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)

The major invasive factor of Yersinia enterocolitica, the invasin (Inv) protein, induces proinflammatory host cell responses, including interleukin-8 (IL-8) secretion from human epithelial cells, by engagement of beta1 integrins. The Inv-triggered beta1 integrin signaling involves the small GTPase Rac; the activation of MAP kinases, such as p38, MEK1, and JNK; and the activation of the transcription factor NF-kappaB. In the present study, we demonstrate that Y. enterocolitica YadA, which is a major adhesin of Y. enterocolitica with pleiotropic virulence effects, induces IL-8 secretion in epithelial cells. The abilities of YadA and Inv to promote adhesion to and invasion of HeLa cells and to induce IL-8 production by the cells were investigated by expression of YadA and Inv in Escherichia coli. While YadA mediates efficacious adhesion to HeLa cells, it mediates marginal invasion compared with Inv. Both YadA and Inv trigger comparable levels of IL-8 production. Conformational changes of the YadA head domain by mutation of NSVAIG-S motifs, which abolish collagen binding, also abolish adhesion of Yersinia to HeLa cells and YadA-mediated IL-8 secretion. Furthermore, experiments in which blocking antibodies against beta1 integrins were used demonstrate that beta1 integrins are crucial for YadA-mediated IL-8 secretion. Inhibitor studies demonstrate the involvement of small GTPases and MAP kinases, such as p38, MEK1, and JNK, indicating that beta1 integrin-dependent signaling mediated by Inv or YadA involves similar signaling pathways. These data present YadA, in addition to Inv, YopB, and Yersinia lipopolysaccharide, as a further inducer of proinflammatory molecules by which Y. enterocolitica might promote inflammatory tissue reactions.
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PMID:Yersinia enterocolitica adhesin A induces production of interleukin-8 in epithelial cells. 1555 98

The induction of hippocampal long-term synaptic plasticity is exquisitely sensitive to behavioral stress, but the underlying mechanisms are still unclear. We report here that hippocampal slices prepared from adult rats that had experienced unpredictable and inescapable restraint tail-shock stress showed marked impairments of long-term potentiation (LTP) in the CA1 region. The same stress promoted the induction of long-term depression (LTD). These effects were prevented when the animals were given the glucocorticoid receptor antagonist 11beta, 17beta-11[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)-estra-4-9-dien-3-one before the stress. Immunoblotting analyses revealed that stress induced a profound and prolonged extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK1/2 MAPK) hyperphosphorylation through small GTPase Ras, Raf-1, and MAPK kinase 1/2 (MEK1/2). Furthermore, the stress effects were obviated by the intrahippocampal injection of specific inhibitors of MEK1/2 (U0126), protein kinase C (bisindolylmaleimide I), tyrosine kinase (K252a), and BDNF antisense oligonucleotides. These results suggest that the effects of stress on LTP and LTD originate from the corticosterone-induced sustained activation of ERK1/2-coupled signaling cascades.
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PMID:Behavioral stress modifies hippocampal synaptic plasticity through corticosterone-induced sustained extracellular signal-regulated kinase/mitogen-activated protein kinase activation. 1559 Sep 19

The BCR/ABL fusion tyrosine kinase activates various intracellular signaling pathways, thus causing chronic myeloid leukemia (CML). Here we demonstrate that the inducible expression of BCR/ABL in a murine hematopoietic cell line, TonB210, leads to the activation of the Ras family small GTPase Rap1, which is inhibited by the ABL kinase inhibitor imatinib. The Rap1 activity in a CML cell line, K562, was also inhibited by imatinib. Inhibition of Rap1 activation by a dominant negative mutant of Rap1, Rap1-N17, or SPA-1 inhibited the BCR/ABL-induced activation of Elk-1. BCR/ABL also activated in a kinase activity-dependent manner the B-Raf kinase, which is an effector molecule of Rap1 and a potent activator of the MEK/Erk/Elk-1 signaling pathway. Together, these data suggest that, in addition to the well-established Ras/Raf-1 pathway, BCR/ABL activates the alternative signaling pathway involving Rap1 and B-Raf to activate Erk, which may play important roles in leukemogenesis.
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PMID:BCR/ABL activates Rap1 and B-Raf to stimulate the MEK/Erk signaling pathway in hematopoietic cells. 1559 48

The YadA protein of Yersinia pseudotuberculosis promotes tight adhesion and invasion into mammalian cells through beta(1)-integrins. In this work, we demonstrate that YadA also triggers the production of interleukin-8 (IL-8) in host cells and we identify intracellular signal transduction mechanisms involved in YadA-initiated cell invasion and/or IL-8 synthesis. Tyrosine protein kinases, including the focal adhesion kinase (FAK) and c-Src, as well as the small GTPase Ras, were shown to play a significant role in both YadA-promoted cell processes. YadA-mediated cell contact led to autophosphorylation of FAK at position Tyr397 and induced GTP-loading of Ras. Furthermore, IL-8 production and invasion induced by YadA were strongly reduced in FAK- and c-Src-deficient cells and in cells overexpressing dominant interfering forms of FAK, c-Src or Ras. We also demonstrate that YadA activates the Ras-dependent Raf-MEK1/2-ERK1/2 pathway and mitogen-activated protein kinases (MAPKs) p38 and JNK. Moreover, inhibition of ERK1/2 by pharmacological agents or overexpression of dominant negative FAK, c-Src or Ras abrogated IL-8 release, whereas invasion remained unaffected. In contrast, actin polymerization and phosphatidylinositol 3-kinase (PI3K) activity is essential for YadA-promoted cell entry, but not for cytokine secretion. We conclude that YadA triggers FAK-Src complex formation and subsequent Ras activation, which leads to the stimulation of MAPKs-dependent IL-8 production or to PI3K-dependent invasion.
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PMID:Cell invasion and IL-8 production pathways initiated by YadA of Yersinia pseudotuberculosis require common signalling molecules (FAK, c-Src, Ras) and distinct cell factors. 1561 24

The mammalian Rit and Rin proteins, along with the Drosophila homologue RIC, comprise a distinct and evolutionarily conserved subfamily of Ras-related small GTP-binding proteins. Unlike other Ras superfamily members, these proteins lack a signal for prenylation, contain a conserved but distinct effector domain, and, in the case of Rin and RIC, contain calmodulin-binding domains. To address the physiological role of this Ras subfamily in vivo, activated forms of the Drosophila Ric gene were introduced into flies. Expression of activated RIC proteins altered the development of well-characterized adult structures, including wing veins and photoreceptors of the compound eye. The effects of activated RIC could be mitigated by a reduction in dosage of several genes in the Drosophila Ras cascade, including Son of sevenless (Sos), Dsor (MEK), rolled (MAPK), and Ras itself. On the other hand, reduction of calmodulin exacerbated the defects caused by activated RIC, thus providing the first functional evidence for interaction of these molecules. We conclude that the activation of the Ras cascade may be an important in vivo requisite to the transduction of signals through RIC and that the binding of calmodulin to RIC may negatively regulate this small GTPase.
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PMID:Activated RIC, a small GTPase, genetically interacts with the Ras pathway and calmodulin during Drosophila development. 1571 77

Synaptic trafficking of AMPA-Rs, controlled by small GTPase Ras signaling, plays a key role in synaptic plasticity. However, how Ras signals synaptic AMPA-R trafficking is unknown. Here we show that low levels of Ras activity stimulate extracellular signal-regulated kinase kinase (MEK)-p42/44 MAPK (extracellular signal-regulated kinase [ERK]) signaling, whereas high levels of Ras activity stimulate additional Pi3 kinase (Pi3K)-protein kinase B (PKB) signaling, each accounting for approximately 50% of the potentiation during long-term potentiation (LTP). Spontaneous neural activity stimulates the Ras-MEK-ERK pathway that drives GluR2L into synapses. In the presence of neuromodulator agonists, neural activity also stimulates the Ras-Pi3K-PKB pathway that drives GluR1 into synapses. Neuromodulator release increases with increases of vigilance. Correspondingly, Ras-MEK-ERK activity in sleeping animals is sufficient to deliver GluR2L into synapses, while additional increased Ras-Pi3K-PKB activity in awake animals delivers GluR1 into synapses. Thus, state-dependent Ras signaling, which specifies downstream MEK-ERK and Pi3K-PKB pathways, differentially control GluR2L- and GluR1-dependent synaptic plasticity.
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PMID:State-dependent Ras signaling and AMPA receptor trafficking. 1610 14

Endogenous beta-neuregulin-1 is required for the plasma membrane expression of large-conductance (BK-type) Ca2+-activated K+ channels in developing chick ciliary neurons of the chick ciliary ganglion. During normal development, beta-neuregulin-1 acts in concert with transforming growth factor-beta1 to stimulate movement of large-conductance Ca2+-activated K+ channels from intracellular stores into the plasma membrane, although these two growth factors preferentially act on different intracellular pools. We have previously shown that actions of transforming growth factor-beta1 on ciliary neurons require activation of phosphoinositol 3-kinase and Akt, as well as a parallel cascade composed of the small GTPase Ras and a mitogen-activated protein kinase (extracellular signal-regulated kinase). In addition, we have shown that the actions of beta-neuregulin-1 require activation of phosphoinositol 3-kinase and the protein kinase Akt. Here we examine whether beta-neuregulin-1-evoked mobilization of large-conductance Ca2+-activated K+ channels also requires activation of a Ras-extracellular signal-regulated kinase signaling cascade. We observed that application of beta-neuregulin-1 caused a robust and MEK1/2-dependent increase in extracellular signal-regulated kinase diphosphorylation that indicates activation of this signaling cascade in ciliary ganglion neurons, similar to what we have previously observed for transforming growth factor-beta1. However, activation of this cascade is not necessary for beta-neuregulin-1-evoked mobilization because stimulation of macroscopic large-conductance Ca2+-activated K+ channels persisted in cells treated with the MEK1/2 inhibitors PD98059 or U0126, in cells over-expressing dominant-negative forms of extracellular signal-regulated kinase, and in cells treated with the Ras inhibitor FTI-277. These results indicate that the mechanisms that underlie beta-neuregulin-1 and transforming growth factor-beta1 mobilization of large-conductance Ca2+-activated K+ channels are only partly overlapping, possibly because they cause recruitment of spatially distinct signaling complexes.
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PMID:Regulation of neuronal K(Ca) channels by beta-neuregulin-1 does not require activation of Ras-MEK-extracellular signal-regulated kinase signaling cascades. 1616 93

Mechanical transection of the nigrostriatal dopamine pathway at the medial forebrain bundle (MFB) results in the delayed degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). We have previously demonstrated that c-Jun activation is an obligate component of neuronal death in this model. Here we identified the small GTPase, cdc42, and mixed lineage kinases (MLKs) as upstream factors regulating neuronal loss and activation of c-Jun following MFB axotomy. Adenovirus-mediated expression of a dominant-negative form of cdc42 in nigral neurons blocked MFB axotomy-induced activation (phosphorylation) of MAP kinase kinase 4 (MKK4) and c-Jun, resulting in attenuation of SNpc neuronal death. Pharmacological inhibition of MLKs, MKK4-activating kinases, significantly reduced the phosphorylation of c-Jun and abrogated dopaminergic neuronal degeneration following MFB axotomy. Taken together, these findings suggest that death of nigral dopaminergic neurons following axotomy can be attenuated by targeting cell signaling events upstream of c-Jun N-terminal mitogen-activated protein kinase/c-Jun.
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PMID:Regulation of axotomy-induced dopaminergic neuron death and c-Jun phosphorylation by targeted inhibition of cdc42 or mixed lineage kinase. 1633 20

The establishment of a polarized morphology is an essential event in the differentiation of neurons into a single axon and dendrites. We previously showed that glycogen synthase kinase-3beta (GSK-3beta) is critical for specifying axon/dendrite fate by the regulation of the phosphorylation of collapsin response mediator protein-2 (CRMP-2). Here, we found that the overexpression of the small GTPase Ras induced the formation of multiple axons in cultured hippocampal neurons, whereas the ectopic expression of the dominant negative form of Ras inhibited the formation of axons. Inhibition of phosphatidylinositol-3-kinase (PI3-kinase) or extracellular signal-related kinase (ERK) kinase (MEK) suppressed the Ras-induced formation of multiple axons. The expression of the constitutively active form of PI3-kinase or Akt (also called protein kinase B) induced the formation of multiple axons. The overexpression of Ras prevented the phosphorylation of CRMP-2 by GSK-3beta. Taken together, these results suggest that Ras plays critical roles in establishing neuronal polarity upstream of the PI3-kinase/Akt/GSK-3beta/CRMP-2 pathway and mitogen-activated protein kinase cascade.
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PMID:Ras regulates neuronal polarity via the PI3-kinase/Akt/GSK-3beta/CRMP-2 pathway. 1634 26

Invasive tumour cells, such as gliomas, frequently express EGF (epidermal growth factor) receptor at a high level and they exhibit enhanced cell migration in response to EGF. We reported previously that tumour cell migration is associated with ectodomain cleavage of CD44, the major adhesion molecule that is implicated in tumour invasion and metastasis, and that the cleavage is enhanced by ligation of CD44. In the present study, we show that EGF promotes CD44 cleavage and CD44-dependent cell migration. Introduction of a dominant-negative mutant of the small GTPase Rac1 or depletion of Rac1 by RNAi (RNA interference) abrogated CD44 cleavage induced by EGF. Treatment with PD98059, an inhibitor for MEK (mitogen-activated protein kinase/extracellular-signal-regulated kinase kinase), also suppressed the CD44 cleavage. Furthermore, RNAi studies showed that EGF induced ADAM10 (a disintegrin and metalloproteinase 10)-dependent CD44 cleavage and cell migration. These results indicate that EGF induces ADAM10-mediated CD44 cleavage through Rac1 and mitogen-activated protein kinase activation, and thereby promotes tumour cell migration and invasion.
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PMID:Epidermal growth factor-regulated activation of Rac GTPase enhances CD44 cleavage by metalloproteinase disintegrin ADAM10. 1639 Mar 31


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