Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatocytes were established in tissue culture in order to study the effects of pertussis toxin (PT) on epidermal growth factor (EGF)-mediated cellular responses under in vitro conditions. EGF caused a 3-fold increase of myo-inositol 1,4,5-trisphosphate (Ins-1,4,5-P3) mass and a 50% increase of diacylglycerol mass within the first minute, with the change of diacylglycerol content being 100-fold greater than that of Ins-1,4,5-P3. Diacylglycerol, but not Ins-1,4,5-P3, continued to accumulate over several hours, indicating that EGF increased the hydrolysis of lipids other than phosphatidylinositol 4,5-bisphosphate (PIP2). EGF increased phosphoinositide-specific phospholipase C-gamma (PLC-gamma) tyrosine phosphorylation within 1 min, but no effect was observed with vasopressin, insulin, or glucagon after 5 min. EGF also caused a rapid, tyrosine kinase-dependent association of G(i) alpha with PLC-gamma, which was maximal within 10 min. In contrast to our previous data on fresh hepatocytes, PT had no effect on the EGF-induced tyrosine phosphorylation of PLC-gamma, although Ins-1,4,5-P3 and diacylglycerol production were inhibited. The role of G-proteins in EGF signaling was investigated further by microinjection of G alpha antibodies into single fura-2-loaded hepatocytes. Anti-G(i) alpha (common) antibodies prevented EGF-induced but not vasopressin-induced Ca2+ transients. These results strengthen previous observations that a PT-sensitive G-protein is involved in EGF-mediated phospholipid metabolism in hepatocytes and show that tyrosine phosphorylation of PLC-gamma is an insufficient signal for activation of PIP2 hydrolysis.
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PMID:Epidermal growth factor-mediated signaling of G(i)-protein to activation of phospholipases in rat-cultured hepatocytes. 842 49

Tyrosine kinase inhibitors such as erbstatin and lavendustin derivative inhibited platelet-derived growth factor (PDGF)- and bombesin-induced inositol phosphate formation and phospholipase C (PLC) activation in quiescent NIH3T3 cells. However, bombesin-induced PLC activation was only partially inhibited by tyrosine kinase inhibitors, whereas PDGF-induced activation was completely. Moreover, although bombesin-induced PLC activation was partially inhibited by pertussis toxin alone, this toxin inhibited almost completely in the presence of tyrosine kinase inhibitors. Thus, tyrosine kinase was suggested to be involved in PDGF- and bombesin-induced PLC activation in a different manner.
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PMID:Involvement of tyrosine kinase in growth factor-induced phospholipase C activation in NIH3T3 cells. 844 36

We have previously shown that in neutrophils classical transmembrane signaling consisting of increased [Ca2+]i and hydrolysis of phospholipids was not essential for phagocytosis mediated by more than one receptor (yeast-IgG, yeast-C3b/bi, yeast-Con A). This work deals with the role of this transmembrane signaling in phagocytosis of erythrocyte (E) IgG, which is mediated only by receptors for IgG (Fc gamma Rs). The ingestion of E-IgG was associated with an increase in [Ca2+]i and production of inositol phosphates, phosphatidic acid, diacylglycerol, and arachidonic acid, via activation of phospholipases C, D and A2. Related to the same number of particles ingested, the respiratory burst and the transmembrane signaling during phagocytosis of E-IgG were much smaller than during phagocytosis of yeast-IgG. In Ca(2+)-depleted neutrophils, where the increase in [Ca2+]i and hydrolysis of phospholipids were lacking, the phagocytosis of E-IgG was depressed by about 60%; the respiratory burst was also depressed due to the decrease of ingestion and of stimulation of NADPH oxidase by residual phagocytosis. Pertussis toxin (PT) did not inhibit the phagocytosis of E-IgG but depressed by about 40% the stimulation of lipidic transmembrane signaling and the respiratory burst in normal neutrophils. In Ca(2+)-depleted neutrophils the toxin was without effect on ingestion and respiratory burst. Staurosporine did not inhibit the ingestion of E-IgG in normal and Ca(2+)-depleted neutrophils but depressed by 30-40% the respiratory burst in normal and not in Ca(2+)-depleted neutrophils. Genistein, an inhibitor of tyrosine kinase, did not inhibit the ingestion of E-IgG but depressed by 30-40% the respiratory burst both in normal and Ca(2+)-depleted neutrophils. These results demonstrate the following findings in human neutrophils. (1) Contrary to the phagocytosis mediated by more than one receptor (yeast-IgG, yeast-Con A, yeast-C3b/bi), the transmembrane signaling involving increase in [Ca2+]i and hydrolysis of phospholipids plays a role in the phagocytosis and respiratory burst mediated by Fc gamma Rs alone. Thus, different signal transduction pathways can be involved in phagocytosis and associated respiratory burst depending on the receptor or combination of receptors activated. (2) Fc gamma Rs alone promote phagocytosis with two signaling pathways independent of and dependent on [Ca2+]i changes and phospholipid hydrolysis and insensitive to PT, staurosporine, and genistein. (3) The signaling pathways promoting phagocytosis triggered by Fc gamma Rs alone are in some way, or at some step, different from those that activate the respiratory burst.
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PMID:Transmembrane signaling pathways involved in phagocytosis and associated activation of NADPH oxidase mediated by Fc gamma Rs in human neutrophils. 848 23

This study was undertaken to identify the signaling events involved in activation of neutrophil superoxide anion (O2-) production by eosinophil granule major basic protein (MBP). MBP did not produce an immediate increase in the cytosolic free calcium concentration ([Ca2+]i), characteristic of phospholipase C activation, but did cause a gradual increase in [Ca2+]i in cytochalasin B-treated cells. Preincubation with 0.01 to 3 micrograms/mL pertussis toxin did not inhibit MBP-stimulated O2- production, and MBP did not stimulate an increase in diradylglycerol levels. MBP did stimulate a low level of phospholipase D activity, as measured by a time-dependent increase in phosphatidic acid and, in the presence of 0.5% ethanol, phosphatidylethanol. Inhibition of MBP-stimulated O2- production by genistein and Western blot analysis using an antiphosphotyrosine antibody showed tyrosine kinase activation by MBP. Calmodulin antagonists (calmidazolium and W-7) caused up to 80% inhibition of MBP-stimulated O2- production. In agreement with the pharmacologic sensitivity, MBP did not stimulate any 51Cr release. These data indicate that tyrosine kinase and calmodulin-dependent steps are involved in the noncytotoxic stimulation of neutrophil O2- production by MBP.
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PMID:Analysis of signaling events associated with activation of neutrophil superoxide anion production by eosinophil granule major basic protein. 854 54

Tyrosine kinases are involved in cell signalling of growth factors such as insulin and insulin-like growth factor (IGF-I) and others. Insulin and IGF-I receptors which possibly feedback on insulin release are established in insulin-secreting cells. The role of tyrosine kinase in insulin secretion is controversial. Both the tyrosine kinase inhibitors tyrphostin 25 (TYR) and genistein (GEN), but not its structurally similar albeit biologically inactive analogue daidzein, increase insulin release at 16.7 mM glucose in INS-1 cells, an insulin secreting cell line. Tyrosine kinase activity is inhibited by GEN, but not diadzein. The inhibitory effects of either insulin or IGF-I on insulin release are abolished by 10(-4) M GEN but not by daidzein indicating an involvement of tyrosine kinase in the inhibitory effect of both insulin and IGF-I on insulin release. Since GEN was argued not to be specific for tyrosine kinase, several second messengers were investigated. cAMP is not influenced. The insulinotropic effect of acutely administered TPA is not influenced by GEN while in protein kinase C (PKC)-downregulated cells the insulinotropic effect of GEN is preserved: both indicate no involvement of PKC in GEN effect. Since pertussis toxin (PT) pretreatment has no effect on the inhibitory effects of IGF-I on insulin release, a PT-sensitive G-protein is not likely to be involved. The data indicate that tyrosine kinase is involved in the inhibitory effects of insulin and IGF on insulin release in INS-1 cells, possibly mediating the negative feedback effect.
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PMID:Role of tyrosine kinase in insulin release in an insulin secreting cell line (INS-1). 856 11

Myogenic cells provide excellent in vitro models for studying the cell growth and differentiation. In this study we report that lysophosphatidic acid (LPA), a bioactive phospholipid contained in serum, stimulates the growth and inhibits the differentiation of mouse C2C12 myoblast cells, in a distinct manner from basic fibroblast growth factor (bFGF) whose mitotic and anti-differentiation actions have been well investigated. These actions of LPA were both blocked by pertussis toxin, suggesting the involvement of Gi class of G proteins, whereas bFGF acts through receptor tyrosine kinases. Detailed analysis revealed that LPA and bFGF act differently in regulating the myogenic basic helix-loop-helix (bHLH) proteins, the key players in myogenic differentiation process. LPA stimulates the proliferation of undifferentiated myoblasts allowing the continued expression of MyoD, but in contrast, bFGF does so with the MyoD expression suppressed at the mRNA level. Both compounds maintain the myf-5 expression, and suppress the myogenin expression. In addition, while LPA did not inhibit cell-cell contact-induced differentiation, bFGF strongly inhibited this process. Furthermore, LPA and bFGF act cooperatively in their mitogenic and anti-differentiation abilities. These findings indicate that LPA and bFGF differently stimulate intracellular signaling pathways, resulting in proliferating myoblasts each bearing a distinct expression pattern of myogenic bHLH proteins and distinct differentiation potentials in response to cell-cell contact, and illustrate the biological significance of Gi-mediated and tyrosine kinase-mediated signals.
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PMID:Lysophosphatidic acid and bFGF control different modes in proliferating myoblasts. 856 22

Angiotensin II (Ang II) is a potent regulator of proximal tubule functions, including transport, metabolism, and cell proliferation. The opossum kidney (OK) cell line is a useful model of renal proximal tubule. Mitogen-activated protein (MAP) kinases are rapidly phosphorylated and activated in response to various agonists. We investigated Ang II effects on serine/threonine kinase cascades in OK cells. The major findings of the present study are that Ang II stimulated MAP kinase kinase (MAPKK), MAP kinase (MAPK), and S6 kinase activities, and that it increased phosphorylation of Raf-1 kinase and p42 MAP kinase in OK cells. These stimulations of kinases were dose-dependent (from 10(-6) to 10(-11) M). The time course of activation was sequential; the peak stimulation was reached at 5 to 10 minutes for Raf-1 kinase, MAPKK and MAPK, and at 20 minutes for S6 kinase. The activation of MAPK was inhibited by approximately 70% with prolonged 24-hour PMA pretreatment or in the presence of calphostin C or H-7. Tyrosine kinase inhibitors (genistein and herbimycin) did not inhibit AngII-induced MAPK activity. This activation of MAPK was also inhibited via AT1 receptor antagonist, Dup753 and pertussis toxin. This evidence suggests that the activation of serine/threonine cascades by Ang II is largely dependent on PMA-sensitive PKC, and is not dependent on tyrosine kinase and pertussis toxin.
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PMID:Sequential activation of MAP kinase cascade by angiotensin II in opossum kidney cells. 858 39

Stimulation of monocytic THP-1 cells by a lectin, concanavalin A (Con A), resulted in protein-tyrosine phosphorylation and association of some of the thus phosphorylated proteins with the 85 kDa regulatory subunit of PtdIns 3-kinase. Both actions of Con A were not inhibited by wortmannin, a PtdIns 3-kinase inhibitor, or by prior exposure of cells to pertussis toxin which uncouples certain G-proteins from receptors. The binding of PtdIns 3-kinase to the tyrosine-phosphorylated proteins increased upon Con A stimulation; there was a marked increase in the enzymic activity in the anti-phosphotyrosine immuno-precipitates from Con A-treated cells. The increase was abolished by wortmannin but not affected by pertussis toxin. The incorporation of 32P into PtdInsP3 also increased during incubation of [32P]P(i)-prelabelled cells with Con A, reflecting activation of whole-cell PtdIns 3-kinase which could not be accounted for solely by the increase in the phosphotyrosine-bound enzyme activity from the following aspects: (1) different concentration dependencies for Con A; and (2) almost total susceptibility of the incorporation to pertussis toxin. This notion appears to be supported by different time courses between increases in PtdInsP3 production and the phosphotyrosine-bound activity. The susceptibility to the toxin may reflect involvement of the toxin-sensitive G-proteins. In contrast, insulin-induced increases in PtdInsP3 production, as well as increases in phosphotyrosine-bound PtdIns 3-kinase activity, were blocked by wortmannin, but never affected by prior exposure of cells to pertussis toxin, excluding a possible involvement of G-proteins in the insulin-induced activation. Con-A-induced O2- production was almost inhibited by either pertussis toxin or wortmannin. These results suggest that oligomerization of cell-surface glycoproteins with Con A gives rise to activation of G-protein(s) and certain tyrosine kinase(s), both of which were responsible for PtdIns 3-kinase activation; the G-protein-mediated activation led to the respiratory burst.
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PMID:Activation of phosphatidylinositol 3-kinase by concanavalin A through dual signaling pathways, G-protein-coupled and phosphotyrosine-related, and an essential role of the G-protein-coupled signals for the lectin-induced respiratory burst in human monocytic THP-1 cells. 861 21

Experiments were performed to investigate the relative role of phospholipase A2 (PLA2) in the activation and cytokine-mediated priming of neutrophil superoxide production. PLA2 activity was measured with a radiometric assay which discriminates between PLA2 and the downstream enzyme, 5-lipoxygenase. In cells that had not been primed by prior incubation with granulocyte-macrophage colony stimulating factor (GM-CSF), PLA2 and NADPH oxidase were differentially stimulated by the chemotactic peptide N-formyl-met-leu-phe (FMLP), calcium ionophore, or phorbol ester. In addition, inhibition of PLA2 by mepacrine (0-100 micromol/l) did not concomitantly inhibit FMLP-stimulated superoxide production. These findings suggest that the activity of PLA2 and NADPH oxidase may be uncoupled in the unprimed cell. In cells preincubated with GM-CSF, time- and dose-dependent priming of FMLP-stimulated PLA2 responses were observed and inhibition of PLA2 by mepacrine was accompanied by the inhibition of FMLP-stimulated superoxide production down to the level of unprimed cells. The effect of mepacrine was not due to inhibition of FMLP receptor expression. These data suggest that a mepacrine-sensitive PLA2 may have a role in the GM-CSF mediated priming of superoxide production. Using ionophore-stimulated PLA2 activity as a model, we showed that Bordatella pertussis toxin did not inhibit GM-CSF mediated priming, demonstrating that a pertussis-sensitive GTP-binding protein does not mediate signal transduction from the GM-CSF receptor to PLA2. The tyrosin kinase inhibitor, genestein, selectively inhibited GM-CSF primed but not unprimed PLA2 activity, demonstrating that GM-CSF-mediated priming requires tyrosine kinase activity.
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PMID:The regulation of neutrophil phospholipase A2 by granulocyte-macrophage colony-stimulating factor and its role in priming superoxide production. 861 70

Hormones that interact with seven-transmembrane spanning receptors, generally considered to be involved in acute signaling functions, also induce longer term effects on gene expression and cell growth. These genetic and proliferative effects can be induced by activation of receptors that signal through heterotrimeric GTP-binding proteins (G-proteins) of the Gq family, pertussis toxin-sensitive Gi/Go proteins, Gs, or G12/G13. Numerous growth-promoting G protein-coupled receptors activate the low molecular weight G-protein Ras and stimulate mitogen-activated protein kinase. Recent data suggest that c-Jun NH2-terminal kinase is also activated, possibly through interaction with low molecular weight G-proteins of the Rho family. Because G protein-coupled receptors lack intrinsic tyrosine kinase activity, the mechanisms by which heterotrimeric G-proteins couple to these kinase cascades remain to be elucidated. By analogy to growth factor receptors, G protein-coupled receptors may access these kinase cascades through binding of adapter proteins or recruitment of cytosolic tyrosine kinases. It is likely that interactions between multiple signaling pathways are required for G protein-coupled receptors to propagate signals to the nucleus.
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PMID:G protein-coupled receptors and signaling pathways regulating growth responses. 863 91


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