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

---

Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Elucidation of mechanisms by which receptor protein tyrosine phosphatases (PTPs) regulate neurite outgrowth will require characterization of ligand-receptor interactions and identification of ligand-induced signalling components mediating neurite outgrowth. The first identified ligand of the leucocyte common antigen-related (LAR) receptor PTP consists of a 99-residue ectodomain isoform, termed LARFN5C, which undergoes homophilic binding to LAR and promotes neurite outgrowth. We employed peptide mapping of LARFN5C to identify an active neurite-promoting domain of LAR. A peptide mimetic consisting of 37 residues (L59) and corresponding to the fifth LAR fibronectin type III (FNIII) domain prevented LARFN5C homophilic binding, demonstrated homophilic binding to itself and promoted neurite outgrowth of mouse E16-17 hippocampal neurons and of dorsal root ganglia explants. Response to L59 was partially lost when using neurons derived from LAR-deficient (-/-) mice or neurons treated with LAR siRNA, consistent with homophilic interaction of L59 with LAR. L59 neurite-promoting activity was decreased in the presence of inhibitors of Src, Trk, PLCgamma, PKC, PI3K and MAPK. L59 activated Src (a known substrate of LAR), FAK and TrkB and also activated downstream signalling intermediates including PKC, ERK, AKT and CREB. BDNF augmented the maximal neurite-promoting activity of L59, a finding consistent with the presence of shared and distinct signalling pathways activated by L59 with BDNF and L59 with TrkB. These studies are the first to identify an ectodomain of LAR (located within the fifth FNIII domain) capable of promoting neurite outgrowth and point to novel approaches for promotion of neurite outgrowth.
...
PMID:Identification of an ectodomain within the LAR protein tyrosine phosphatase receptor that binds homophilically and activates signalling pathways promoting neurite outgrowth. 1626 54

Cyclin-dependent kinase-5 (Cdk5) is required for neuronal survival, but its targets in the apoptotic pathways remain unknown. Here, we show that Cdk5 kinase activity prevents neuronal apoptosis through the upregulation of Bcl-2. Treatment of SH-SY5Y cells with retinoid acid (RA) and brain-derived neurotrophic factor (BDNF) generates differentiated neuron-like cells. DNA damage triggers apoptosis in the undifferentiated cells through mitochondrial pathway; however, RA/BDNF treatment results in Bcl-2 upregulation and inhibition of the mitochondrial pathway in the differentiated cells. RA/BDNF treatment activates Cdk5-mediated PI3K/Akt and ERK pathways. Inhibition of Cdk5 inhibits PI3K/Akt and ERK phosphorylation and Bcl-2 expression, and thus sensitizes the differentiated cells to DNA-damage. Inhibition of ERK, but not PI3K/Akt, abrogates Cdk5-medidated Bcl-2 upregulation and the protection of the differentiated cells. This study suggests that ERK-mediated Bcl-2 upregulation contributes to BDNF-induced Cdk5-mediated neuronal survival.
...
PMID:Cyclin-dependent kinase-5 prevents neuronal apoptosis through ERK-mediated upregulation of Bcl-2. 1627 78

Valproic acid (VPA) is a potent anti-epileptic and effective mood stabilizer. It is known that VPA enhances central GABAergic activity and activates the mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK-ERK) pathway. It can also inhibit various isoforms of the enzyme, histone deacetylase (HDAC), which is associated with modulation of gene transcription. Recent in vivo studies indicate a neuroprotective role for VPA, which has been found to up-regulate the expression of brain-derived neurotrophic factor (BDNF) in the rat brain. Given the interaction between the pineal hormone, melatonin, and GABAergic systems in the central nervous system, the effects of VPA on the expression of the mammalian melatonin receptor subtypes, MT1 and MT2, were examined in rat C6 glioma cells. The effects of VPA on the expression of glial cell line-derived neurotrophic factor (GDNF) and BDNF were also examined. RT-PCR studies revealed a significant induction of melatonin MT1 receptor mRNA in C6 cells following treatment with 3 or 5 mm VPA for 24 h or 5 mm VPA for 48 h. Western analysis and immunocytochemical detection confirmed that the VPA-induced increase in MT1 mRNA results in up-regulation of MT1 protein expression. Blockade of the MAPK-ERK pathway by PD98059 enhanced the effect of VPA on MT1 expression, suggesting a negative role for this pathway in MT1 receptor regulation. In addition, significant increases in BDNF, GDNF and HDAC mRNA expression were observed after treatment with VPA for 24 or 48 h. Taken together, the present findings suggest that the neuroprotective properties of VPA involve modulation of neurotrophic factors and receptors for melatonin, which is also thought to play a role in neuroprotection. Moreover, the foregoing suggests that combinations of VPA and melatonin could provide novel therapeutic strategies in neurological and psychiatric disorders.
...
PMID:Novel targets for valproic acid: up-regulation of melatonin receptors and neurotrophic factors in C6 glioma cells. 1631 12

Prevailing views of neurotrophin action hold that the transcription factor CREB is constitutively bound to target genes with transcriptional activation occurring via CREB phosphorylation. However, we report that within several CRE-containing genes, CREB is not constitutively bound. Upon exposure of neurons to brain-derived neurotrophic factor (BDNF), CREB becomes rapidly bound to DNA coincident with phosphorylation at its transcriptional regulatory site, Ser133. This inducible CREB-DNA binding is independent of CREB Ser133 phosphorylation and is not affected by inhibition of the ERK or PI3K signaling pathways. Instead, BDNF regulates CREB binding by initiating a nitric oxide-dependent signaling pathway that leads to S-nitrosylation of nuclear proteins that associate with CREB target genes. Pharmacological manipulation of neurons in vitro and analysis of mice lacking neuronal nitric oxide synthase (nNOS) suggest that NO mediates BDNF and activity-dependent expression of CREB target genes. Thus, in conjunction with CREB phosphorylation, the NO pathway controls CREB-DNA binding and CRE-mediated gene expression.
...
PMID:A nitric oxide signaling pathway controls CREB-mediated gene expression in neurons. 1642 17

Erythropoietin (EPO) is a hormone that is neuroprotective in models of neurodegenerative diseases. This study examined whether EPO can protect against neuronal death in the CA1 region of the rat hippocampus following global cerebral ischemia. Recombinant human EPO was infused into the intracerebral ventricle either before or after the induction of ischemia produced by using the four-vessel-occlusion model in rat. Hippocampal CA1 neuron damage was ameliorated by infusion of 50 U EPO. Administration of EPO was neuroprotective if given 20 hr before or 20 min after ischemia, but not 1 hr following ischemia. Coinjection of the phosphoinositide 3 kinase inhibitor LY294002 with EPO inhibited the protective effects of EPO. Treatment with EPO induced phosphorylation of both AKT and its substrate, glycogen synthase kinase-3beta, in the CA1 region. EPO also enhanced the CA1 level of brain-derived neurotrophic factor. Finally, we determined that ERK activation played minor roles in EPO-mediated neuroprotection. These studies demonstrate that a single injection of EPO ICV up to 20 min after global ischemia is an effective neuroprotective agent and suggest that EPO is a viable candidate for treating global ischemic brain injury.
...
PMID:Erythropoietin protects CA1 neurons against global cerebral ischemia in rat: potential signaling mechanisms. 1651 66

Our previous studies have revealed the involvement of signaling pathways of BDNF and NT-4/5 via TrkB in the development, regeneration, survival and maintenance of the Ruffini endings, primary mechanoreceptors in the periodontal ligament. However, the involvement of other neurotrophins remains unclear. The present study examined the expression of GDNF, GFRalpha1, and RET in the incisor periodontal ligament and trigeminal ganglion of young rats by RT-PCR and immunocytochemistry. All these mRNAs were detected in both tissues by RT-PCR. These immunoreactions were found in the terminal Schwann cells associated with the periodontal Ruffini endings, as confirmed by histochemistry for non-specific cholinesterase activity. Their axonal branches showed GFRalpha1- and RET-immunoreactions but lacked GDNF-immunoreactivity. In the trigeminal ganglion, about 30% of the neurons were immunoreactive to GFRalpha1 and RET. Averages of cross-sectional areas of their positive neurons demonstrated that they could mainly be categorized as medium-sized neurons. GDNF-immunoreaction was restricted to the satellite cells and not in trigeminal ganglion neurons. These findings indicate that GDNF mediates trophic effects on the survival and target innervation of the periodontal Ruffini endings via GFRalpha1 and RET.
...
PMID:Expression of GDNF and its receptors in the periodontal mechanoreceptor. 1651 66

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

Both antidepressant treatment and physical exercise have been shown to increase circulating levels of norepinephine (NE) and hippocampal brain-derived neurotrophic factor (BDNF). Increases in BDNF have been shown to be associated with enhanced dendritic arborization and neuronal survival, which forms the theoretical basis of the Neurotrophin Hypothesis of antidepressant action. Using isolated embryonic hippocampal neurons and immunoblotting, we show that application of NE increases BDNF and phosphorylated Trk, and that these increases can be prevented by ERK and PI-3K inhibitors. In addition, NE-induced increases in phospho-ERK2 and PI-3K were each suppressed by a PI-3K and MAPK inhibitor, respectively. Furthermore, phosphorylation of cAMP-response element binding (CREB) protein was also increased by NE and brought down to baseline levels by MAPK and PI-3K inhibitors. And finally, because both the MAPK and PI-3K inhibitors suppress phosphorylation of both TrkB (upstream) and CREB (downstream), these results indicate that NE-induced BDNF expression follows a cyclic pathway, reminiscent of a positive feedback loop. The results of this study provide an in vitro model of the intracellular signaling mechanisms activated by NE, via ligand-G-protein-coupled receptor (GPCR)-to-BDNF-RTK transactivation, that is putatively thought to occur in vivo as a result of excitatory neural activity.
...
PMID:Norepinephrine induces BDNF and activates the PI-3K and MAPK cascades in embryonic hippocampal neurons. 1687 82

Ovarian cancer remains the leading cause of fatality among all gynecologic cancers, although promising therapies are in the making. It has been speculated that metastasis is critical for ovarian cancer, and yet the molecular mechanisms of metastasis in ovarian cancer are poorly understood. Growth factors have been proven to play important roles in cell migration associated with metastasis, and inhibition of growth factor receptors and their distinct cell signaling pathways has been intensively studied, and yet the uncovered interaction or crosstalk among various growth factor receptors complicates this otherwise promising approach. We investigated the crosstalk between EGFR and TrkB, both of which have been known to be important in cell survival and migration in response to EGF and BDNF. Our results showed that both EGF and BDNF induced cell migration and cell proliferation in cultured human ovarian cancer cells (Caov3 cell line). EGF and BDNF transactivated TrkB and EGFR respectively, and activated downstream cell survival components such as Akt. EGFR and TrkB kinase inhibitors inhibited EGF- and BDNF-induced TrkB and EGFR activation and Akt phosphorylation, and cell proliferation and migration. Using EGFR knockout cells, we further demonstrated that EGFR is required for EGF-induced cell migration. Collectively, our data indicate that EGFR and TrkB crosstalk each other in response to EGF and BDNF, leading to cell survival pathway activation in ovarian cancer cells. Our data suggest that a combination of inhibitors of both receptors with cell survival pathway inhibitors would provide a better outcome in the clinical treatment of ovarian cancer.
...
PMID:Crosstalk between EGFR and TrkB enhances ovarian cancer cell migration and proliferation. 1696 97

1. According to its duration there are, at least, two major forms of memory in mammals: short term memory (STM) which develops in a few seconds and lasts several hours and long-term memory (LTM) lasting days, weeks and even a lifetime. In contrast to LTM, very little is known about the neural, cellular and molecular requirements for mammalian STM formation. 2. Here we show that early activation of extracellular signal-regulated kinases 1/2 (ERK1/2) in the hippocampus is required for the establishment of STM for a one-trial inhibitory avoidance task in the rat. Immediate posttraining infusion of U0126 (a selective inhibitor of ERK kinase) into the CA1 region of the dorsal hippocampus blocked STM formation. 3. Reversible inactivation of the entorhinal cortex through muscimol infusion produced deficits in STM and a selective and rapid decrease in hippocampal ERK2 activation.4. Together with our previous findings showing a rapid decrease in ERK2 activation and impaired STM after blocking BDNF function, the present results strongly suggest that ERK2 signaling in the hippocampus is a critical step in STM processing.
...
PMID:Early activation of extracellular signal-regulated kinase signaling pathway in the hippocampus is required for short-term memory formation of a fear-motivated learning. 1697 92


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

---