Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The amino terminus of nerve growth factor (NGF) is susceptible to proteolytic cleavage. A comparison of the bioactivity of highly purified full-length recombinant human (1-118)rhNGF and NH2-terminal truncated (10-118)rhNGF revealed lower potency of (10-118)rhNGF with regard to early NGF responses in neuron-like PC12 cells. Approximately 50 times higher concentrations of (10-118)rhNGF than (1-118)rhNGF were required to elicit the same extent of tyrosine phosphorylation of key enzymes in different second messenger pathways, i.e. the NGF receptor tyrosine kinase p140trkA, phospholipase C gamma-1, and the extracellular signal-regulated kinase ERK1. A similar reduced potency for induction of the transcription factor c-Fos was observed with (10-118)rhNGF compared to (1-118)rhNGF. The lower potency of (10-118)rhNGF in triggering early responses correlated with its 40-fold lower affinity for PC12 cells. Whereas (10-118)rhNGF had a more than 300-fold lower affinity for the high affinity receptor p140trkA than (1-118)rhNGF, amino-terminal truncation of NGF changed its affinity for the low affinity receptor p75NGFR only slightly (5-10-fold). These observations suggest that amino acids 1-9 of NGF are important for binding to the signal transducing receptor p140trkA. Proteolytic cleavage of the NGF amino terminus, therefore, reduces its potency in starting several second messenger pathways leading to neuronal differentiation of PC12 cells.
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PMID:The amino terminus of nerve growth factor is involved in the interaction with the receptor tyrosine kinase p140trkA. 142 22

A culture system enriched for nerve growth factor (NGF) receptor bearing cells was developed to investigate signal transduction events activated by NGF in postmitotic central nervous system neurons. Cells from the septal region of embryonic rats at 16 days of gestation were grown on glass coverslips above a glial cell layer established from postnatal rat cortex. The separation of glial and neuronal planes in this "bilaminar" system permits the diffusion of glial-derived factors required by septal neurons for survival yet allows the investigation of NGF responses in a pure neuronal population. Approximately 15% of the neurons in this culture system were immunoreactive for the low affinity NGF receptor. NGF rapidly increased MAP kinase activity (2-5 min) and transiently induced expression of c-fos in septal neurons. NGF treatment also increased choline acetyltransferase activity, while the number of cholinergic neurons remained constant. Septal neuron survival depended on the presence of glial cells, but neuronal viability in the bilaminar system was unaffected by anti-NGF antiserum, indicating that glial-derived neurotrophic support is not mediated by NGF alone. These data suggest that the bilaminar culture system is a useful system for the study of early events in NGF-activated signal transduction and the nature of glial-derived trophic support of developing basal forebrain neurons.
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PMID:Early nerve growth factor-induced events in developing rat septal neurons. 810 40

We have previously shown that nerve growth factor (NGF) induces a rapid and relatively continuous activation of Ras in rat pheochromocytoma PC12 cells while epidermal growth factor (EGF) activates Ras transiently, and that tyrosine kinase activity of the NGF receptor is essential for the activation of Ras (Muroya et al., Oncogene, 7, 277-281, 1992). In order to explore the signaling mechanism from tyrosine kinase to Ras activation in more detail, interactions between two adaptor molecules, Shc and Grb2/Ash, which contain Src homology regions, and their interactions with the NGF and EGF receptors were examined. Both NGF and EGF induced rapid tyrosine phosphorylation of Shc and its association with both the receptors and with Grb2/Ash. When cells were stimulated with EGF at 4 degrees C, the activation of Ras proceeded slowly and MAP kinase activation was quite low. Under such restricted conditions, tyrosine-phosphorylated Shc formed a complex with Grb2/Ash, suggesting that the complex formation may be one of the immediate early responses. In contrast to Shc, Grb2/Ash bound to EGF receptor but did not form a stable complex with the NGF receptor. These results suggest that there may be an alternative pathway for the activation of Ras in PC12 cells.
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PMID:Different interactions of Grb2/Ash molecule with the NGF and EGF receptors in rat pheochromocytoma PC12 cells. 810 30

Extracellular signal-regulated protein kinases (ERKs) constitute a family of protein serine-threonine kinases implicated in a variety of cell-signaling pathways. In cultured rat pheochromocytoma PC12 cells, ERK1 and ERK2 are activated by nerve growth factor (NGF), which also induces rapid association between ERK1 and the high affinity gp140prototrk tyrosine kinase NGF receptor. In the present work, we investigated the possible association between ERKs and the low affinity NGF receptor, p75. Extracts of PC12 cells (before and after NGF treatment) were subjected to immunoprecipitation with anti-p75 antibodies or antiserum; the immune complexes were then assessed for the presence of ERK proteins and tyrosine phosphorylation or for ERK activity using a specific substrate peptide. ERK1 and, to a lesser extent, ERK2 were found to be constitutively associated with p75. NGF did not modulate the total amount of ERK proteins coimmunoprecipitated with p75 but did markedly stimulate the level of p75-associated ERK catalytic activity. NGF treatment also enhanced the tyrosine phosphorylation of a p75-associated species that co-migrates with ERK1 in Western blots. Finally, K-252a, a compound that specifically inhibits activation by NGF of gp140prototrk, abolished the latter effect. These findings indicate that NGF, via activation of gp140prototrk, leads to association of enzymatically active ERKs with p75 and raise the possibility that this interaction may play a role in the NGF mechanism of action.
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PMID:Association of protein kinases ERK1 and ERK2 with p75 nerve growth factor receptors. 840 83

The trkB gene encodes a tyrosine kinase receptor, gp145trkB, for brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4). To understand the role of gp145trkB in the nervous system, we have investigated its expression in embryonic rat hippocampal pyramidal cell cultures and examined the effects of BDNF on signal transduction in the primary neurons. The expression of trkB transcripts was established by PCR analysis and in situ hybridization. In addition to gp145trkB, the pyramidal neuronal cultures expressed transcripts specific for the NT-3 receptor gp145trkC, but not for the high-affinity NGF receptor gp140trk or for p75LNGFR, a low-affinity receptor for all known members of the NGF family of neurotrophins including the gp145trkB ligands, BDNF and NT-4. The presence of gp145trkB receptors in the primary neuronal cultures was confirmed by immunocytochemical analysis in which > 90% of the cells stained with affinity-purified polyclonal antibodies to gp145trkB. Immunoblots using this antibody revealed a single approximately 140 kDa protein in both adult hippocampus and pyramidal cultures. Addition of recombinant BDNF to these cultures induced the tyrosine phosphorylation of gp145trkB, as determined by antiphosphotyrosine staining of gp145trkB immunoprecipitates. Moreover, BDNF treatment activated the microtubule-associated protein (MAP) kinases, as determined by an increase in MAP2 phosphorylation in vitro. Both the 41 and 44 kDa forms of MAP kinase were activated by BDNF. BDNF also increased c-fos expression in over 90% of the cells. These results indicate that gp145trkB does not require p75LNGFR to form a functional receptor for BDNF in hippocampal pyramidal neurons.
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PMID:Signal transduction events mediated by the BDNF receptor gp 145trkB in primary hippocampal pyramidal cell culture. 841 Jan 87

There is increasing evidence that the neurotrophins, particularly nerve growth factor (NGF) and neurotrophin-3 (NT-3), play a role in the regulation of glial development in the CNS. Recent studies have shown that the proliferation of optic nerve-derived O2A progenitors (OLPs) is potentiated by NT-3 in combination with platelet-derived growth factor, whereas NT-3 alone supports the survival of their differentiated progeny (Barres et al., 1994). In this study, we have examined the expression of the high-affinity neurotrophin receptors (trks) and the low-affinity nerve growth factor receptor p75 in developing oligodendrocytes (OLs). In addition, we have examined the effects of NGF and NT-3 on proliferation and survival of OLPs and OLs, respectively. TrkC, the high-affinity NT-3 receptor, and trkA, the high-affinity NGF receptor, are both expressed from the early OLP through the mature OL stage. The truncated form of trkB, lacking the tyrosine kinase domain, and the low-affinity neurotrophin receptor p75 are expressed at low levels in OLPs and are upregulated in mature OLs. NGF and NT-3 both induced the phosphorylation of mitogen-activated protein kinase (MAPK) in OLPs and in OLs. In both OLPs and OLs, NT-3 sustained the activation of MAPK more than NGF. NT-3 enhanced the proliferation of OLPs and supported the survival of OLs. By contrast, unless coadministered with FGF-2, NGF did not exhibit mitogenic effects on OLPs but did enhance the survival of differentiated OLs. Our data demonstrate the presence of functional trkA and trkC in developing OLs and indicate that both NGF and NT-3 have a broad spectrum of developmental actions on cells of the OL lineage.
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PMID:Nerve growth factor and neurotrophin-3 differentially regulate the proliferation and survival of developing rat brain oligodendrocytes. 881 22

In contrast to the intensively studied nerve growth factor (NGF)-related family of cytokines, relatively little is known about the mechanisms of neurotrophic activity elicited by the cytokine interleukin-6 (IL-6). We have examined the mechanisms of IL-6-induced neuronal differentiation of the pheochromocytoma cell line PC12. IL-6 independently induced the expression of peripherin, identifying this gene as the first neuronal-specific target of IL-6. However, IL-6 alone failed to elicit neurite outgrowth in PC12 cells and instead required low levels of Trk/NGF receptor tyrosine kinase activity to induce neuronal differentiation. The cooperating Trk signal could be provided by either overexpression of Trk or exposure to low concentrations of NGF. IL-6 also functioned cooperatively with basic fibroblast growth factor to promote PC12 differentiation. IL-6 and Trk/NGF synergized in enhancing tyrosine phosphorylation of the Erk-1 mitogen-activated protein kinase and in activating expression of certain NGF target genes. NGF also induced expression of the gp80 subunit of the IL-6 receptor, providing another potential mechanism of cooperativity between NGF and IL-6 signaling. We propose that IL-6 functions as an enhancer of NGF signaling rather than as an autonomous neuronal differentiation signal. Moreover, our results demonstrate that a Trk receptor-specific cellular response can be achieved in the absence of NGF through amplification of its basal signaling activity by the IL-6 receptor system.
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PMID:Interleukin-6 induces expression of peripherin and cooperates with Trk receptor signaling to promote neuronal differentiation in PC12 cells. 885 17

Tumor necrosis factor alpha (TNF-alpha) is a pleiotropic cytokine produced predominantly by macrophages. In addition, macrophages respond to TNF-alpha by differentiating to express different groups of gene products. Our laboratory recently showed that the context in which TNF-alpha is recognized by macrophages dramatically impacts the pattern of gene expression and hence investigating the mechanism of TNF-alpha signal transduction will be important in understanding how this molecule regulates macrophage differentiation. TNF-alpha is recognized by two cell surface receptors, CD120a (p55) and CD120b (p75) that belong to the TNF/NGF receptor family. Signalling is initiated by receptor multimerization in the plane of the plasma membrane. The initial signalling events activated by receptor cross-linking are unknown although activation of the mitogen-activated protein kinase (MAPK) cascade occurs shortly after ligand binding to CD120a (p55). We have investigated the upstream kinases that mediate the activation of p42mapk/erk2 following cross-linking of CD120a (p55) in mouse macrophages. Exposure of mouse macrophages to TNF-alpha stimulated a time-dependent increase in the activity of MEK1, that temporally preceded peak activation of p42mapk/erk2. MEKs, dual specificity T/Y kinases, act as a convergence point for several signalling pathways including Ras/Raf, MEKK and Mos. Incubation of macrophages with TNF-alpha was found to transiently stimulate an MEKK that peaked in activity within 30 sec of exposure and progressively declined towards basal levels by 5 min. By contrast, under these conditions, activation of either c-Raf-1 or Raf-B was not detected. These data suggest that the activation of the MAPK cascade in response to TNF-alpha is mediated by the sequential activation of an MEKK and MEK1 in a c-Raf-1 and Raf-B-independent fashion. The implications of these findings will be discussed in the context of the regulation of macrophage gene expression.
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PMID:TNF-alpha-induced regulation and signalling in macrophages. 893 52

The activated tyrosine kinase oncoprotein BCR-ABL is responsible for pathogenesis of Philadelphia chromosome-positive human leukemias. Because BCR carries a GAP (GTPase-activating protein) activity toward cytoskeleton-related small GTP-binding proteins, we utilized a neuronal PC12 cell system to test morphogenic potentials of BCR-ABL or BCR. We report here unique morphological phenotypes of PC12 cells expressing either BCR-ABL or a BCR mutant which lacks the SH2-binding domain (BCR Delta162-413). Although MAP kinase was not activated in PC12 cells expressing BCR-ABL, they showed incomplete neurite extensions even in the absence of the nerve growth factor (NGF). Overproduction of BCR Delta162-413 in PC12 cells, on the other hand, induced cell rounding in the absence of NGF. Interestingly, those cells could hardly make terminal differentiation in the presence of NGF and continued to grow without changing their round shape, although NGF receptor as well as MAP kinase appeared to be activated. Interestingly, the botulinum C3 toxin induced neurite-like structures in PC12 cells overexpressing BCR Delta162-413 without NGF.
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PMID:BCR-ABL induces neurite-like structures and BCR lacking the SH2-binding domain induces cell rounding in PC12 cells. 898 27

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


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