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:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the past few years, a number of experimental observations have provided more insight into the mechanisms of action of tumor necrosis factor (TNF)/lymphotoxin (LT) ligand-receptor system. This system consists of three ligands, TNF, LT alpha (LT alpha) and LT beta (LT beta), and three membrane-associated receptors, p55, p75 and LT beta-receptor (LT beta-R). Like TNF, LT alpha is a secreted protein which in solution forms a homotrimer molecule, with a conformation similar to that of TNF. LT beta is a transmembrane protein that provides the membrane anchor for the attachment to the cell surface of the heteromeric complex of LT alpha and LT beta. This complex retains a structure related to TNF and LT alpha homotrimers, with the homology regions interacting in a heterotypic fashion. The LT alpha 1:LT beta 2 heteromer has been found to be a predominant form of surface LT. The biological effects of TNF and LT alpha homotrimers are mediated by p55 and p75 receptors, while the heteromeric complex of LT alpha/LT beta transduces its cellular signal via LT beta-R. Membrane-associated receptor affinities as well as final biological effects of TNF/LT can be modulated by the influence of naturally occurring soluble receptors, derived from the cell surface by proteolytic cleavage. The multimerization of receptor cytoplasmic domains upon TNF/LT ligation is postulated to activate the intracellular signal-transduction pathways. One of them is the activation of phospholipase A2 (PL-A2) resulting in the production of arachidonic acid (AA) and other metabolites, including leukotriens, phosphatidycholine-specific phospholipase C (PC-PLC) with subsequent production of diacylglycerol (DAG) and activation of protein kinase C (PKC). As a third signaling pathway, TNF/LT employ the sphingomyelinase (SMase)-mediated hydrolysis of membrane sphingomyelin (SM) to ceramide. The final link in the TNF/LT signaling is activation of nuclear transcription factors, such as NF-kappa B, AP-1, interferon regulatory factors-1 and -2 (IRF-1, IRF-2), and NF-GMa. Since induction of AP-1, IRF-1 and IRF-2 as well as NF-GMa proceeds through translational event, the posttranslational TNF/LT-driven activation of NF-kappa B remains the only cellular event identified so far that serves as a direct target in their signaling cascade.
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PMID:Mechanisms of action of the tumor necrosis factor and lymphotoxin ligand-receptor system. 757 92

The biological activity of nerve growth factor (NGF) has been shown to be mediated by the p140trkA receptor tyrosine kinase, while the role of the p75 NGF receptor (p75NGFR) is still unresolved. Here we have investigated the relative contribution of p140trkA and p75NGFR to early consequences of NGF binding: ligand internalization, p140trkA autophosphorylation, and tyrosine phosphorylation of Shc, phospholipase C gamma-1 (PLC gamma-1), and extracellular signal-regulated kinases (ERKs). It was found that NGF internalization was neither prevented by blocking p140trkA activity using the protein kinase inhibitors methylthioadenosine, staurosporine, and K-252a, nor by inhibiting NGF binding to p75NGFR with antibodies. However, when NGF binding to p140trkA was reduced by the use of a synthetic peptide corresponding to amino acids 36-53 of human p140trkA, internalization of NGF was decreased. Thus, at least in PC12 cells, internalization appears to require binding of NGF to p140trkA, but occurs irrespective of p140trkA kinase activity and ligand occupancy of p75NGFR. The NGF triple mutant Lys-32/Lys-34/Glu-35 to Ala, which has been demonstrated to bind to p140trkA, but not to p75NGFR, induced tyrosine phosphorylation more rapidly than wild-type NGF. Likewise, NGF-induced tyrosine phosphorylation was accelerated when NGF binding to p75NGFR was prevented with REX-IgG. These findings indicate that NGF bindign by p75NGFR may modulate NGF-induced p140trkA kinase activity.
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PMID:p75 nerve growth factor receptor modulates p140trkA kinase activity, but not ligand internalization, in PC12 cells. 781 75

Glycosylphosphatidylinositols (GPIs) are membrane anchors for cell surface proteins of several major protozoan parasites of humans, including Trypanosoma cruzi, the causative agent of Chagas' disease. To investigate the general role of GPIs in T. cruzi, we generated GPI-deficient parasites by heterologous expression of T. brucei GPI-phospholipase C. Putative protein-GPI intermediates were depleted, causing the biochemical equivalent of a dominant-negative loss of function mutation in the GPI pathway. Cell surface expression of major GPI-anchored proteins was diminished in GPI-deficient T. cruzi. Four proteins that are normally GPI-anchored in T. cruzi exhibited different fates during the GPI shortage; Ssp-4 and p75 were secreted prematurely, while protease gp50/55 and p60 were degraded intracellularly. These observations demonstrate that secretion and intracellular degradation of GPI-anchored proteins may occur in the same genetic background during a GPI deficiency. We postulate that the interaction between a protein-GPI transamidase and the COOH-terminal GPI signal sequence plays a pivotal role in determining the fate of these proteins. At a nonpermissive GPI deficiency, T. cruzi amastigotes inside mammalian cells replicated their single kinetoplast but failed at mitosis. Hence, in these protozoans, GPIs appear to be essential for nuclear division, but not for mitochondrial duplication.
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PMID:Proteins with glycosylphosphatidylinositol (GPI) signal sequences have divergent fates during a GPI deficiency. GPIs are essential for nuclear division in Trypanosoma cruzi. 913 97

It has previously been shown that nerve growth factor (NGF) is of functional significance for mature pig oligodendrocytes (OLs) in culture. The present data give evidence for the expression of TrkA, the so-called high-affinity NGF receptor, and of p75NTR, the so-called low-affinity NGF receptor. TrkA is upregulated during culturing, in contrast to the p75 receptor. Exposure of OLs to NGF induces an autophosphorylation of TrkA via its intrinsic tyrosine kinase. K-252a inhibits the TrkA autophosphorylation, which reduces the OL process formation to control levels. To the tyrosine-phosphorylated sites of TrkA several proteins, such as phospholipase C-gamma1, the adaptor protein SHC, the phosphotyrosine phosphatase SH-PTP2 (SYP) associate via their SH2 phosphotase SH-PTP2 domain. The association of SHC to TrkA is shown by co-immunoprecipitation. Indirect evidence for a possible activation of PLC-gamma1 is given by an NGF-induced increase of oligodendroglial [Ca2+]i. Downstream from TrkA, a mitogen-activated protein kinase cascade, which includes Erk1 and Erk2, is operating. An in-gel myelin basic protein kinase assay revealed that NGF activates predominantly Erk1. Finally, it is shown that NGF stimulates expression of c-fos.
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PMID:Nerve growth factor signal transduction in mature pig oligodendrocytes. 941 61

The cellular mechanisms that underlie nerve growth factor (NGF) induced increase in Ca(2+)-channel current in adult bullfrog sympathetic B-neurons were examined by whole cell recording techniques. Cells were maintained at low density in neuron-enriched, defined-medium, serum-free tissue culture for 6 days in the presence or absence of NGF (200 ng/ml). The increase in Ba2+ current (IBa) density induced by NGF was attenuated by the RNA synthesis inhibitor cordycepin (20 microM), by the DNA transcription inhibitor actinomycin D (0.01 microgram/ml), by inhibitors of Ras isoprenylation (perillic acid 0.1-1.0 mM or alpha-hydroxyfarnesylphosphonic acid 10-100 microM), by tyrosine kinase inhibitors genistein (20 microM) or lavendustin A (1 microM), and by PD98059 (10-100 microM), an inhibitor of mitogen-activated protein kinase kinase. Inhibitors of the phosphatidylinositol 3-kinase (PI3K) pathway (wortmannin, 100 nM, or LY29400, 100 microM) were ineffective as were inhibitors of phospholipase C gamma (U73122 or neomycin, both 100 microM). The effect of NGF persisted in Ca(2+)-free medium that contained 1.8 mM Mg2+ and 2 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. It was mimicked by a Trk antibody that was capable of inducing neurite outgrowth in explant cultures of bullfrog sympathetic ganglion. Antibodies raised against the low-affinity p75 neurotrophin receptor were ineffective in blocking the effect of NGF on IBa. These results suggest that NGF-induced increase in Ca2+ channel current in adult sympathetic neurons results, at least in part, from new channel synthesis after Trk activation of Ras and mitogen activated protein kinase by a mechanism that is independent of extracellular Ca2+.
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PMID:Involvement of Ras/MAP kinase in the regulation of Ca2+ channels in adult bullfrog sympathetic neurons by nerve growth factor. 974 44

The TrkA receptor is activated primarily by nerve growth factor (NGF), but it can also be activated by high concentrations of neurotrophin 3 (NT-3). The pan-neurotrophin receptor p75(NTR) strongly inhibits activation of TrkA by NT-3 but not by NGF. To examine the role of p75(NTR) in regulating the specificity of TrkA signaling, we expressed both receptors in Xenopus oocytes. Application of NGF or NT-3 to oocytes expressing TrkA alone resulted in efflux of (45)Ca(2+) by a phospholipase C-gamma-dependent pathway. Coexpression of p75(NTR) with TrkA inhibited (45)Ca(2+) efflux in response to NT-3 but not NGF. The inhibitory effect on NT-3 activation of TrkA increased with increasing expression of p75(NTR). Coexpression of a truncated p75(NTR) receptor lacking all but the first 9 amino acids of the cytoplasmic domain inhibited NT-3 stimulation of (45)Ca(2+) efflux, whereas coexpression of an epidermal growth factor receptor/p75(NTR) chimera (extracellular domain of epidermal growth factor receptor with transmembrane and cytoplasmic domains of p75(NTR)) did not inhibit NT-3 signaling through TrkA. These studies demonstrated that the extracellular domain of p75(NTR) was necessary to inhibit NT-3 signaling through TrkA. Remarkably, p75(NTR) binding to NT-3 was not required to prevent signaling through TrkA, since occupying p75(NTR) with brain-derived neurotrophic factor or anti-p75 antibody (REX) did not rescue the ability of NT-3 to activate (45)Ca(2+) efflux. These data suggested a physical association between TrkA and p75(NTR). Documenting this physical interaction, we showed that p75(NTR) and TrkA could be coimmunoprecipitated from Xenopus oocytes. Our results suggest that the interaction of these two receptors on the cell surface mediated the inhibition of NT-3-activated signaling through TrkA.
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PMID:The extracellular domain of p75NTR is necessary to inhibit neurotrophin-3 signaling through TrkA. 1115 Feb 91

Nerve growth factor (NGF) is a key element of inflammatory pain. It induces hyperalgesia by up-regulating the transcription of genes encoding receptors, ion channels, and neuropeptides. Acid-sensing ion channel 3 (ASIC3), a depolarizing sodium channel gated by protons during tissue acidosis, is specifically expressed in sensory neurons. It has been associated to cardiac ischemic and inflammatory pains. We previously showed that low endogenous NGF was responsible for ASIC3 basal expression and high NGF during inflammation increased ASIC3 expression parallely to the development of neuron hyperexcitability associated with hyperalgesia. NGF is known to activate numerous signaling pathways through trkA and p75 receptors. We now show that (i). NGF controls ASIC3 basal expression through constitutive activation of a trkA/phospholipase C/protein kinase C pathway, (ii). high inflammatory-like NGF induces ASIC3 overexpression through a trkA/JNK/p38MAPK pathway and a p75-dependent mechanism as a transcriptional switch, and (iii). NGF acts through AP1 response elements in ASIC3 encoding gene promoter. These new data indicate potential targets that could be used to develop new treatments against inflammatory pain.
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PMID:How nerve growth factor drives physiological and inflammatory expressions of acid-sensing ion channel 3 in sensory neurons. 1452 57

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

Neurotrophins are a family of closely related proteins that were identified initially as survival factors for sensory and sympathetic neurons, and have since been shown to control many aspects of survival, development and function of neurons in both the peripheral and the central nervous systems. Each of the four mammalian neurotrophins has been shown to activate one or more of the three members of the tropomyosin-related kinase (Trk) family of receptor tyrosine kinases (TrkA, TrkB and TrkC). In addition, each neurotrophin activates p75 neurotrophin receptor (p75NTR), a member of the tumour necrosis factor receptor superfamily. Through Trk receptors, neurotrophins activate Ras, phosphatidyl inositol-3 (PI3)-kinase, phospholipase C-gamma1 and signalling pathways controlled through these proteins, such as the MAP kinases. Activation of p75NTR results in activation of the nuclear factor-kappaB (NF-kappaB) and Jun kinase as well as other signalling pathways. Limiting quantities of neurotrophins during development control the number of surviving neurons to ensure a match between neurons and the requirement for a suitable density of target innervation. The neurotrophins also regulate cell fate decisions, axon growth, dendrite growth and pruning and the expression of proteins, such as ion channels, transmitter biosynthetic enzymes and neuropeptide transmitters that are essential for normal neuronal function. Continued presence of the neurotrophins is required in the adult nervous system, where they control synaptic function and plasticity, and sustain neuronal survival, morphology and differentiation. They also have additional, subtler roles outside the nervous system. In recent years, three rare human genetic disorders, which result in deleterious effects on sensory perception, cognition and a variety of behaviours, have been shown to be attributable to mutations in brain-derived neurotrophic factor and two of the Trk receptors.
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PMID:Neurotrophin-regulated signalling pathways. 1693 74

The neurotrophins are a family of closely related proteins that were first identified as survival factors for sympathetic and sensory neurons, and have since been shown to control a number of aspects of survival, development and function of neurons in both the central and peripheral nervous systems. Limiting quantities of neurotrophins during development control the numbers of surviving neurons to ensure a match between neurons and the requirement for a suitable density of target innervation. Biological effects of each of the four mammalian neurotrophins are mediated through activation of one or more of the three members of the tropomyosin-related kinase (Trk) family of receptor tyrosine kinases (TrkA, TrkB and TrkC). In addition, all neurotrophins activate the p75 neurotrophin receptor (p75(NTR)), a member of the tumour necrosis factor receptor superfamily. Nerve growth factor (NGF), the best characterised member of the neurotrophin family, sends its survival signals through activation of TrkA and can induce death by binding to p75(NTR). Neurotrophin engagement of Trk receptors leads to activation of Ras, phosphatidylinositol 3-kinase, phospholipase C-gamma1 and signalling pathways controlled through these proteins, including the mitogen-activated protein kinases. Neurotrophin availability is required into adulthood, where they control synaptic function and plasticity, and sustain neuronal cell survival, morphology and differentiation. Preclinical studies point to the therapeutic potential of neurotrophic factors in preventing or slowing the progression of neurodegenerative conditions. Given the difficulties inherent with a protein therapeutic approach to treating central nervous system disorders, increasing attention has turned to the development of alternative strategies and, in particular, small molecule mimetics. This article will provide an overview of neurotrophin biology, their receptors, and signalling pathways, followed by a description of functional mimetics of neurotrophins acting at Trk receptors. Moreover, exciting recent data describing G-protein-coupled receptor transactivation of Trk receptors and their downstream signalling pathways raise the possibility of using small molecules to elicit neuroprotective effects.
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PMID:The biology of neurotrophins, signalling pathways, and functional peptide mimetics of neurotrophins and their receptors. 1828 31


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