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)

Delipidation of carp liver mitochondria by treatment with methyl ethyl ketone (MEK) or Triton X-100 and then perchlorate greatly reduced MAO activities. Treatment with only Triton X-100 resulted in less reduction in activity. The Km values of the remaining activities were similar regardless of these treatments. The sensitivities towards clorgyline and l-deprenyl of the remaining activity in the Triton X-100-treated residue and the phospholipase C-treated carp brain mitochondria were found to be unchanged, but those of the activity remaining in the MEK-treated residue were similarly decreased. No evidence was obtained suggesting conversion of carp MAO to either MAO-A or MAO-B by the modification of the mitochondrial lipid environment by the treatments employed.
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PMID:Membrane lipid environment of carp brain and liver mitochondrial monoamine oxidase. 286 Oct 3

Mitogen-activated protein kinases (MAPKs) are activated upon a variety of extracellular stimuli in different cells. In macrophages, colony-stimulating factor 1 (CSF-1) stimulates proliferation, while bacterial lipopolysaccharide (LPS) inhibits cell growth and causes differentiation and activation. Both CSF-1 and LPS rapidly activate the MAPK network and induce the phosphorylation of two distinct ternary complex factors (TCFs), TCF/Elk and TCF/SAP. CSF-1, but not LPS, stimulated the formation of p21ras. GTP complexes. Expression of a dominant negative ras mutant reduced, but did not abolish, CSF-1-mediated stimulation of MEK and MAPK. In contrast, activation of the MEK kinase Raf-1 was Ras independent. Treatment with the phosphatidylcholine-specific phospholipase C inhibitor D609 suppressed LPS-mediated, but not CSF-1-mediated, activation of Raf-1, MEK, and MAPK. Similarly, down-regulation or inhibition of protein kinase C blocked MEK and MAPK induction by LPS but not that by CSF-1. Phorbol 12-myristate 13-acetate pretreatment led to the sustained activation of the Raf-1 kinase but not that of MEK and MAPK. Thus, activated Raf-1 alone does not support MEK/MAPK activation in macrophages. Phosphorylation of TCF/Elk but not that of TCF/SAP was blocked by all treatments that interfered with MAPK activation, implying that TCF/SAP was targeted by a MAPK-independent pathway. Therefore, CSF-1 and LPS target the MAPK network by two alternative pathways, both of which induce Raf-1 activation. The mitogenic pathway depends on Ras activity, while the differentiation signal relies on protein kinase C and phosphatidylcholine-specific phospholipase C activation.
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PMID:Ras-dependent and -independent pathways target the mitogen-activated protein kinase network in macrophages. 779 56

Expression of the GTPase-deficient G alpha 16 polypeptide G alpha 16Q212L, a member of the Gq family of heterotrimeric G proteins, constitutively activated phospholipase C beta activity in Swiss 3T3 cells. Expression of G alpha 16Q212L appears to persistently stimulte a low level of protein kinase C activity which also increases protein kinase A activity in Swiss 3T3 cells. Growth of G alpha 16Q212L expressing cells was significantly inhibited relative to wild-type Swiss 3T3 cells. Bombesin-stimulated DNA synthesis was completely inhibited in G alpha 16Q212L expressing clones, whereas the growth responses to platelet-derived growth factor (PDGF) and serum were inhibited 50-80% relative to wild-type cells. In addition to the inhibition of cell growth, G alpha 16Q212L expression significantly inhibited the stimulation of protein kinase C, Raf-1, MEK, mitogen-activated protein kinase, phospholipase A2 activity, and Ca2+ mobilization in response to PDGF. In contrast, PDGF receptor activation of phospholipase C gamma, phosphatidylinositol 3-kinase, and Ras GTP loading was similar in wild-type and G alpha 16Q212L expressing clones. PDGF regulation of membrane ruffling and actin fiber assembly, responses mediated in part by phosphatidylinositol 3-kinase, were unaffected in G alpha 16Q212L expressing clones. The growth inhibitory action of G alpha 16Q212L expression in Swiss 3T3 cells is downstream of the initial SH2 domain-encoded signal transduction proteins regulated in response to PDGF receptor autophosphorylation. The findings demonstrate that constitutively activated G alpha 16Q212L persistently activates phospholipase C activity and effectively inhibits a subset of cytoplasmic signal transduction pathways involved in growth factor tyrosine kinase receptor stimulation of cell growth. G16/Gq-regulated signal transduction can acutely stimulate specific response pathways involved in mitogenesis; but persistent activation of G16/Gq-regulated effectors, including phospholipase C beta, inhibit tyrosine kinase-initiated mitogenesis. One role for G16/Gq response systems may be to modulate growth factor receptor signaling.
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PMID:Expression of GTPase-deficient G alpha 16 inhibits Swiss 3T3 cell growth. 802 Dec 43

A common response of cells to mitogenic and hypertrophic factors is the activation of high rates of protein synthesis. To investigate the molecular basis of this action, we have used the recently developed MAP kinase/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor PD 98059 to examine the involvement of the ERK pathway in the regulation of global protein synthesis by growth factors in rat aortic smooth muscle cells (SMC). Incubation with PD 98059 blocked angiotensin II (AII)-dependent phosphorylation and enzymatic activity of both MEK1 and MEK2 isoforms, leading to inhibition of the phosphorylation and activation of p44(mapk) and p42(mapk). The compound was found to selectively inhibit activation of the ERK pathway by AII, but not the stimulation of p70 S6 kinase, phospholipase C, or tyrosine phosphorylation. Most importantly, treatment of aortic SMC with PD 98059 potently inhibited AII-stimulated protein synthesis with a half-maximal inhibitory concentration of 4.3 microM. The effect of PD 98059 was not restricted to AII, since the compound also blocked to various extent the induction of protein synthesis by growth factors acting through tyrosine kinase receptors, G protein-coupled receptors, or protein kinase C. These results provide strong evidence that activation of ERK isoforms is an obligatory step for growth factor-induced protein synthesis in aortic SMC.
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PMID:Inhibition of growth factor-induced protein synthesis by a selective MEK inhibitor in aortic smooth muscle cells. 866 42

The serine/threonine-specific protein kinase Raf-1 plays a key role in mitogenic signal transduction by coupling Ras to the mitogen-activated protein (MAP) kinase cascade. Ras-mediated translocation to the plasma membrane represents a crucial step in the process of serum-stimulated Raf-1 kinase activation. The exact role of the multisite phosphorylation in Raf regulation, however, is not clear. We have previously reported that the mobility shift-associated hyperphosphorylation of Raf correlates with a reduction of serum-stimulated Raf kinase activity (Wartmann, M., and Davis, R. J. (1994) J. Biol. Chem. 269, 6695-6701). Here we show that incubation of serum-starved CHO cells with D609, a purported inhibitor of phosphatidylcholine-specific phospholipase C, also results in a mobility shift of Raf-1 that is due to hyperphosphorylation on sites identical to those observed following mitogen stimulation. Subcellular fractionation analyses revealed that D609-induced mobility shift-associated hyperphosphorylation was paralleled by a decreased membrane association of Raf-1. Similar results were obtained in an in vitro reconstitution system. Furthermore, PD98059, a specific inhibitor of activation of the MAP kinase kinase MEK, prevented D609-induced Raf hyperphosphorylation and restored the amount of membrane-bound Raf to control levels. Taken together, these data suggest that mobility shift-associated hyperphosphorylation of Raf-1, by virtue of reducing the amount of plasma membrane-bound Raf-1, represents a negative feedback mechanism contributing to the desensitization of the MAP kinase signaling cascade.
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PMID:Negative modulation of membrane localization of the Raf-1 protein kinase by hyperphosphorylation. 902 94

c-Src, the prototype of the cytoplasmic, membrane-associated,non-receptor tyrosine kinases, is a co-transducer of mitogenic signals emanating from a number of tyrosine kinase polypeptide growth factor receptors. Examples of such receptors include those that bind the platelet-derived growth factor (PDGF), colony stimulating factor-1 (CSF-1), and epidermal growth factor (EGF). Investigations into the mechanisms by which c-Src contributes to receptor signaling suggest that interactions between the two proteins are bidirectional, i.e., that c-Src can bind, phosphorylate, and activate the receptor, and vice versa. The consequences of these interactions appear to be enhanced phosphorylation of specific substrates. Delineating which cellular proteins are substrates of which tyrosine kinase and determining the consequences of tyrosine phosphorylation on the function of specific substrates are the goals of current investigations. Utilizing the murine C3H10T fibroblast model, in which a panel of wild type and mutant c-Src/EGF receptor overexpressors has been studied for temporal and spatial second messenger responses to EGF, distinctions between substrates of c-Src and the EGF receptor and the effects of tyrosine phosphorylation on substrate function are beginning to emerge. In the 10T model, preferred substrates of c-Src are almost exclusively comprised of those molecules that associate with the actin cytoskeleton or with focal adhesions, such as cortactin, p190RhoGAP, and p130CAS, while preferred substrates of the EGF receptor include the receptor itself, SHC, phospholipase C-gamma and p62DOK. While the major mitogenic signaling pathway is thought to proceed directly from the receptor (through SHC/GRB2/SOS/Ras/Raf/MEK/MAPkinase/Elk1), more evidence is accumulating to suggest that proteins involved in regulating the actin cytoskeleton (such as c-Src substrates) also participate in mitogenesis, either as unique transducers of growth signals and/or as monitors of anti-apoptotic conditions (substratum attachment). How c-Src may contribute to the EGF mitogenic response through tyrosine phosphorylation of or association with its specific substrates is discussed. Cellular Src (c-Src), prototype for a family of intracellular membrane-associated tyrosine kinases, is required for mitogenesis initiated by multiple growth factor receptors, including the receptors for epidermal growth factor (EGF), platelet-derived growth factor (PDGF), colony stimulating factor-1 (CSF-1), and the basic fibroblast growth factor (bFGF). C-Src is also overexpressed and/or activated in many of the same human carcinomas that overexpress members of the EGF receptor (EGFR) family, suggesting that the two types of tyrosine kinases can cooperate during the genesis of human tumors. This review focuses on the role of c-Src in EGF-dependent mitogenesis and tumorigenesis, i.e., on the interactions between c-Src and the receptor and on identification of c-Src substrates, their functions, and the effects of tyrosine phosphorylations on their functions. A synopsis of other mitogenic and signaling systems is also included for comparative purposes.
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PMID:Role of c-Src tyrosine kinase in EGF-induced mitogenesis. 933 27

A current model of growth factor-induced cell motility invokes integration of diverse biophysical processes required for cell motility, including dynamic formation and disruption of cell/substratum attachments along with extension of membrane protrusions. To define how these biophysical events are actuated by biochemical signaling pathways, we investigate here whether epidermal growth factor (EGF) induces disruption of focal adhesions in fibroblasts. We find that EGF treatment of NR6 fibroblasts presenting full-length WT EGF receptors (EGFR) reduces the fraction of cells presenting focal adhesions from approximately 60% to approximately 30% within 10 minutes. The dose dependency of focal adhesion disassembly mirrors that for EGF-enhanced cell motility, being noted at 0.1 nM EGF. EGFR kinase activity is required as cells expressing two kinase-defective EGFR constructs retain their focal adhesions in the presence of EGF. The short-term (30 minutes) disassembly of focal adhesions is reflected in decreased adhesiveness of EGF-treated cells to substratum. We further examine here known motility-associated pathways to determine whether these contribute to EGF-induced effects. We have previously demonstrated that phospholipase C(gamma) (PLCgamma) activation and mobilization of gelsolin from a plasma membrane-bound state are required for EGFR-mediated cell motility. In contrast, we find here that short-term focal adhesion disassembly is induced by a signaling-restricted truncated EGFR (c'973) which fails to activate PLCgamma or mobilize gelsolin. The PLC inhibitor U73122 has no effect on this process, nor is the actin severing capacity of gelsolin required as EGF treatment reduces focal adhesions in gelsolin-devoid fibroblasts, further supporting the contention that focal adhesion disassembly is signaled by a pathway distinct from that involving PLCgamma. Because both WT and c'973 EGFR activate the erk MAP kinase pathway, we additionally explore here this signaling pathway, not previously associated with growth factor-induced cell motility. Levels of the MEK inhibitor PD98059 that block EGF-induced mitogenesis and MAP kinase phosphorylation also abrogate EGF-induced focal adhesion disassembly and cell motility. In summary, we characterize for the first time the ability of EGFR kinase activity to directly stimulate focal adhesion disassembly and cell/substratum detachment, in relation to its ability to stimulate migration. Furthermore, we propose a model of EGF-induced motogenic cell responses in which the PLCgamma pathway stimulating cell motility is distinct from the MAP kinase-dependent signaling pathway leading to disassembly and reorganization of cell-substratum adhesion.
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PMID:EGF receptor regulation of cell motility: EGF induces disassembly of focal adhesions independently of the motility-associated PLCgamma signaling pathway. 945 35

1. Although stimulation of mouse RAW 264.7 macrophages by UTP elicits a rapid increase in intracellular free Ca2+ ([Ca2+]i), phosphoinositide (PI) turnover, and arachidonic acid (AA) release, the causal relationship between these signalling pathways is still unclear. In the present study, we investigated the involvement of phosphoinositide-dependent phospholipase C (PI-PLC) activation, Ca2+ increase and protein kinase activation in UTP-induced AA release. The effects of stimulating RAW 264.7 cells with thapsigargin, which cannot activate the inositol phosphate (IP) cascade, but results in the release of sequestered Ca2+ and an influx of extracellular Ca2+, was compared with the effects of UTP stimulation to elucidate the multiple regulatory pathways for cPLA2 activation. 2. In RAW 264.7 cells UTP (100 microM) and thapsigargin (1 microM) caused 2 and 1.2 fold increases, respectively, in [3H]-AA release. The release of [3H]-AA following treatment with UTP and thapsigargin were non-additive, totally abolished in the Ca2+-free buffer, BAPTA (30 microM)-containing buffer or in the presence of the cPLA2 inhibitor MAFP (50 microM), and inhibited by pretreatment of cells with pertussis toxin (100 ng ml(-1)) or 4-bromophenacyl bromide (100 microM). By contrast, aristolochic acid (an inhibitor of sPLA2) had no effect on UTP and thapsigargin responses. 3. U73122 (10 microM) and neomycin (3 mM), inhibitors of PI-PLC, inhibited UTP-induced IP formation (88% and 83% inhibition, respectively) and AA release (76% and 58%, respectively), accompanied by a decrease in the [Ca2+]i rise. 4. Wortmannin attenuated the IP response of UTP in a concentration-dependent manner (over the range 10 nM-3 microM), and reduced the UTP-induced AA release in parallel. RHC 80267 (30 microM), a specific diacylglycerol lipase inhibitor, had no effect on UTP-induced AA release. 5. Short-term treatment with PMA (1 microM) inhibited the UTP-stimulated accumulation of IP and increase in [Ca2+]i, but had no effect on the release of AA. In contrast, the AA release caused by thapsigargin was increased by PMA. 6. The role of PKC in UTP- and thapsigargin-mediated AA release was shown by the blockade of these effects by staurosporine (1 microM), Ro 31-8220 (10 microM), Go 6976 (1 microM) and the down-regulation of PKC. 7. Following treatment of cells with SK&F 96365 (30 microM), thapsigargin-, but not UTP-, induced Ca2+ influx, and the accompanying AA release, were down-regulated. 8. Neither PD 98059 (100 microM), MEK a inhibitor, nor genistein (100 microM), a tyrosine kinase inhibitor, had any effect on the AA responses induced by UTP and thapsigargin. 9. We conclude that UTP-induced cPLA2 activity depends on the activation of PI-PLC and the sustained elevation of intracellular Ca2+, which is essential for the activation of cPLA2 by UTP and thapsigargin. The [Ca2+]i-dependent AA release that follows treatment with both stimuli was potentiated by the activity of protein kinase C (PKC). A pertussis toxin-sensitive pathway downstream of the increase in [Ca2+]i was also shown to be involved in AA release.
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PMID:Pharmacological comparison of UTP- and thapsigargin-induced arachidonic acid release in mouse RAW 264.7 macrophages. 955 2

1. Extracellular adenosine triphosphate (ATP) is mitogenic for vascular smooth muscle cells (VSMC) and stimulates several events that are important for cell proliferation: DNA synthesis, protein synthesis, increase of cell number, immediate early genes, cell-cycle progression, and tyrosine phosphorylation. 2. Receptor characterization indicates mitogenic effects of both P2U and P2Y receptors. The P2X receptor is lost in cultured VSMC and is not involved. Several related biological substances such as UTP, ITP, GTP, AP4A, ADP, and UDP are also mitogenic. 3. Signal transduction is mediated via Gq-proteins, phospholipase C beta, phospholipase D, diacyl glycerol, protein kinase C alpha, delta, Raf-1, MEK, and MAPK. 4. ATP acts synergistically with polypeptide growth factors (PDGF, bFGF, IGF-1, EGF, insulin) and growth factors acting via G-protein-coupled receptors (noradrenaline, neuropeptide Y, 5-hydroxytryptamine, angiotensin II, endothelin-1). 5. The mitogenic effects have been demonstrated in rat, porcine, and bovine VSMC and cells from human coronary arteries, aorta, and subcutaneous arteries and veins. 6. The trophic effects on VSMC and the abundant sources for extracellular ATP in the vessel wall make a pathophysiological role probable in the development of atherosclerosis, neointima-formation after angioplasty, and possibly hypertension.
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PMID:Extracellular ATP: a growth factor for vascular smooth muscle cells. 959 70

Endothelin (ET)-1 is an endothelium-derived vasoconstrictor as well as a mitogen. We have recently described a novel role of ET-1 as a survival factor for rat endothelial cells from serum deprivation-induced apoptosis. The present study was designed to determine which receptor subtype (ETA or ETB) is responsible for and what intracellular mediators are involved in endothelial apoptosis. Apoptotic cell death was evaluated by nucleosomal ladders on agarose gel electrophoresis and immunohistochemical study using anti-single-stranded DNA antiserum. ET-1 and an ETB receptor agonist suppressed endothelial apoptosis, whose effects were abrogated by an ETB receptor antagonist but not by an ETA receptor antagonist. Addition of an ETB receptor antagonist or nonselective ETA/B receptor antagonists, but not an ETA receptor antagonist, enhanced the apoptotic events caused by serum deprivation, suggesting an autocrine/paracrine role of endogenous ET-1 in protecting against endothelial apoptosis. The effect of ET-1 in suppressing apoptosis was unaffected by any of the following reagents: a phospholipase C inhibitor (U73122), a tyrosine kinase inhibitor (ST638), an MEK inhibitor (PD98059), a phosphatidylinositol-3 kinase inhibitors (wortmannin, LY294002). Taken together, these results confirm a role for ET-1 as an autocrine/paracrine survival factor for rat endothelial cells, in which neither phospholipase C, tyrosine kinase, MAP kinase, nor phosphatidylinositol-3 kinase is involved in mediating the antiapoptotic effect of ET-1.
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PMID:Endothelin-B receptor-mediated suppression of endothelial apoptosis. 959 22


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