Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Spinal cord injury in adult mammals results in little axonal regeneration, although the mechanism of regeneration failure still remains elusive. Recent research has revealed that activation of the extracellular-signal-regulated kinases (ERKs) plays an important role in the neurite outgrowth. In the present study, we constructed a replication-defective adenovirus vector carrying mutated form of MEK1 (CA-MEK virus), which constitutively activate ERK pathway, and investigated its effect on thoracic spinal cord injury model in young adult rats as well as neurite outgrowth in vitro. In rat pheocromocytoma cell line PC12 cells, CA-MEK virus infection induced sustained activation of ERKs and stimulated neurite outgrowth in the absence of neurotrophic factors. In rat spinal cord transection model, injection of CA-MEK virus into the completely transected spinal cord efficiently activated ERKs in the supraspinal neurons and induced axonal regeneration across the transection site, which was confirmed by anterograde labeling with wheat-germ-agglutinin conjugated peroxidase (WGA-HRP). Spinal cord evoked potentials (SCEP) showed that these regenerated axons were electroconductive. Most importantly, CA-MEK virus-treated rats showed significant recovery of hind limb function 2 weeks after operation compared to the control rats treated with no virus or LacZ virus. These results suggest that adenovirus-mediated CA-MEK gene transduction offers a novel strategy for the gene therapy of spinal cord injury.
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PMID:Partial functional recovery of paraplegic rat by adenovirus-mediated gene delivery of constitutively active MEK1. 1103 Oct 88

Although neurons of the PNS no longer require neurotrophins such as Nerve Growth Factor (NGF) for their survival, such factors are involved in regulating axonal sprouting and regeneration after injury. In addition to the neurotrophin receptors, sensory neurons are reported to express IGF-1, EGF and FGF receptors. To investigate the influence of growth factors in addition to NGF, we examined the effects of IGF-1 EGF and FGF on neurite growth from adult rat dorsal root ganglion sensory neurons in both dissociated cultures and in compartmented cultures. As expected, NGF elicited robust neuritic growth in both the dissociated and compartmented cultures. The growth response to IGF-1 was similar, although there was minimal neurite growth in response to EGF or FGF. In addition, IGF-1 (but neither FGF nor EGF), when applied to cell bodies in compartmented cultures, potentiated the distal neurite growth into NGF-containing side compartments. This potentiation was not seen when these factors were provided along with NGF in the side compartments of compartmented cultures, or in the dissociated cultures. To determine the contribution of signaling intermediates downstream of receptor activation, we used inhibitors of the potential effectors and Western blotting. The PI 3-kinase inhibitor, LY294002 attenuated neurite growth evoked by NGF, IGF and EGF in dissociated cultures, although the MAP kinase kinase (MEK) inhibitor PD098059 diminished the growth in only IGF. Immunoprecipitation and Western blotting results demonstrated differential activation of MAPK, PI 3-kinase, PLCgamma1 and SNT by the different factors. Activation of PI 3-kinase and SNT by both NGF and IGF-1 correlated with their effects on neurite growth. These results support the hypothesis that the PI 3-kinase pathway plays an important role in neuritogenesis.
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PMID:Neurite growth promotion by nerve growth factor and insulin-like growth factor-1 in cultured adult sensory neurons: role of phosphoinositide 3-kinase and mitogen activated protein kinase. 1124 84

We studied the roles of mGlu2/3 receptors (mGlu2/3) in glutamatergic transmission at corticostriatal synapses in mice brain slices. Perfusion of the selective mGlu2/3 agonists LY354740 and L-CCG1 caused the long term depression (LTD) of evoked synaptic responses. Photonic and electronic microscopy showed mGlu2/3 on axonal fibers and glial processes but not on striatal dendrites. mGlu2/3-LTD was independent of synaptic activity and insensitive to specific antagonists of dopamine D1, D2, GABA(B), N-methyl-D-aspartate or adenosine A1 receptors. Manipulation of the cAMP/protein kinase A cascade had no effect on the mGlu2/3-LTD. In contrast, MEK1-2 inhibitors reduced both mGlu2/3 initial depression and LTD suggesting the involvement of the mitogen activated kinase pathway in mGlu2/3-LTD.
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PMID:Group 2 metabotropic glutamate receptors induced long term depression in mouse striatal slices. 1174 31

The neural cell adhesion molecule (NCAM) stimulates axonal outgrowth by activation of the Ras-mitogen activated protein kinase (MAPK) pathway and by generation of arachidonic acid. We investigated whether the transcription factors, cyclic-AMP response-element binding protein (CREB) and c-Fos play roles in this process by estimating NCAM-dependent neurite outgrowth from PC12-E2 cells grown in co-culture with NCAM-negative or NCAM-positive fibroblasts. PC12-E2 cells were transiently transfected with expression plasmids encoding wild-type or dominant negative forms of CREB and c-Fos or an activated form of the MAPK kinase, MEK2. Alternatively, PC12-E2 cells were treated with arachidonic acid, the cAMP analogue dBcAMP, or protein kinase A (PKA) inhibitors. The negative forms of CREB and c-Fos inhibited neurite outgrowth mediated by NCAM, arachidonic acid, dBcAMP, or MEK2. Neither CREB nor c-Fos could compensate for the inactivation of the other, indicating that both factors are important in NCAM-mediated neuritogenesis. Treatment of primary hippocampal neurons with a synthetic NCAM peptide ligand known to stimulate neurite outgrowth induced phosphorylation of CREB and expression of c-fos. We thus present evidence that NCAM-mediated neurite outgrowth involves a series of signal transduction pathways, including the cAMP/PKA pathway, targeting c-Fos and CREB.
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PMID:The transcription factors CREB and c-Fos play key roles in NCAM-mediated neuritogenesis in PC12-E2 cells. 1175 56

PD98059 blocks mitogen-activated protein kinase (MAPK) by inhibiting its activator, MAP kinase kinase (MEK). We have previously found that PD98059 only transiently inhibits spontaneous axonal outgrowth from adult mouse dorsal root ganglia (DRG) explants, whereas it causes sustained inhibition of nerve growth factor (NGF)-stimulated growth. Surprisingly, the present results showed that outgrowth stimulation by neurotrophin-3 (NT-3), interacting with another neuronal subgroup, was markedly enhanced by PD98059 and also by U0126, another inhibitor of MAPK activation. In contrast, the effects of glial cell line-derived neurotrophic factor (GDNF), which stimulates still another subgroup of DRG neurons, was opposed by PD98059. Axonal outgrowth in vitro can also be strongly increased by a prior axotomy in vivo. The increased outgrowth in preaxotomized explants was effectively inhibited by the presence of PD98059. Immunocytochemistry based on whole-mount labelling revealed the presence of neuronal MAPK, which was found to be activated by NGF, NT-3, and GDNF in separate axonal populations and by a prior axotomy in a majority of growing axons. The results suggest that there are important differences in the NGF and NT-3 signalling pathways, which may involve positive and negative control mechanisms by MAPK activation, respectively. Other findings indicate that GDNF exerts its growth effects by activation of MAPK and that expression of the conditioning effect in vitro in preaxotomized preparations also requires activation of MAPK.
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PMID:Mitogen-activated protein kinase inhibition reveals differences in signalling pathways activated by neurotrophin-3 and other growth-stimulating conditions of adult mouse dorsal root ganglia neurons. 1175 81

To further our understanding of the functions of the major myelin proteins, myelin basic protein (MBP) and proteolipid protein (PLP), and other myelin proteins, such as 2'3'-cyclic nucleotide 3'-phosphodiesterase (CNP) and myelin-associated glycoprotein (MAG), bovine brain myelin was extracted with Triton X-100, and protein complexes in the detergent-soluble fraction were isolated by coimmunoprecipitation and sucrose density gradient sedimentation. MBP, PLP, and the small isoform of MAG (S-MAG) were coimmunoprecipitated from the detergent-soluble fraction by anti-PLP, anti-MBP or anti-MAG monoclonal antibodies. Additionally, a 30 kDa phosphoserine-containing protein and two phosphotyrosine-containing proteins (M(r) 30 and 42 kDa) were found in the coimmunoprecipitates. The 42 kDa protein is probably p42MAPK, in that MAPK was shown also to be present in the immunoprecipitated complex. CNP, the small PLP isoform DM20, the large MAG isoform L-MAG, MOG, CD44, MEK, p44MAPK, and actin were not present in the immunoprecipitates, although they were present in the detergent-soluble fraction. Lipid analysis revealed that the PLP-MBP-S-MAG coimmunoprecipitated with some phospholipids and sulfatide but not cholesterol or galactosylceramide. However, the complex had a high density, indicating that the lipid/protein ratio is low, and it was retained on a Sepharose CL6B column, indicating that it is not a large membrane fragment. Given that MAG is localized mainly in the periaxonal region of myelin, where it interacts with axonal ligands, the PLP-MBP-S-MAG complex may come from these regions, where it could participate in dynamic functions in the myelin sheath and myelin-axonal interactions.
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PMID:Myelin proteolipid protein, basic protein, the small isoform of myelin-associated glycoprotein, and p42MAPK are associated in the Triton X-100 extract of central nervous system myelin. 1223 60

Growth factors such as vascular endothelial growth factor (VEGF) exert their proliferative properties partly through activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK1/2). Although both VEGF and inactive ERK could be detected in the inner ear of guinea pigs, under normal conditions activated ERK (phospho-ERK) was found only sparely. Cochleae of adult guinea pigs were removed, incubated with VEGF in a carbogen-gased organ-bath for 5, 15, 30 and 60 min (n=6 in each group), fixed with PFA 4%, embedded in paraffin and sectioned, followed by immunohistochemical staining to inactive and active ERK. Whereas inactive ERK was found in all cochleae, in sensory and supporting cells of the apex activated ERK was strongly detected after 5-min VEGF-incubation. After 15 min all Corti-organs showed clear staining corresponding to activated ERK, which decreased again after 30 min. Faint staining in endothelial cells of the spring-coil-vessels and in the spiral ganglion cells was found after 30 min and was increased after 60 min, while the staining in the Corti-organs vanished. Addition of the MEK-inhibitor PD 98059 to the organ-bath led to diminished phospho-ERK1/2 immunostaining. These findings provide evidence for a VEGF-dependent phosphorylation of ERK1/2 in the cochlea. Activated ERK1/2 is thought to support axonal outgrowth, enhancement of cell survival and to regulate the turnover of the NO/cGMP-pathway.
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PMID:In vitro activation of extracellular signal-regulated kinase1/2 in the inner ear of guinea pigs. 1244 91

In neuronal stress and degeneration, mitogen-activated protein (MAP) kinase signaling pathways play an important role. We studied the pattern of activation of the c-Jun N terminal kinase (JNK) signal transduction pathway during the course of a subacute MPTP mouse model of Parkinson's disease. In this model, there was no significant neuronal loss, but the function of the dopaminergic neurons was significantly decreased. During MPTP administration, phosphorylation of p-Jun was increased in the substantia nigra, and MKK4 was increased both in the striatum and substantia nigra. We conclude that after MPTP intoxication in the mouse, activation of the JNK pathway occurs both in the striatum and in the substantia nigra. This activation does not seem to corrrelate with loss of neuronal cell bodies but might represent a response to damage/loss of axonal terminals.
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PMID:Activation of the c-Jun N terminal kinase pathway in an animal model of Parkinson's disease. 1248 68

Eph receptors and their ligands (ephrins) play an important role in axonal guidance, topographic mapping, and angiogenesis. The signaling pathways mediating these activities are starting to emerge and are highly cell- and receptor-type specific. Here we demonstrate that activated EphB1 recruits the adaptor proteins Grb2 and p52Shc and promotes p52Shc and c-Src tyrosine phosphorylation as well as MAPK/extracellular signal-regulated kinase (ERK) activation. EphB1-mediated increase of cell migration was abrogated by the MEK inhibitor PD98059 and Src inhibitor PP2. In contrast, cell adhesion, which we previously showed to be c-jun NH2-terminal kinase (JNK) dependent, was unaffected by ERK1/2 and Src inhibition. Expression of dominant-negative c-Src significantly reduced EphB1-dependent ERK1/2 activation and chemotaxis. Site-directed mutagenesis experiments demonstrate that tyrosines 600 and 778 of EphB1 are required for its interaction with c-Src and p52Shc. Furthermore, phosphorylation of p52Shc by c-Src is essential for its recruitment to EphB1 signaling complexes through its phosphotyrosine binding domain. Together these findings highlight a new aspect of EphB1 signaling, whereby the concerted action of c-Src and p52Shc activates MAPK/ERK and regulates events involved in cell motility.
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PMID:EphB1 recruits c-Src and p52Shc to activate MAPK/ERK and promote chemotaxis. 1292 10

Olfactory ensheathing cells (OECs) are a unique type of macroglia with axonal growth-promoting properties. However, our understanding of the factors that regulate OECs is at early stages. Lysophosphatidic acid (LPA) is a lipid that influences diverse functions in the nervous system. Recent studies suggest that glial cells, including astrocytes and Schwann cells, are important targets of LPA. However, the influences of LPA on OECs are not known. To address if LPA can influence OECs, we examined effects of LPA on the proliferation and migration of OECs and intracellular effector events. Initially, we observed that OECs expressed the genes for LPA1, LPA2, and LPA3 receptors. When OECs were treated with LPA, we observed stimulated proliferation and migration of OECs. Treatment of OECs with LPA also induced actin cytoskeleton reorganization and focal adhesion assembly. These effects of LPA were blocked by treatment with C3 exoenzyme or Y-27632, which inhibit Rho-GTPase and Rho-associated kinase, respectively. Effects of LPA on OEC proliferation were blocked by the MEK inhibitors PD098059 and U0126 and by the phosphotidylinositol 3-kinase (PI 3-K) inhibitors LY0294002 and wortmannin. These results show that LPA acts via Rho-GTPase, MAPK, and PI 3-K signaling cascades to influence OEC proliferation, migration, and cytoskeleton assembly.
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PMID:Lysophosphatidic acid regulates the proliferation and migration of olfactory ensheathing cells in vitro. 1295 54


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