Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The NTRK1 gene encodes the high affinity receptor for Nerve Growth Factor, and its action regulates neural development and differentiation. Deregulation of NTRK1 activity is associated with several human disorders. Loss of function mutations causes the genetic disease congenital insensitivity to pain with anhidrosis (CIPA). Constitutive activation of NTRK1 has been detected in several tumor types. An autocrine loop involving NTRK1 and NGF is associated with tumor progression in prostate carcinoma and in breast cancer. A novel alternative splicing variant with constitutive oncogenic potential has been recently described in neuroblastoma. Somatic rearrangements of NTRK1, producing chimeric oncogenes with constitutive tyrosine kinase activity, have been detected in a consistent fraction of papillary thyroid tumors. The topic of this review is a detailed analysis of the thyroid TRK oncogenes. The modalities of their activation, their mechanism of action, the contribution of activating sequences, and the molecular mechanisms underlying their generation will be discussed.
 ...
PMID:Oncogenic rearrangements of the NTRK1/NGF receptor. 1624 38

Ndrg4 is expressed predominantly in the early postnatal rat brain and may be related to neural cell differentiation. PC12 cell lines stably expressing increased levels of Ndrg4 protein display enhanced NGF-induced phosphorylation of MEK and ERK. In contrast, the Ndrg4-C2-overexpressed PC12 cell lines showed attenuated NGF-promoted phosphorylation of Elk-1, which is a nuclear target of ERK. A reporter assay also indicated that Ndrg4-C2 suppresses Elk-1-mediated transcriptional activation and SRE reporter expression. The suppressive effect of Ndrg4-C2 on NGF-induced activation of Elk-1 was abolished by colchicine but not by cytochalasin D, suggesting that microtubules are involved in the reduced activation of Elk-1 by Ndrg4. Ndrg4 may play a role in supporting the activation of ERK and its target proteins needed for neuronal differentiation and in reducing the activation of Elk-1 implicated in cell growth.
 ...
PMID:Ndrg4 enhances NGF-induced ERK activation uncoupled with Elk-1 activation. 1640 4

Cell survival is an essential function in the development and maintenance of the nervous system. We demonstrate here a previously unappreciated role for extracellular nucleotide signaling through the P2Y2 receptor in the survival of neurons: PC12 (pheochromocytoma 12) cells and dorsal root ganglion neurons are protected from serum starvation-induced apoptosis by ATP, UTP, and ATPgammaS, an effect mediated via P2Y2 receptors, as demonstrated by small interfering RNA and genetic knock-out models. This protection occurs independently of neurophin signaling but requires Src activation of ERK (extracellular signal-regulated kinase) and Akt. Moreover, ATPgammaS and NGF act synergistically to enhance neuronal survival through enhanced TrkA signaling. The results, which define a novel mechanism for inhibition of apoptosis, implicate parallel, interacting systems--extracellular nucleotides/P2Y2 receptors and neurotrophin/TrkA--to sustain neuronal survival.
 ...
PMID:Inhibition of apoptosis by P2Y2 receptor activation: novel pathways for neuronal survival. 1659 33

This study is to investigate the effects of huperzine A on memory deficits, neuronal damage and neurotrophic factors production after transient cerebral ischemia and reperfusion in mice, as well as the potential downstream signaling pathway. Bilateral common carotid occlusion (BCCAo) combined with systemic hypotension induced severe memory deficits in a water maze task and neuronal degeneration in cerebral cortex and hippocampus in mice. Oral administration of huperzine A (0.2 mg/kg, once per day, started 2 days before surgery and lasted for 7 days after surgery) markedly attenuated the memory deficits and neuronal damage. Meanwhile, huperzine A significantly increased the mRNA and protein levels of NGF, BDNF and TGF-beta(1), and potentiated phosphorylation of MAPK/ERK 1/2 in both cerebral cortex and hippocampus compared with transient cerebral ischemia and reperfusion group. This study provides evidence for the protective effects of huperzine A against transient cerebral ischemia and reperfusion in mice, and suggests potentially important roles that neurotrophic factors might play in these effects. It also indicates that the MAPK/ERK pathway might be involved in the in vivo neurotrophic effects of huperzine A against transient cerebral ischemia and reperfusion.
 ...
PMID:Effects of huperzine A on memory deficits and neurotrophic factors production after transient cerebral ischemia and reperfusion in mice. 1668 66

PC12 rat phaeochromocytoma cells show neuronal differentiation upon NGF treatment. NGF induces prolonged activation of the Ras/Raf/MEK/ERK pathway in which the 42/44 kDa mitogen-activated protein kinases (MAPKs), ERK 1 and 2 are thought to be the key mediators of the differentiation signals. Activation of ERKs leads to the increased transcription of early response genes resulting in cell cycle arrest. Upon NGF treatment the p53 protein, the most commonly mutated tumor suppressor in human cancers, translocates to the nucleus and may play a role in the mediation of NGF-induced cell cycle arrest and neuronal differentiation. Here we demonstrate that in PC12 cells expressing both wild-type and V143A mutant p53 proteins (p143p53PC12 cells), p53-mediated biological responses are critically influenced. p143p53PC12 cells are not able to cease their proliferation and begin their neuronal differentiation program upon NGF treatment. The presence of mutant p53 also reduces the DNA-binding activity of endogenous p53 and disturbs the regulatory machinery of p53 including both the phosphorylation of ERK 1/2, p38 and SAPK/JNK MAP kinases and itself.
 ...
PMID:The effects of a mutant p53 protein on the proliferation and differentiation of PC12 rat phaeochromocytoma cells. 1681 27

The localization and expression of neurotrophins and their receptors during distraction osteogenesis was investigated in 72 male rat femurs (11 weeks old) to further clarify the concurrence of cellular and molecular events of new bone formation. After osteotomy, a 7-day lag phase was followed by distraction at the rate of 0.25 mm/12 h for 21 days (distraction phase), and a 7-day consolidation phase. The localization of neurotrophins (NGF, BDNF and NT-3) and their receptors tropomyosinrelated kinases (TRKA, TRKB and TRKC) by immunostaining showed positive staining in bone forming cells in each stage, although the presence and staining intensity varied by cell type and phase. The expressions of NGF, BDNF and NT-3 by real-time polymerase chain reaction (real-time PCR) showed that the peak of the mRNA expression of NGF occurred 10 days after distraction. NT-3 increased during bone extension, but decreased when distraction stopped. In contrast, BDNF continued to increase gradually throughout the distraction and consolidation phases. These findings suggest that neurotrophins and their receptors may play different roles in endochondral and intramembranous ossification in distraction osteogenesis. The tension stress caused by distraction may stimulate the expression of neurotrophins and their receptors, and promote osteogenesis.
 ...
PMID:Expression of neurotrophins and their receptors tropomyosin-related kinases (Trk) under tension-stress during distraction osteogenesis. 1707 73

MAPK-dependent activation of AP-1 protein c-Jun is involved in PC12 cell differentiation and apoptosis. However, the role of other AP-1 proteins and their connection to MAPKs during growth, differentiation and apoptosis has remained elusive. Here we studied the activation of AP-1 proteins in response to ERK, JNK, and p38 signaling upon NGF, EGF and anisomycin exposures. All treatments caused different kinetics and strength of MAPK and AP-1 activities. NGF induced persistent ERK and AP-1 activities, whereas upon EGF and anisomycin exposures, their activities were only weakly and transiently induced. The sustained AP-1 activity was associated with concomitant c-Fos and c-Jun expression and phoshorylation, which were JNK and ERK dependent. While inhibition of the ERK, JNK, and p38 activities partially prevented AP-1 activity and suppressed differentiation, none of them was required for anisomycin-induced apoptosis. The importance of c-Fos and c-Jun as mediators of differentiation was demonstrated by the findings that the corresponding siRNAs suppressed NGF-induced neurite outgrowth. However, the capacity of c-Fos to promote differentiation required cooperation with Jun proteins. In contrast, Fra-2 expression was not required for the differentiation response. Together, the results show that sustained c-Jun and c-Fos activities mediate MAPK signaling and are essential for differentiation of PC12 cells.
 ...
PMID:Mitogen activated protein kinase-dependent activation of c-Jun and c-Fos is required for neuronal differentiation but not for growth and stress response in PC12 cells. 1711 71

Alpha-synuclein is an abundant neuronal protein that has been linked to both normal synaptic function and neurodegeneration--in particular, Parkinson's disease (PD). Uncovering mechanisms that control alpha-synuclein transcription is therefore critical for PD pathogenesis and synaptic function. We previously reported that in PC12 cells and primary neurons, alpha-synuclein is transcriptionally up-regulated after application of growth factors. In the current work we have characterized the pathway involved in this regulation in PC12 cells. The MAP/ERK pathway, and in particular Ras, is both sufficient and necessary for the NGF and basic fibroblast growth factor (bFGF) -mediated response. Significantly, response elements for this pathway, including a putative occult promoter, lie within intron 1, a hitherto unappreciated regulatory region of the gene that may be utilized in this or other settings. The PI3 kinase pathway is also involved in alpha-synuclein regulation, but response elements for this pathway appear to lie primarily outside of intron 1. These findings indicate that NGF- and bFGF-mediated signal transduction via the MAP/ERK and PI3 kinase pathways, and in part via regulatory regions within intron 1, may be involved in alpha-synuclein transcriptional regulation. Targeting of these pathways may serve to modulate alpha-synuclein so that it achieves desirable levels within neuronal cells.
 ...
PMID:A novel pathway for transcriptional regulation of alpha-synuclein. 1716 67

The balance between specific signals from different growth factors dictates the biological response of mammalian cells including cell proliferation, differentiation and survival. PC12 cells represent a model of choice to compare the signalling of differentiative growth factors, as NGF, and of mitogenic growth factors, as EGF. In these cells the prolonged activity of the ERK kinase dictates the decision of cells to differentiate. Here we focused on the cytosolic tyrosine phosphatase Shp2 as an established regulator of the Ras-ERK cascade, to elucidate its involvement in determining the stimulation-dependent PC12 cell fate. To this end, we generated PC12 derived cell lines that express the interfering mutant of Shp2 under a tetracycline-inducible promoter. Our findings show that Shp2 participates to the opposite effects induced in PC12 cells by EGF and NGF and that the interactions with the multidocking Gab2 protein mediate such effects.
 ...
PMID:Shp2 in PC12 cells: NGF versus EGF signalling. 1728 9

The Rit GTPase is widely expressed in developing and adult nervous systems, and our previous data with pheochromocytoma cells implicate Rit signaling in NGF-induced neurite outgrowth. In this study, we investigated a role for Rit in neuronal morphogenesis. Expression of a dominant-negative (dn) Rit mutant in hippocampal neurons inhibited axonal growth but potentiated dendritic growth. Conversely, a constitutively active (ca) Rit mutant promoted axonal growth but inhibited dendritic growth. Dendritogenesis is regulated differently in sympathetic neurons versus hippocampal neurons in that sympathetic neurons require NGF and bone morphogenetic proteins (BMPs) to trigger dendritic growth. Despite these differences, dnRit potentiated and caRit blocked BMP7-induced dendritic growth in sympathetic neurons. Biochemical studies indicated that BMP7 treatments that caused dendritic growth also decreased Rit GTP loading. Additional studies demonstrate that caRit increased extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and pharmacological inhibition of MEK1 (mitogen-activated protein kinase/ERK 1) blocked the axon-promoting and dendrite-inhibiting effects of caRit. These observations suggest that Rit is a convergence point for multiple signaling pathways and it functions to promote axonal growth but inhibit dendritic growth via activation of ERK1/2. Modulation of the activational status of Rit may therefore represent a generalized mechanism across divergent neuronal cell types for regulating axonal versus dendritic growth modes.
 ...
PMID:The novel GTPase Rit differentially regulates axonal and dendritic growth. 1746 85


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>