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)

Further decoding of a novel adenylyl cyclase signaling mechanism (ACSM) of the action of insulin and related peptides detected earlier (Pertseva et al. Comp Biochem Physiol B Biochem Mol Biol 1995;112:689-95 and Pertseva et al. Biochem Pharmacol 1996;52:1867-74) was carried out with special attention given to the role of protein kinase C (PKC) in the ACSM. It was shown for the first time that transduction of the insulin signal via the ACSM followed by adenylyl cyclase (AC, EC 4.6.1.1) activation was blocked in the muscle tissues of rat and mollusc Anodonta cygnea in the presence of pertussis toxin, inducing the impairment of G(i)-protein function, wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3-K), and calphostin C, a blocker of PKC. The cholera toxin treatment of muscle membranes led to an increase in basal AC activity and a decrease in enzyme insulin reactivity. Phorbol ester and diacylglycerol activation of PKC (acute treatment) induced the inhibition of the insulin AC activating effect. This negative influence was also observed in the case of the AC system activated by biogenic amines. It was first concluded that the ACSM of insulin action involves the following signaling chain: receptor tyrosine kinase => G(i) (betagamma) => PI3-K => PKCzeta (?) => G(s) => AC => adenosine 3',5'-cyclic monophosphate. It was also concluded that the PKC system has a dual role in the ACSM: (1) a regulatory role (PKC sensitive to phorbol esters) that is manifested as a negative feedback modulation of insulin signal transduction via the ACSM; (2) a transductory role, which consists in direct participation of atypical PKC (PKCzeta) in the process of insulin signal transduction via the ACSM.
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PMID:A dual role of protein kinase C in insulin signal transduction via adenylyl cyclase signaling system in muscle tissues of vertebrates and invertebrates. 1132 32

The signaling pathway through which LHRH acts in endometrial and ovarian cancers is distinct from that in the anterior pituitary. The LHRH receptor interacts with the mitogenic signal transduction of growth factor receptors, resulting in down-regulation of expression of c-fos and proliferation. Only limited data are available on the cross-talk between LHRH receptor signaling and inhibition of mitogenic signal transduction. The present experiments were performed to analyze in endometrial and ovarian cancer cells: 1) whether mutations or splice variants of the LHRH receptor are responsible for differences in LHRH signaling, 2) the coupling of G protein subtypes to LHRH receptor, 3) the phosphotyrosine phosphatase (PTP) activation counteracting growth factor receptor tyrosine kinase activity. For these studies, the well characterized human Ishikawa and Hec-1A endometrial cancer cell lines and human EFO-21 and EFO-27 ovarian cancer cell lines were used, which express LHRH and its receptor. 1) Sequencing of the complementary DNA of the LHRH receptor from position 31 to position 1204, covering the complete coding region (position 56 to position 1042) showed that there are neither mutations nor splice variants of the LHRH receptor transcript in Ishikawa and Hec-1A endometrial cancer cells or in EFO-21 and EFO-27 ovarian cancer cells. 2) All analyzed cell lines except for the ovarian cancer cell line EFO-27 expressed both G proteins, alpha(i) and alpha(q), as shown by RT-PCR and Western blotting. In the EFO-27 cell line only G protein alpha(i), not G protein alpha(q), expression was found. Cross-linking experiments using disuccinimidyl suberate revealed that in the cell lines expressing G protein alpha(i) and G protein alpha(q), both G proteins coupled to the LHRH receptor. Inhibition of epidermal growth factor (EGF)-induced c-fos expression by LHRH, however, was mediated through pertussis toxin (PTX)-sensitive G protein alpha(i). Moreover, LHRH substantially antagonized the PTX-catalyzed ADP-ribosylation of G protein alpha(i). 3) Using a phosphotyrosine phosphatase assay based on molybdate-malachite green, treatment of quiescent EFO-21 and EFO-27 ovarian cancer cells and quiescent Ishikawa and Hec-1A endometrial cancer cells with 100 nM of the LHRH agonist triptorelin resulted in a 4-fold increase in PTP activity (P < 0.001). This effect was completely blocked by simultaneous treatment with PTX, supporting the concept of mediation through G protein alpha(i). As shown by quantitative Western blotting, EGF-induced tyrosine autophosphorylation of EGF receptors was reduced 45-63% after LHRH (100 nM) treatment (P < 0.001). This effect was completely blocked using the PTP inhibitor vanadate (P < 0.001). These results demonstrate that mutations or splice variants of the LHRH receptor in human endometrial and ovarian cancer cells are not responsible for the different signal transduction compared with that in pituitary gonadotrophs. We provide evidence that the tumor LHRH receptor couples to multiple G proteins, but the antiproliferative signal transduction is mediated through the PTX-sensitive G protein alpha(i). The tumor LHRH receptor activates a PTP counteracting EGF-induced tyrosine autophosphorylation of EGF receptor, resulting in down-regulation of mitogenic signal transduction and cell proliferation.
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PMID:Antiproliferative signaling of luteinizing hormone-releasing hormone in human endometrial and ovarian cancer cells through G protein alpha(I)-mediated activation of phosphotyrosine phosphatase. 1135 84

Here we provide evidence to show that the platelet-derived growth factor beta receptor is tethered to endogenous G-protein-coupled receptor(s) in human embryonic kidney 293 cells. The tethered receptor complex provides a platform on which receptor tyrosine kinase and G-protein-coupled receptor signals can be integrated to produce more efficient stimulation of the p42/p44 mitogen-activated protein kinase pathway. This was based on several lines of evidence. First, we have shown that pertussis toxin (which uncouples G-protein-coupled receptors from inhibitory G-proteins) reduced the platelet-derived growth factor stimulation of p42/p44 mitogen-activated protein kinase. Second, transfection of cells with inhibitory G-protein alpha subunit increased the activation of p42/p44 mitogen-activated protein kinase by platelet-derived growth factor. Third, platelet-derived growth factor stimulated the tyrosine phosphorylation of the inhibitory G-protein alpha subunit, which was blocked by the platelet-derived growth factor kinase inhibitor, tyrphostin AG 1296. We have also shown that the platelet-derived growth factor beta receptor forms a tethered complex with Myc-tagged endothelial differentiation gene 1 (a G-protein-coupled receptor whose agonist is sphingosine 1-phosphate) in cells co-transfected with these receptors. This facilitates platelet-derived growth factor-stimulated tyrosine phosphorylation of the inhibitory G-protein alpha subunit and increases p42/p44 mitogen-activated protein kinase activation. In addition, we found that G-protein-coupled receptor kinase 2 and beta-arrestin I can associate with the platelet-derived growth factor beta receptor. These proteins play an important role in regulating endocytosis of G-protein-coupled receptor signal complexes, which is required for activation of p42/p44 mitogen-activated protein kinase. Thus, platelet-derived growth factor beta receptor signaling may be initiated by G-protein-coupled receptor kinase 2/beta-arrestin I that has been recruited to the platelet-derived growth factor beta receptor by its tethering to a G-protein-coupled receptor(s). These results provide a model that may account for the co-mitogenic effect of certain G-protein-coupled receptor agonists with platelet-derived growth factor on DNA synthesis.
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PMID:Tethering of the platelet-derived growth factor beta receptor to G-protein-coupled receptors. A novel platform for integrative signaling by these receptor classes in mammalian cells. 1135 79

The ability of dopamine D(4) and D(2) receptors to activate extracellular signal-regulated kinases (ERKs) 1 and 2 was compared using Chinese hamster ovary (CHO-K1) cells transfected with D(4.2), D(4.4), D(4.7), and D(2L) receptors. Dopamine stimulation of D(4) or D(2L) receptors produced a transient, dose-dependent increase in ERK1/2 activity. Receptor-specific activation of the ERK mitogen-activated protein kinase (MAPK) pathway was confirmed using the D(2)-like receptor-selective agonist quinpirole, whereas the specific antagonist haloperidol blocked activation. MAPK stimulation was dependent on a pertussis-toxin-sensitive G protein (G(i/o)). trans-Activation of the platelet-derived growth factor (PDGF) receptor was an essential step in D(4) and D(2L) receptor-induced MAPK activation. PDGF receptor-selective tyrosine kinase inhibitors tyrphostin A9 and AG1295 abolished or significantly inhibited ERK1/2 activation by D(4) and D(2L) receptors. Dopamine stimulation of the D(4) receptor also produced a rapid increase in tyrosine phosphorylation of the PDGF receptor-beta. The Src-family tyrosine kinase inhibitor PP2 blocked MAPK activation by dopamine; however, this drug was also found to inhibit PDGF-BB-stimulated ERK activity and autophosphorylation of the PDGF receptor-beta. Downstream signaling pathways support the involvement of a receptor tyrosine kinase. The phosphoinositide 3-kinase inhibitors wortmannin and LY294002, protein kinase C inhibitors GF109203X and Calphostin C, dominant-negative RasN17, and the MEK inhibitor PD98059 significantly attenuated or abolished activation of MAPK by dopamine D(4) and D(2L) receptors. Our results indicate that D(4) and D(2L) receptors activate the ERK kinase cascade by first mobilizing signaling by the PDGF receptor, followed by the subsequent activation of ERK1/2 by pathways associated with this receptor tyrosine kinase.
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PMID:Dopamine D(4) and D(2L) Receptor Stimulation of the Mitogen-Activated Protein Kinase Pathway Is Dependent on trans-Activation of the Platelet-Derived Growth Factor Receptor. 1140 4

Mechanical stimuli are transduced into intracellular signals in lung alveolar epithelial cells (AEC). We studied whether mitogen-activated protein kinase (MAPK) pathways are activated during cyclic stretch of AEC. Cyclic stretch induced a rapid (within 5 min) increase in extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation in AEC. The inhibition of Na(+), L-type Ca(2+) and stretch-activated ion channels with amiloride, nifedipine, and gadolinium did not prevent the stretch-induced ERK1/2 activation. The inhibition of Grb2-SOS interaction with an SH3 binding sequence peptide, Ras with a farnesyl transferase inhibitor, and Raf-1 with forskolin did not affect the stretch-induced ERK1/2 phosphorylation. Moreover, cyclic stretch did not increase Ras activity, suggesting that stretch-induced ERK1/2 activation is independent of the classical receptor tyrosine kinase-MAPK pathway. Pertussis toxin and two specific epidermal growth factor receptor (EGFR) inhibitors (AG-1478 and PD-153035) prevented the stretch-induced ERK1/2 activation. Accordingly, in primary AEC, cyclic stretch activates ERK1/2 via G proteins and EGFR, in Na(+) and Ca(2+) influxes and Grb2-SOS-, Ras-, and Raf-1-independent pathways.
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PMID:Cyclic stretch activates ERK1/2 via G proteins and EGFR in alveolar epithelial cells. 1194 50

In this study we continued decoding the adenylate cyclase signaling mechanism that underlies the effect of insulin and related peptides. We show for the first time that insulin signal transduction via an adenylate cyclase signaling mechanism, which is attended by adenylate cyclase activation, is blocked in the muscle tissues of the rat and the mollusk Anodonta cygnea in the presence of: 1) pertussis toxin, which impairs the action of the inhibitory GTP-binding protein (Gi); 2) wortmannin, a specific blocker of phosphatidylinositol 3-kinase; and 3) calphostin C, an inhibitor of different isoforms of protein kinase C. The treatment of sarcolemmal membrane fraction with cholera toxin increases basal adenylate cyclase activity and decreases the sensitivity of the enzyme to insulin. We suggest that the stimulating effect of insulin on adenylate cyclase involves the following stages of hormonal signal transduction cascade: receptor tyrosine kinase --> Gi protein (betagamma) --> phosphatidylinositol 3-kinase --> protein kinase C (zeta?) --> Gs protein --> adenylate cyclase --> cAMP.
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PMID:Study of the functional organization of a novel adenylate cyclase signaling mechanism of insulin action. 1197 Jul 32

The coupling of the group I metabotropic glutamate receptors, mGlu1a and mGlu5a, to the extracellular signal-regulated protein kinase (ERK) pathway has been studied in Chinese hamster ovary cell-lines where receptor expression is under inducible control. Both mGlu receptors stimulated comparable, robust and agonist concentration-dependent ERK activations in the CHO cell-lines. The mGlu1a receptor-mediated ERK response was almost completely attenuated by pertussis toxin (PTx) pretreatment, whereas the mGlu5a-ERK response, and the phosphoinositide response to activation of either receptor, was PTx-insensitive. mGlu1a and mGlu5a receptor coupling to ERK occurred via mechanisms independent of phosphoinositide 3-kinase activity and intracellular and/or extracellular Ca2+ concentration. While acute treatment with a protein kinase C (PKC) inhibitor did not attenuate agonist-stimulated ERK activation, down-regulation of PKCs by phorbol ester treatment for 24 h did attenuate both mGlu1a and mGlu5a receptor-mediated responses. Further, inhibition of Src non-receptor tyrosine kinase activity by PP1 attenuated the ERK response generated by both receptor subtypes, but only mGlu1a receptor-ERK activation was attenuated by PDGF receptor tyrosine kinase inhibitor AG1296. These findings demonstrate that, although expressed in a common cell background, these closely related mGlu receptors utilize different G proteins to cause ERK activation and may recruit different tyrosine kinases to facilitate this response.
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PMID:Group-I metabotropic glutamate receptors, mGlu1a and mGlu5a, couple to extracellular signal-regulated kinase (ERK) activation via distinct, but overlapping, signalling pathways. 1243 85

The collagen-induced phosphorylation of discoidin domain receptor 1 (DDR1) in Wnt-5a-expressing HB2 mammary cells was effectively inhibited by pertussis toxin, but not by cholera toxin or antibodies blocking beta(1) integrins. Moreover, pertussis toxin reduced adhesion of the cells to collagen by approximately 50%, and antibodies against beta(1) integrins had a similar effect that was in fact additive to that of pertussis toxin. Cholera toxin had accordingly no such effect on adhesion. By comparison, pertussis toxin did not influence adhesion of Wnt-5a-antisense HB2 cells or MCF-7 mammary tumor cells, neither of which express Wnt-5a or exhibit activation of DDR1. In accordance with these results, direct mastoparan-induced activation of G-proteins in Wnt-5a-deficient MCF-7 cells enabled collagen-induced phosphorylation of DDR1 and enhanced their adhesion. The inactive analogue mastoparan-17 had no such effects on MCF-7 cells nor did active mastoparan affect adhesion of Wnt-5a-expressing HB2 cells. A possible explanation for how DDR1, a receptor tyrosine kinase (RTK), potentiates mammary cell adhesion comes from our observations that pertussis toxin also inhibited the recruitment of the cytoskeletal regulator phosphatidylinositol 3-kinase (PI3K) to DDR1 as well as its phosphorylation/activation. In accordance with that, the PI3K inhibitor wortmannin significantly impaired adhesion of normal Wnt-5a-expressing HB2 cells but had little effect on adhesion of Wnt-5a-antisense HB2 cells. Thus, a G(i/o)-protein signaling pathway mediates the effect of Wnt-5a expression by enabling collagen-induced activation of DDR1, which, in parallel with beta(1) integrins, regulates adhesion of mammary cells.
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PMID:Wnt-5a and G-protein signaling are required for collagen-induced DDR1 receptor activation and normal mammary cell adhesion. 1247 17

PLCepsilon (phospholipase Cepsilon) is a novel PLC that has a CDC25 guanine nucleotide exchange factor domain and two RA (Ras-association) domains of which the second (RA2) is critical for Ras activation of the enzyme. In the present studies, we examined hormonal stimulation to elucidate receptor-mediated pathways that functionally regulate PLCepsilon. We demonstrate that EGF (epidermal growth factor), a receptor tyrosine kinase agonist, and LPA (lysophosphatidic acid), S1P (sphingosine 1-phosphate) and thrombin, GPCR (G-protein-coupled receptor) agonists, stimulate PLCepsilon overexpressed in COS-7 cells. EGF stimulated PLCepsilon in an RA2-dependent manner through Ras and Rap. In contrast, LPA, S1P and thrombin stimulated PLCepsilon by both RA2-independent and -dependent mechanisms. To determine the G-proteins that mediate the effects of these GPCR agonists, we co-expressed constitutively active G-proteins with PLCepsilon and found that G(alpha12), G(alpha13), Rho, Rac and Ral stimulate PLCepsilon in an RA2-independent manner; whereas TC21, Rap1A, Rap2A and Rap2B stimulate PLCepsilon in an RA2-dependent manner similar to H-Ras. Of these G-proteins, we show that G(alpha12)/G(alpha13) and Rap partly mediate the effects of LPA, S1P and thrombin to stimulate PLCepsilon. In addition, the stimulation by LPA and S1P is also partly sensitive to pertussis toxin. These studies demonstrate diverse hormonal regulation of PLCepsilon by distinct and overlapping pathways.
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PMID:Hormonal regulation of phospholipase Cepsilon through distinct and overlapping pathways involving G12 and Ras family G-proteins. 1456 55

Activation of cell surface G protein-coupled receptors leads to transphosphorylation and activation of a number of receptor tyrosine kinases. Human mast cells express G protein-coupled receptors for the complement component C3a (C3aR) and high affinity nerve growth factor (NGF) receptor tyrosine kinase, TrkA. To determine whether C3a cross-regulates TrkA signaling and biological responses, we used a human mast cell-line, HMC-1, that natively expresses both receptors. We found that NGF caused tyrosine phosphorylation of TrkA, resulting in a sustained Ca(2+) mobilization, NFAT activation, extracellular-signal regulated kinase (ERK) phosphorylation, and chemokine, macrophage inflammatory protein-1beta (MIP-1beta) production. In contrast, C3a induced a transient Ca(2+) mobilization and ERK phosphorylation but failed to stimulate TrkA phosphorylation, NFAT activation, or MIP-1beta production. Surprisingly, C3a significantly enhanced NGF-induced NFAT activation, ERK phosphorylation, and MIP-1beta production. Pertussis toxin, a G(i/o) inhibitor, selectively blocked priming by C3a but had no effect on NGF-induced responses. Mitogen-activated protein/ERK kinase inhibitor U0126 caused approximately 30% inhibition of NGF-induced MIP-1beta production but had no effect on priming by C3a. However, cyclosporin A, an inhibitor of calcineurin-mediated NFAT activation, caused substantial inhibition of NGF-induced MIP-1beta production both in the absence and presence of C3a. These data demonstrate that NGF caused tyrosine phosphorylation of TrkA to induce chemokine production in HMC-1 cells via a pathway that mainly depends on sustained Ca(2+) mobilization and NFAT activation. Furthermore, C3a enhances NGF-induced transcription factor activation and chemokine production via a G protein-mediated pathway that does not involve TrkA phosphorylation.
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PMID:C3a enhances nerve growth factor-induced NFAT activation and chemokine production in a human mast cell line, HMC-1. 1515 16


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