibitor cordycepin (20 microM), by the DNA transcription inhibitor actinomycin D (0.01 microgram/ml), by inhibitors of Ras isoprenylation (perillic acid 0.1-1.0 mM or alpha-hydroxyfarnesylphosphonic acid 10-100 microM), by tyrosine kinase inhibitors genistein (20 microM) or lavendustin A (1 microM), and by PD98059 (10-100 microM), an inhibitor of mitogen-activated protein kinase kinase. Inhibitors of the phosphatidylinositol 3-kinase (PI3K) pathway (wortmannin, 100 nM, or LY29400, 100 microM) were ineffective as were inhibitors of phospholipase C gamma (U73122 or neomycin, both 100 microM). The effect of NGF persisted in Ca(2+)-free medium that contained 1.8 mM Mg2+ and 2 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. It was mimicked by a Trk antibody that was capable of inducing neurite outgrowth in explant cultures of bullfrog sympathetic ganglion. Antibodies raised against the low-affinity p75 neurotrophin receptor were ineffective in blocking the effect of NGF on IBa. These results suggest that NGF-induced increase in Ca2+ channel current in adult sympathetic neurons results, at least in part, from new channel synthesis after Trk activation of Ras and mitogen activated protein kinase by a mechanism that is independent of extracellular Ca2+.
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PMID:Involvement of Ras/MAP kinase in the regulation of Ca2+ channels in adult bullfrog sympathetic neurons by nerve growth factor. 974 44

We have shown that estrogen elicits a selective enhancement of the growth and differentiation of axons and dendrites (neurites) in the developing CNS. We subsequently demonstrated widespread colocalization of estrogen and neurotrophin receptors (trk) within developing forebrain neurons and reciprocal transcriptional regulation of these receptors by their ligands. Using organotypic explants of the cerebral cortex, we tested the hypothesis that estrogen/neurotrophin receptor coexpression also may result in convergence or cross-coupling of their signaling pathways. Estradiol elicited rapid (within 5-15 min) tyrosine phosphorylation/activation of the mitogen-activated protein (MAP) kinases, ERK1 and ERK2, that persisted for at least 2 hr. This extracellular signal-regulated protein kinase (ERK) activation was inhibited successfully by the MEK1 inhibitor PD98059, but not by the estrogen receptor (ER) antagonist ICI 182,780, and did not appear to result from estradiol-induced activation of trk. Furthermore, we also found that estradiol elicited an increase in B-Raf kinase activity. The latter and subsequent downstream events leading to ERK activation may be a consequence of our documentation of a multimeric complex consisting of, at least, the ER, hsp90, and B-Raf. These novel findings provide an alternative mechanism for some of the estrogen actions in the developing CNS and could explain not only some of the very rapid effects of estrogen but also the ability of estrogen and neurotrophins to regulate the same broad array of cytoskeletal and growth-associated genes involved in neurite growth and differentiation.
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PMID:Estrogen-induced activation of mitogen-activated protein kinase in cerebral cortical explants: convergence of estrogen and neurotrophin signaling pathways. 995 96

The signaling pathways that regulate smooth muscle cell migration and proliferation are incompletely understood. Smooth muscle cells express at least 3 families of receptor tyrosine kinases that mediate cell migration: platelet-derived growth factor (PDGF) receptors, the trk family of neurotrophin receptors, and insulin-like growth factor 1 receptor. The neurotrophin, nerve growth factor (NGF), and insulin-like growth factor 1 induce the migration but not the proliferation of smooth muscle cells, whereas PDGF-BB stimulates both responses. To determine whether distinct signaling pathways downstream of receptor tyrosine kinases specifically mediate smooth muscle cell migration or proliferation, the ligand-induced activation of different signaling pathways in smooth muscle cells was examined. NGF induces prolonged activation of the Shc/MAP kinase pathway and phospholipase Cgamma compared with PDGF-BB. The activation of phosphatidylinositol-3 kinase, however, was 10-fold greater in response to PDGF-BB compared with NGF. Insulin-like growth factor 1 activates only phosphatidylinositol-3 kinase. Pharmacological inhibitors of phosphatidylinositol-3 kinase, Wortmannin and LY294002, inhibit PDGF-BB and NGF-induced migration, whereas an inhibitor of MAP kinase kinase, PD98059, has no effect. Our results suggest that (1) different receptor tyrosine kinases use similar patterns of activation of signaling pathways to mediate distinct biological outcomes of cell migration and proliferation, (2) NGF activates signaling proteins in smooth muscle cells similar to those activated during NGF-induced neuronal differentiation, and (3) the combinatorial effects of different signaling pathways are important for the regulation of smooth muscle cell migration and proliferation. Further studies using mutant trk receptors will help to define the signal transduction pathways mediating NGF-induced smooth muscle cell migration.
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PMID:NGF activates similar intracellular signaling pathways in vascular smooth muscle cells as PDGF-BB but elicits different biological responses. 1019 34

The human nerve growth factor receptor (TrkA) contains four potential N-glycosylation sites that are highly conserved within the Trk family of neurotrophin receptors, and nine additional sites that are less well conserved. Using a microscale deglycosylation assay, we show here that both conserved and variable N-glycosylation sites are used during maturation of TrkA. Glycosylation at these sites serves two distinct functions. First, glycosylation is necessary to prevent ligand-independent activation of TrkA. Unglycosylated TrkA core protein is phosphorylated even in the absence of ligand stimulation and displays constitutive kinase activity as well as constitutive interaction with the signaling molecules Shc and PLC-gamma. Second, glycosylation is required to localize TrkA to the cell surface, where it can trigger the Ras/Raf/MAP kinase cascade. Using confocal microscopy, we show that unglycosylated active Trk receptors are trapped intracellularly. Furthermore, the unglycosylated active TrkA receptors are unable to activate kinases in the Ras-MAP kinase pathway, MEK and Erk. Consistent with these biochemical observations, unglycosylated TrkA core protein does not promote neuronal differentiation in Trk PC12 cells even at high levels of constitutive catalytic activity.
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PMID:TrkA glycosylation regulates receptor localization and activity. 1023 85

Brain-derived neurotrophic factor (BDNF) can regulate the maturation of developing cerebellar granule neurons. Within 1-2 days of culture, BDNF induces the expression of granule neuron terminal differentiation markers, particularly GABA(A) receptor alpha6 subunit (GABA(A)alpha6) mRNA. Other trophic factors including insulin-like growth factor, the neurotrophin NT-3, pituitary adenylate cyclase-activating polypeptide (PACAP), and fetal bovine serum failed to induce this early expression. The expression of other GABA(A) receptor subunits, including alpha1 and gamma2, was also enhanced by exposure of developing granule neurons to BDNF. This BDNF-dependent expression of GABA(A) receptor subunit mRNAs could be effectively blocked by treatment with the mitogen-activated protein kinase kinase (MEK) inhibitors, PD98059 or U0126. In the absence of BDNF, GABA(A)alpha6 expression occurs but not until 3-4 days of culture. This BDNF-independent expression of GABA(A)alpha6 was also inhibited by PD98059. Further studies showed that the BDNF-dependent expression GABA(A)alpha6 could also be reduced by LY294002, an inhibitor of the phosphatidylinositol 3-kinase, or depolarizing concentrations of KCl. These results thus suggest that both BDNF-dependent and -independent expressions of GABA(A) receptor subunits require the activation of MEK and the mitogen-activated protein kinase (MAPK) pathway. However, it is also likely that other signaling pathways modulate this maturation process.
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PMID:MEK inhibitors block BDNF-dependent and -independent expression of GABA(A) receptor subunit mRNAs in cultured mouse cerebellar granule neurons. 1064 67

Conditioned medium from stimulated microglia and from the monocyte/macrophage cell line (RAW 264.7; MC-CM) promotes the differentiation of cholinergic neurons from undifferentiated progenitors in the septal nuclei and adjacent basal forebrain (BF). We have studied the regulation of this process by measuring the activity of choline acetyltransferase (ChAT) in cultured BF taken from embryonic day 16 rat brain. Inhibition of either xanthine oxidase with allopurinol or nitric oxide synthase with N(G)-monomethyl-l-arginine produces a small but significant improvement in the efficacy of MC-CM while inclusion of pyrrolidine dithiocarbamate, a hydroxyl radical scavenger widely used as an antioxidant, lowers MC-CM-induced ChAT activity. Addition of nerve growth factor (NGF) but not brain-derived neurotrophic factor or glial-derived neurotrophic factor together with MC-CM has a synergistic effect on both ChAT activity and ChAT mRNA, raising ChAT activity as much as 29-fold and ChAT mRNA almost 15-fold. While MC-CM raised mRNA for trkA, the effect was not synergistic with NGF. mRNA for the common neurotrophin receptor (p75NTR) showed a modest synergistic increase. Blockade of the Ras/Raf/ERK [extracellular signal-regulated kinase, also known as mitogen-activated protein [(MAP) kinase] signal transduction pathway with either PD28059 (an inhibitor of MAP kinase/ERK kinase kinase or MEK) or N-acetyl-S-farnesyl-l-cysteine (an inhibitor of Ras farnesylation and, hence, activation) inhibited the action of MC-CM. Moreover, a subpopulation of cells responded rapidly to MC-CM with an increased appearance of phosphorylated ERK. Because NGF also utilizes this pathway, synergy may occur along this signal transduction pathway.
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PMID:Macrophage cell-conditioned medium promotes cholinergic differentiation of undifferentiated progenitors and synergizes with nerve growth factor action in the developing basal forebrain. 1068 94

The common neurotrophin receptor (p75NGFR) can signal in vitro through activation of the c-Jun N-terminal kinase (JNK) pathway and nuclear translocation of NFKappaB. Activation of JNK and its substrate c-Jun can lead to apoptosis. We investigated these activities in vivo by comparing immunoreactivity for phosphorylated(p) SEK-1 (or MKK4, which activates JNK), c-Jun (ser63, ser73) and nuclear translocation of NFKappaB-p50 in tissue sections through the forebrain of control and p75NGFR-deficient mice. During postnatal development, SEK1p-immunoreactivity was detectable in p75NGFR-positive cholinergic neurons and p75NGFR-negative neurons throughout the forebrain in control mice. During development, few cells contained c-Junp, although many neurons contained c-Jun. No obvious c-Jun immunostaining was present in the adult forebrain. At any age, NFKappaB-p50 immunoreactivity was seen in nuclei of most cells throughout the forebrain. Following fimbria fornix transection in adult mice, few basal forebrain neurons contained SEK1p while many axotomized choline acetyltransferase (ChAT)-positive neurons contained c-Junp and nuclear NFKappaB-p50. The immunostaining patterns of SEK1p, c-Junp and NFKB during development and following injury were largely similar in p75NGFR-deficient mice. During development, cells throughout the forebrain had TdT-mediated dUTP-biotin nick end labelling (TUNEL)-labelling (a potential marker for apoptosis), however, their presence was not predicted by number of neurons stained for SEK1p or c-Junp. These results suggest that the expected activation of the JNK pathway by p75NGFR, as well as the expected relationship between SEK1 and downstream activation of c-Jun do not occur in the mammalian forebrain. Also, these results suggest that this activation does not necessarily lead to cell death.
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PMID:SEK1/MKK4, c-Jun and NFKappaB are differentially activated in forebrain neurons during postnatal development and injury in both control and p75NGFR-deficient mice. 1088 28

To determine how signals emanating from Trk transmit neurotrophin actions in primary neurons, we tested the ability of TrkB mutated at defined effector binding sites to promote sympathetic neuron survival or local axon growth. TrkB stimulated signaling proteins and induced survival and growth in a manner similar to TrkA. TrkB mutated at the Shc binding site supported survival and growth poorly relative to wild-type TrkB, whereas TrkB mutated at the PLC-gamma1 binding site supported growth and survival well. TrkB-mediated neuronal survival was dependent on P13-kinase and to a lesser extent MEK activity, while growth depended upon both MEK and P13-kinase activities. These results indicate that the TrkB-Shc site mediates both neuronal survival and axonal outgrowth by activating the P13-kinase and MEK signaling pathways.
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PMID:The TrkB-Shc site signals neuronal survival and local axon growth via MEK and P13-kinase. 1098 47


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