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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurotrophins (NTs) induce gene transcription by binding their high-affinity tropomyosin-related kinase (Trk) receptors and initiating intracellular signal transduction cascades. In particular, activation of the cyclic AMP response element (CRE) in the promoters of target genes serves as surrogate markers for Trk receptor activation as demonstrated in both in vivo and in vitro systems. We used a HEK293 cell line stably expressing a CRE-luciferase reporter gene to develop an assay for monitoring Trk activation in response to their cognate ligands. Using TrkB, we showed that the assay was sensitive to physiological concentrations of brain-derived neurotrophic factor (BDNF) and that the signal was sufficiently robust to be suitable for implementation in high-throughput format. Further characterization of the TrkB expressing stable cell lines showed high-affinity binding for BDNF, a high density of receptor expression, and supported BDNF-mediated phosphorylation signaling. Consistent with this, inhibitors of phosphatidylinositol 3-kinase and the phospholipase C-gamma pathways led to reduction of BDNF-mediated luciferase responses. In contrast, inhibitors of mitogen-activated protein kinase pathways further potentiated BDNF responses. This assay was NT-Trk receptor pair-selective and shown to be further applicable to other Trk family members. This assay may be useful in screening compound libraries to identify Trk agonists, which may be applied towards discriminating between the activities of the different Trk receptor family members and the development of pharmacological drugs.
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PMID:Cyclic-AMP response element-based signaling assays for characterization of Trk family tyrosine kinases modulators. 1683 82

BDNF, which acts through tropomyosin-related kinase B (TrkB) receptors during mammalian development, also enhances long-term synaptic facilitation (LTF) in adult Aplysia. Because LTF is a substrate for long-term memory (LTM) in Aplysia, we examined the requirement of a secreted TrkB ligand in LTM formation at molecular, synaptic, and behavioral levels. Using an extracellular fusion protein that sequesters secreted TrkB ligands, we show that TrkB function is required for serotonin-induced activation of extracellular signal-regulated kinase, tail nerve shock-induced LTF in the CNS, and tail shock-induced LTM but is not necessary for short-term synaptic facilitation or short-term memory. These results show that a secreted growth factor, acting through a TrkB signaling cascade, is critical for the induction of long-lasting plasticity and memory formation in Aplysia.
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PMID:A tropomyosin-related kinase B ligand is required for ERK activation, long-term synaptic facilitation, and long-term memory in aplysia. 1696 62

Osmotic stress induces activation of an adaptive mitogen-activated protein kinase pathway in concert with disassembly of the actin cytoskeleton by a mechanism that is not understood. We have previously shown that the conserved actin-interacting MAP kinase kinase kinase Ssk2p/MEKK4, a member of the high-osmolarity glycerol (HOG) MAPK pathway of Saccharomyces cerevisiae, mediates recovery of the actin cytoskeleton following osmotic stress. In this study, we have employed in vitro kinase assays to show that Ssk2p kinase activity is activated for the actin recovery pathway via a noncanonical, Ssk1p-independent mechanism. Our work also shows that Ssk2p requires the polarisome proteins Bud6p and Pea2p to promote efficient, polarized actin reassembly but that this requirement can be bypassed by overexpression of Ssk2p. Formin (BNI1 or BNR1) and tropomyosin functions are also required for actin recovery but, unlike for Bud6p and Pea2p, these requirements cannot be bypassed by overexpression of Ssk2p. These results suggest that Ssk2p acts downstream of Bud6p and Pea2p and upstream of tropomyosin to drive actin recovery, possibly by upregulating the actin nucleation activity of the formins.
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PMID:Requirement for the polarisome and formin function in Ssk2p-mediated actin recovery from osmotic stress in Saccharomyces cerevisiae. 1723 21

At early developmental stages, correlated neuronal activity is thought to exert a critical control on functional and structural refinement of synaptic connections. In the hippocampus, between postnatal day 2 (P2) and P6, network-driven giant depolarizing potentials (GDPs) are generated by the synergistic action of glutamate and GABA, which is depolarizing and excitatory. Here the rising phase of GDPs was used to trigger Schaffer collateral stimulation in such a way that synchronized network activity was coincident with presynaptic activation of afferent input. This procedure produced a persistent increase in spontaneous and evoked alpha-amino-3-hydroxy-5-methyl-4-isoxadepropionic acid-mediated glutamatergic currents, an effect that required calcium influx through postsynaptic L-type calcium channels. No potentiation was observed when a delay of 3 sec was introduced between GDPs and afferent stimulation. Pairing-induced potentiation was prevented by scavengers of endogenous BDNF or tropomyosin-related kinase receptor B (TrkB) receptor antagonists. Blocking TrkB receptors in the postsynaptic cell did not prevent the effects of pairing, suggesting that BDNF, possibly secreted from the postsynaptic cell during GDPs, acts on TrkB receptors localized on presynaptic neurons. Application of exogenous BDNF mimicked the effects of pairing on synaptic transmission. In addition, pairing-induced synaptic potentiation was blocked by ERK inhibitors, suggesting that BDNF activates the MAPK/ERK cascade, which may lead to transcriptional regulation and new protein synthesis in the postsynaptic neuron. These results support the hypothesis that, during a critical period of postnatal development, GABAA-mediated GDPs are instrumental in tuning excitatory synaptic connections and provide insights into the molecular mechanisms involved in this process.
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PMID:Correlated network activity enhances synaptic efficacy via BDNF and the ERK pathway at immature CA3 CA1 connections in the hippocampus. 1765 55

Endothelial cells are actively involved in regulating the exchanges between blood and tissues. This function is tightly dependent on actin cytoskeleton dynamics and is challenged by a wide variety of stimuli, including oxidative stress. In endothelial cells, oxidative stress quickly activates the extracellular-signal-regulated kinase (ERK) MAP kinase, which results in the phosphorylation of tropomyosin. Here, we investigated further the mechanisms of tropomyosin phosphorylation and its function in actin remodeling. We identified, for the first time, death-associated protein kinase 1 (DAP kinase 1) as the kinase that phosphorylates tropomyosin-1 in response to ERK activation by hydrogen peroxide (H(2)O(2)). We also report that the phosphorylation of tropomyosin-1 mediated by DAP kinase occurs on Ser283. Moreover, the expression of the pseudophosphorylated tropomyosin mutant Ser283Glu triggers by itself the formation of stress fibers in untreated cells, and the effect is maintained in H(2)O(2)-treated cells in which DAP kinase expression is knocked-down by siRNA. By contrast, the expression of the nonphosphorylatable tropomyosin mutant Ser283Ala is not associated with stress fibers and leads to membrane blebbing in response to H(2)O(2). Our finding that tropomyosin-1 is phosphorylated downstream of ERK and DAP kinase and that it helps regulate the formation of stress fibers will aid understanding the role of this protein in regulating the endothelial functions associated with cytoskeletal remodeling.
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PMID:DAP kinase mediates the phosphorylation of tropomyosin-1 downstream of the ERK pathway, which regulates the formation of stress fibers in response to oxidative stress. 1789 59

The neurotrophin receptor homolog (NRH2) is closely related to the p75 neurotrophin receptor (p75NTR); however, its function and role in neurotrophin signaling are unclear. NRH2 does not bind to nerve growth factor (NGF), however, is able to form a receptor complex with tropomyosin-related kinase receptor A (TrkA) and to generate high-affinity NGF binding sites. Despite this, the mechanisms underpinning the interaction between NRH2 and TrkA remain unknown. Here, we identify that the intracellular domain of NRH2 is required to form an association with TrkA. Our data suggest extensive intracellular interaction between NRH2 and TrkA, as either the juxtamembrane or death domain regions of NRH2 are sufficient for interaction with TrkA. In addition, we demonstrate that TrkA signaling is dramatically influenced by the co-expression of NRH2. Importantly, NRH2 did not influence all downstream TrkA signaling pathways, but rather exerted a specific effect, enhancing src homology 2 domain-containing transforming protein (Shc) activation. Moreover, downstream of Shc, the co-expression of NRH2 resulted in TrkA specifically modulating mitogen-activated protein kinase pathway activation, but not the phosphatidylinositol 3-kinase/Akt pathway. These results indicate that NRH2 utilizes intracellular mechanisms to not only regulate NGF binding to TrkA, but also specifically modulate TrkA receptor signaling, thus adding further layers of complexity and specificity to neurotrophin signaling.
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PMID:Neurotrophin receptor homolog-2 regulates nerve growth factor signaling. 1862 9

Brain-derived neurotrophic factor (BDNF) has been implicated in mechanisms of synaptic plasticity such as long-term potentiation (LTP), but its role in associative learning remains largely unknown. In the present study, we investigated the function of BDNF and its receptor tropomyosin-related kinase B (TrkB) in an in vitro model of classical conditioning using pond turtles, Pseudemys scripta elegans. Conditioning resulted in a significant increase in BDNF and phospho (p)-Trk expression. Bath application of antibodies directed against TrkB, but not TrkA or TrkC, abolished acquisition of conditioning, as did a receptor tyrosine kinase inhibitor K252a and an inhibitor of nitric oxide synthase 7-nitroindazole. Significantly, injections of BDNF Ab into the nerve roots of presynaptic axonal projections or postsynaptic motor neurons prevented acquisition of conditioning, suggesting that BDNF is required on both sides of the synapse for modification to occur. The presynaptic proteins synaptophysin and synapsin I were increased upon conditioning or BDNF application. Furthermore, BDNF application alone mimicked conditioning-induced synaptic insertion of GluR1 and GluR4 AMPAR subunits into synapses, which was inhibited by co-application of BDNF and K252a. Data also show that extracellular signal-regulated kinase (ERK) was activated in BDNF-treated preparations. We conclude that coordinate pre- and postsynaptic actions of BDNF are required for acquisition of in vitro classical conditioning.
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PMID:Coordinate action of pre- and postsynaptic brain-derived neurotrophic factor is required for AMPAR trafficking and acquisition of in vitro classical conditioning. 1863 15

Interactions between nerve growth factor (NGF) and its receptor-the tropomyosin related kinase A (trkA)-regulate many neuronal functions including the correct development of sensory neurons during embryogenesis, the survival of sensory neurons and the differentiation and apoptosis of neuronal tumours. Zhangfei is a transcriptional factor that is expressed in differentiated neurons. Since we could detect Zhangfei in mature neurons but not in neuronal tumour cells, we hypothesised that ectopic expression of the protein in medulloblastoma cells may induce the differentiation of these cells. We show that in ONS-76 medulloblastoma cells, resveratrol, an inducer of apoptosis and differentiation, increased the expression of Zhangfei, trkA and Early Growth Response Gene 1 (Egr1), a gene normally activated by NGF-trkA signalling. ONS-76 cells stopped growing soon after treatment with resveratrol. While the induction of Zhangfei in resveratrol-treated cells was modest albeit consistent, the infection of actively growing medulloblastoma cells with an adenovirus vector expressing Zhangfei mimicked some of the effects of resveratrol. Ectopically expressed Zhangfei in ONS-76 cells led to the increased expression of trkA and Egr1, phosphorylation of extracellular signal-regulated kinase (Erk1), and caused ONS-76 cells to display markers of apoptosis. UW228, another medulloblastoma cell-line, was also susceptible to the suppressive effects of resveratrol and Zhangfei. In contrast, while resveratrol suppressed the growth of human diploid fibroblasts (MRC5), Zhangfei had relatively little effect on these cells.
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PMID:Zhangfei induces the expression of the nerve growth factor receptor, trkA, in medulloblastoma cells and causes their differentiation or apoptosis. 1871 57

Among the GABAergic neocortical interneurons, fast-spiking (FS) basket and chandelier cells are essential mediators for feed-forward inhibition, network synchrony and oscillations. The FS properties are in part mediated by the voltage-gated potassium channels Kv3.1b/3.2 which allow the fast repolarization of the membrane necessary for firing non-adapting action potentials at high frequencies. It has been recently reported that the FS phenotype fails to mature in BDNF knockout mice suggesting a role for neurotrophins. We now describe the role of neuronal activity and neurotrophins for Kv3.1b/3.2 expression using organotypic cultures of rat visual cortex as model system. Chronic activity deprivation from 2 days in vitro (DIV) prevented the postnatal developmental increase of Kv3.2, but not Kv3.1b mRNA expression. However, chronic activity deprivation failed to alter Kv3.1b and marginally delayed Kv3.2 protein expression. Activity deprivation by glutamate receptor blockade from 10 to 20 DIV reduced both mRNAs, whereas deprivation with tetrodotoxin (TTX) reduced both mRNAs and the Kv3.2 protein. Thalamic and cortical afferents in cocultures failed to alter the expression. BDNF and NT4 supplemented from 2 DIV onwards increased the expression of Kv3.1b, but not Kv3.2 mRNA in young cultures. Only NT4 increased the expression of both mRNAs later in development. Kv3 protein levels were not changed by exogenous tropomyosin-related kinase B (TrkB) ligands, but the levels decreased upon inhibiting the MAPK signaling suggesting a role for endogenous factors and in particular MEK2 signaling for translation. The results show that Kv3.1b/3.2 expression is differentially controlled by neuronal activity and neurotrophic factors.
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PMID:Neuronal activity and TrkB ligands influence Kv3.1b and Kv3.2 expression in developing cortical interneurons. 1877 67

Neural stem cells (NSC) undergo apoptotic cell death during development of nervous system and in adult. However, little is known about the biochemical regulation of neuroprotection by neurotrophin in these cells. In this report, we demonstrate that Staurosporine (STS) and Etoposide (ETS) induced apoptotic cell death of NSC by a mechanism requiring Caspase 3 activation, poly (ADP-ribose) polymerase and Lamin A/C cleavage. Although C17.2 cells revealed higher mRNA level of p75 neurotrophin receptor (p75(NTR)) compared with TrkA or TrkB receptor, neuroprotective effect of both nerve growth factor (NGF) and brain-derived growth factor (BDNF) mediated through the activation of tropomyosin receptor kinase (Trk) receptors. Moreover, both NGF and BDNF induced the activation of the phosphatidylinositide 3 kinase (PI3K)/Akt and the mitogen-activated protein kinase (MAPK) pathway. Inhibition of Trk receptor by K252a reduced PARP cleavage as well as cell viability, whereas inhibition of p75(NTR) did not affect the effect of neurotrophin on neurotoxic insults. Thus our studies indicate that the protective effect of NGF and BDNF in NSC against apoptotic stimuli is mediated by the PI3K/Akt and MAPK signaling pathway via Trk receptors.
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PMID:Neuroprotection by NGF and BDNF against neurotoxin-exerted apoptotic death in neural stem cells are mediated through Trk receptors, activating PI3-kinase and MAPK pathways. 1884 24


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