Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurotrophins, such as nerve growth factor and brain-derived neurotrophic factor, activate Trk receptor tyrosine kinases through receptor dimerization at the cell surface followed by autophosphorylation and recruitment of intracellular signaling molecules. The intracellular pathways used by neurotrophins share many common protein substrates that are used by other receptor tyrosine kinases (RTK), such as Shc, Grb2, FRS2, and phospholipase C-gamma. Here we describe a novel RTK mechanism that involves a 220-kilodalton membrane tetraspanning protein, ARMS/Kidins220, which is rapidly tyrosine phosphorylated in primary neurons after neurotrophin treatment. ARMS/Kidins220 undergoes multiple tyrosine phosphorylation events and also serine phosphorylation by protein kinase D. We have identified a single tyrosine (Tyr(1096)) phosphorylation event in ARMS/Kidins220 that plays a critical role in neurotrophin signaling. A reassembled complex of ARMS/Kidins220 and CrkL, an upstream component of the C3G-Rap1-MAP kinase cascade, is SH3-dependent. However, Tyr(1096) phosphorylation enables ARMS/Kidins220 to recruit CrkL through its SH2 domain, thereby freeing the CrkL SH3 domain to engage C3G for MAP kinase activation in a neurotrophin dependent manner. Accordingly, mutation of Tyr(1096) abolished CrkL interaction and sustained MAPK kinase activity, a response that is not normally observed in other RTKs. Therefore, Trk receptor signaling involves an inducible switch mechanism through an unconventional substrate that distinguishes neurotrophin action from other growth factor receptors.
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PMID:Identification of a switch in neurotrophin signaling by selective tyrosine phosphorylation. 1628 1

Clostridium perfringens alpha-toxin induces the generation of superoxide anion (O2(-)) via production of 1,2-diacylglycerol (DG) in rabbit neutrophils. The mechanism of the generation, however, remains poorly understood. Here we report a novel mechanism for the toxin-induced production of O2(-) in rabbit neutrophils. Treatment of the cells with the toxin resulted in tyrosine phosphorylation of a protein of about 140 kDa. The protein reacted with anti-TrkA (nerve growth factor high-affinity receptor) antibody and bound nerve growth factor. Anti-TrkA antibody inhibited the production of O2(-) and binding of the toxin to the protein. The toxin induced phosphorylation of 3-phosphoinositide-dependent protein kinase 1 (PDK1). K252a, an inhibitor of TrkA receptor, and LY294002, an inhibitor of phosphatidylinositol 3-kinase (PI3K), reduced the toxin-induced production of O2(-) and phosphorylation of PDK1, but not the formation of DG. These inhibitors inhibited the toxin-induced phosphorylation of protein kinase C theta (PKCtheta). U73122, a phospholipase C (PLC) inhibitor, and pertussis toxin inhibited the toxin-induced generation of O2(-) and formation of DG, but not the phosphorylation of PDK1. These observations show that the toxin independently induces production of DG through activation of endogenous PLC and phosphorylation of PDK1 via the TrkA receptor signaling pathway and that these events synergistically activate PKCtheta in stimulating an increase in O2(-). In addition, we show the participation of mitogen-activated protein kinase-associated signaling events via activation of PKCtheta in the toxin-induced generation of O2(-).
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PMID:Signal transduction mechanism involved in Clostridium perfringens alpha-toxin-induced superoxide anion generation in rabbit neutrophils. 1662 26

Phosphoinositide-specific phospholipase C-gamma1 (PLC-gamma1) has two pleckstrin homology (PH) domains: an amino-terminal domain (PH1) and a split PH domain (PH2). Here, we show that overlay assay of bovine brain tubulin pool with glutathione-S-transferase (GST)-PLC-gamma1 PH domain fusion proteins, followed by matrix-assisted laser-desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), identified 68-kDa neurofilament light chain (NF-L) as a binding protein of amino-terminal PH domain of PLC-gamma1. NF-L is known as a component of neuronal intermediate filaments, which are responsible for supporting the structure of myelinated axons in neuron. PLC-gamma1 and NF-L colocalized in the neurite in PC12 cells upon nerve growth factor stimulation. In vitro binding assay and immunoprecipitation analysis also showed a specific interaction of both proteins in differentiated PC12 cells. The phosphatidylinositol 4, 5-bisphosphate [PI(4,5)P(2)] hydrolyzing activity of PLC-gamma1 was slightly decreased in the presence of purified NF-L in vitro, suggesting that NF-L inhibits PLC-gamma1. Our results suggest that PLC-gamma1-associated NF-L sequesters the phospholipid from the PH domain of PLC-gamma1.
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PMID:Pleckstrin homology domain of phospholipase C-gamma1 directly binds to 68-kDa neurofilament light chain. 1681 85

The PC12 phaeochromocytoma cell line provides a useful model to study nerve growth factor-induced neuronal differentiation. The central signaling route of this process is mediated by the Ras-dependent extracellular signal-regulated kinase cascade. However, Ras-independent pathways are also stimulated by nerve growth factor and may contribute to differentiation signaling. One mediator for Ras-independent signal transduction in PC12 cells is phospholipase C-gamma that generates the second messengers diacylglycerol and inositol-trisphosphate. To probe the possible involvement of this enzyme in nerve growth factor-promoted differentiation, we used the phospholipase C inhibitor U73122 and the inositol-trisphosphate-receptor inhibitor Xestospongin C. Our results show that both chemicals block nerve growth factor-promoted neurite outgrowth, but the blockage of phospholipase C does not inhibit nerve growth factor-induced expression of c-fos, zif268 and transin genes. In addition, induction of these genes by nerve growth factor plus dibutyryl-cAMP is comparable in wild-type PC12 cells as well as in cells in which both Ras- and phospholipase C-gamma-mediated pathways are inhibited. The phospholipase C-gamma pathway thus belongs to those nerve growth factor receptor-originated signaling routes that contribute to the biological response of PC12 cells to nerve growth factor, but its gene activating potential does not have a major role in its neuritogenic effect.
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PMID:Role of phospholipase C-gamma in NGF-stimulated differentiation and gene induction. 1684 66

Regulation of cell survival decisions and neuronal plasticity by neurotrophins are mediated by two classes of receptors, Trks (tropomyosin receptor kinases) and p75, the first discovered member of the tumour necrosis factor receptor superfamily. The p75 receptor participates with the TrkA receptor in the formation of high-affinity nerve growth factor-binding sites to promote survival under limiting concentrations of neurotrophins. Activation of Trk receptors leads to increased phosphorylation of Shc (Src homology and collagen homology), phospholipase C-gamma and novel adaptor molecules, such as the ARMS (ankyrin-rich membrane spanning)/Kidins220 protein. Small ligands that interact with G-protein-coupled receptors can also activate Trk receptor kinase activity. Transactivation of Trk receptors and their downstream signalling pathways raise the possibility of using small molecules to elicit neuroprotective effects for the treatment of neurodegenerative diseases. Like amyloid precursor protein and Notch, p75 is a substrate for gamma-secretase cleavage. The p75 receptor undergoes an alpha-secretase-mediated release of the extracellular domain followed by a gamma-secretase-mediated intramembrane cleavage. Cleavage of p75 may represent a general mechanism for transmitting signals as an independent receptor and as a co-receptor for other signalling systems.
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PMID:Mechanisms of neurotrophin receptor signalling. 1685 73

Transactivation is a process whereby stimulation of G-protein-coupled receptors (GPCR) activates signaling from receptors tyrosine kinase (RTK). In neuronal cells, the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) acting through the GPCR VPAC-1 exerts trophic effects by transactivating the RTK TrkA receptor for the nerve growth factor (NGF). Both PACAP and NGF have pro-inflammatory activities on monocytes. We have tested the possibility that in monocytes, PACAP, as reported in neuronal cells, uses NGF/TrkA signaling pathway. In these cells, PACAP increases TrkA tyrosine phosphorylations through a PI-3kinase dependent but phospholipase C independent pathway. K252a, an inhibitor of TrkA decreases PACAP-induced Akt and ERK phosphorylation and calcium mobilisation resulting in decreases in intracellular H2O2 production and membrane upregulation of CD11b expression, both functions being inhibited after anti-NGF or anti-TrkA antibody treatment. K252a also inhibits PACAP-associated NF-KB activity. Monocytes increase in NGF production is seen after micromolar PACAP exposure while nanomolar treatment which desensitizes cells to high dose of PACAP prevents PACAP-induced TrkA phosphorylation, H2O2 production and CD11b expression. Finally, NGF-dependent ERK activation and H2O2 production is pertussis toxin sensitive. Altogether these data indicate that in PACAP-activated monocytes some pro-inflammatory activities occur through transactivation mechanisms involving VPAC-1, NGF and TrkA-associated tyrosine kinase activity.
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PMID:The neuropeptide pituitary adenylate cyclase activating protein stimulates human monocytes by transactivation of the Trk/NGF pathway. 1691 91

Sensitization of the pain-transducing ion channel TRPV1 underlies thermal hyperalgesia by proalgesic agents such as nerve growth factor (NGF). The currently accepted model is that the NGF-mediated increase in TRPV1 function during hyperalgesia utilizes activation of phospholipase C (PLC) to cleave PIP2, proposed to tonically inhibit TRPV1. In this study, we tested the PLC model and found two lines of evidence that directly challenge its validity: (1) polylysine, a cationic phosphoinositide sequestering agent, inhibited TRPV1 instead of potentiating it, and (2) direct application of PIP2 to inside-out excised patches dramatically potentiated TRPV1. Furthermore, we show four types of experiments indicating that PI3K is physically and functionally coupled to TRPV1: (1) the p85beta subunit of PI3K interacted with the N-terminal region of TRPV1 in yeast 2-hybrid experiments, (2) PI3K-p85beta coimmunoprecipitated with TRPV1 from both HEK293 cells and dorsal root ganglia (DRG) neurons, (3) TRPV1 interacted with recombinant PI3K-p85 in vitro, and (4) wortmannin, a specific inhibitor of PI3K, completely abolished NGF-mediated sensitization in acutely dissociated DRG neurons. Finally, simultaneous electrophysiological and total internal reflection fluorescence (TIRF) microscopy recordings demonstrate that NGF increased the number of channels in the plasma membrane. We propose a new model for NGF-mediated hyperalgesia in which physical coupling of TRPV1 and PI3K in a signal transduction complex facilitates trafficking of TRPV1 to the plasma membrane.
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PMID:Phosphoinositide 3-kinase binds to TRPV1 and mediates NGF-stimulated TRPV1 trafficking to the plasma membrane. 1707 74

Neurotrophins are important modulators of synaptic function at both developing and mature synapses in the CNS and PNS. At the neuromuscular junction (NMJ), neurotrophins, as well as perisynaptic Schwann cells (PSCs) are critical for the long-term maintenance and stability of the synapse. Considering this correlation and the acute interactions that occur at the synapse between PSCs and the nerve terminal, we wondered if neurotrophins could also be involved in neuron-glia signalling. To test if neurotrophins were able to signal to PSCs we used brief applications of neurotrophin-3 (NT-3), brain-derived neurotophic factor (BDNF) or nerve growth factor (NGF; 100 ng/mL). Soleus muscles of mice were incubated with the Ca(2+) indicator Fluo-4AM and Ca(2+) responses in PSCs were elicited through nerve stimulation (50 Hz, 30 s). Our results indicate that acute application of both NT-3 and BDNF, but not NGF, increased PSC Ca(2+) responses. Investigation of the mechanisms involved in these increases revealed distinct pathways for BDNF and NT-3. BDNF increased PSC responsiveness through potentiation of ATP responses while NT-3 modulated muscarinic acetylcholine receptor signalling. Using local applications of the neurotrophins, we found that both neurotrophins were able to elicit Ca(2+) responses in PSCs where BDNF used a phospholipase C-inositol 1,4,5-triphosphate (PLC-IP(3)) mechanism, while NT-3 required extracellular Ca(2+). Our results demonstrate a neurotrophin-dependent modulation of neuron-glia signalling through differential mechanisms employed by NT-3 and BDNF. Hence, neurotrophins precisely and differentially regulate PSC functions through modulation of either purinergic or cholinergic signalling pathways.
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PMID:Neurotrophins modulate neuron-glia interactions at a vertebrate synapse. 1735 53

Since neurotrophic factors are essential for neurons to form neuronal networks and maintain neuronal functions, neurotrophic factor-like substances or inducers of neurotrophic factors can be useful for the treatment of serious neuronal diseases such as Alzheimer's and Parkinson's diseases. In the present study, we examined an effect of 5,19-cyclo-9beta,10xi-androstane-3,17-dione (CAD) on neurotrophic factor synthesis in glial cells and scopolamine-induced impairment of learning in mice. 1321N1 human astrocytoma cells promoted secretion of certain neurotrophic factors in response to CAD with no cytotoxicity, which caused dramatic neurite outgrowth in rat pheochromocytoma (PC12) cells. In fact, CAD significantly enhanced nerve growth factor (NGF) secretion and its gene expression in 1321N1 cells, in a time and concentration-dependent manner. Because second messengers such as cAMP, inositol 1,4,5-trisphosphates and Ca(2+) induce NGF gene expression, we measured activities of adenylyl cyclase and phospholipase C and intracellular Ca(2+) concentration in 1321N1 cells. However, CAD changed neither second messenger levels. CAD enhanced the gene expression of proto-oncogene, c-fos that is one of the components of transcription factor (AP-1). In addition to those above, the in vivo effects of CAD were also examined. Although injection of muscarinic receptor antagonist scopolamine impaired passive avoidance learning in mice, pretreatment with CAD significantly reversed the adverse effect in a dose-dependent manner. Taking these results together, CAD has enormous therapeutic potential for serious neuronal diseases.
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PMID:5,19-cyclo-9beta,10xi-androstane-3,17-dione promotes neurotrophic factor biosynthesis in 1321N1 human astrocytoma cells and improves passive avoidance learning impairment. 1798 Aug 63

The transient receptor potential melastatin 7 (TRPM7) is recently revealed playing a key role in anoxic neuronal death. Meanwhile, nerve growth factor (NGF), through activating TrkA pathway, has been widely accepted as a crucial factor for neuronal survival during cerebral ischemia. In this study, middle cerebral artery occlusion (MCAO) for 1h and reperfusion for 5, 10, 20 and 30 h revealed an increasing up-regulation of TRPM7 expression in ipsilateral hippocampus after reperfusion and such a change reached a peak at 20 h, with high expression being maintained up to 30 h. Intracerebroventricular injection of NGF (500 ng) 30 min before MCAO, the expression of TRPM7 at 20 h after reperfusion was significantly reduced, and the effect of NGF was completely abolished by co-injection of TrkA inhibitor K252a. Furthermore, TRPM7 was found residing on hippocampal neuronal body and process, and TrkA was concurrently observed on the cell body by immunofluorescence staining. In agreement with in vivo, pre-incubation of cultured hippocampal neurons with NGF markedly down-regulated TRPM7 high expression at 20 h after oxygen-glucose deprivation (OGD), and this effect could be abrogated by K252a. In addition, when inhibitors wortmannin, U73122 and U0126 were introduced to block phosphatidylinositol-3 kinase (PI-3K), phospholipase C-gamma (PLC-gamma) and ras/mitogen-activated protein kinase (MAPK) pathways, respectively, only PI-3K inhibitor wortmannin substantially abolished NGF effects. These results suggest that TrkA, after being activated by NGF, can prevent up-regulation of TRPM7 expression in hippocampal neurons during reperfusion through PI-3K signal pathway. These findings open a new way for further investigations of the potential roles of TRPM7 and NGF in cerebral ischemia-reperfusion.
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PMID:TrkA pathway(s) is involved in regulation of TRPM7 expression in hippocampal neurons subjected to ischemic-reperfusion and oxygen-glucose deprivation. 1839 21


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