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: UMLS:C0043167 (pertussis)
19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cholecystokinin (CCK) is the major pancreatic secretagogue and acinar cell mitogen. This study was performed to determine by which effector systems CCK regulates tyrosine kinases, phosphatidylinositol (PtdIns) 3-kinase, and phospholipase D (PLD) activities. Pancreatic acini loaded with [3H]myristic acid or [3H]inositol were used to assay PLD and PtdIns 3-kinase. G protein activation with NaF increased particulate and crude cytosolic tyrosine kinase and PLD activities. PLD activation was pertussis toxin sensitive. Inhibition of phospholipase C (PLC) slightly reduced caerulein-stimulated particulate tyrosine kinase and blocked crude cytosolic tyrosine kinase activity without affecting caerulein-induced PLD activity. Ca2+ is an important factor in caerulein stimulation of tyrosine kinase and PLD activities. Protein kinase C and tyrosine kinase inhibition abolished caerulein-activated particulate and crude cytosolic tyrosine kinase and PtdIns 3-kinase activities without any effect on PLD. Wortmannin inhibited PLD and PtdIns 3-kinase activation. Caerulein-induced amylase secretion was partially reduced by tyrosine kinase inhibition, with no effect from wortmannin. Caerulein can stimulate a pertussis toxin-insensitive G protein, leading to particulate tyrosine kinase activation and a Ca(2+)-sensitive cytosolic tyrosine kinase through PLC activation. However, PLD activation by caerulein is pertussis toxin sensitive, cytosolic Ca2+ sensitive, and independent of previous PLC and tyrosine kinase activation.
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PMID:Novel model of integration of signaling pathways in rat pancreatic acinar cells. 757 45

Degranulation of eosinophils and release of toxic granule proteins play key roles in allergic diseases such as bronchial asthma. However, the intracellular signaling mechanisms that trigger eosinophil degranulation remain unclear. In this study, we investigated protein tyrosine kinase (PTK) involvement in the degranulation of human blood eosinophils induced by immobilized Ig. Eosinophils stimulated with Sepharose beads coated with secretory IgA (slgA) or IgG showed rapid increases in the tyrosine phosphorylation of intracellular proteins with molecular masses of 50 to 56, 73, 78, 100, and 105 kDa. The Ig-induced phosphorylation response was not affected by pertussis toxin, a known inhibitor of Ig-dependent eosinophil activation. The tyrosine kinase inhibitors genistein and herbimycin A inhibited both the tyrosine phosphorylation and degranulation responses of eosinophils induced by sIgA- or IgG-coated beads. In contrast, eosinophil degranulation induced by PMA was not affected by genistein. Treatment of eosinophils with the protein phosphatase inhibitor pervanadate induced the phosphorylation of a similar set of intracellular proteins as well as cellular degranulation. Pervanadate also stimulated an increase in phosphoinositide hydrolysis, which was consistent with the activation of a phospholipase C-gamma isoform by this stimulus. Genistein pretreatment blocked the Ig-induced phospholipase C activation, providing evidence for PTK involvement in this reaction. These findings indicate that a PTK-dependent signaling pathway plays an important role in triggering the degranulation responses of human eosinophils to immobilized sIgA and IgG.
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PMID:Tyrosine phosphorylation is required for eosinophil degranulation induced by immobilized immunoglobulins. 760 11

Hepatic metabolism and gene expression are among the factors controlled by the cellular hydration state, which changes within minutes in response to aniso-osmotic environments, cumulative substrate uptake, oxidative stress and under the influence of hormones such as insulin. The signalling events coupling cell-volume changes to altered cell function were studied in H4IIE rat hepatoma cells. Hypo-osmotic cell swelling resulted within 1 min in a tyrosine kinase-mediated activation of the extracellular signal-regulated protein kinases Erk-1 and Erk-2, which was independent of protein kinase C and cytosolic calcium. Activation of mitogen-activated protein kinases was followed by an increased phosphorylation of c-Jun, which may explain our recently reported finding of an about 5-fold increase in c-jun mRNA level in response to cell swelling. Pretreatment of cells with pertussis or cholera toxin abolished the swelling-induced activation of Erk-1 and Erk-2, suggesting the involvement of G-proteins. Thus, a signal-transduction pathway resembling growth factor signalling is activated already by osmotic water shifts across the plasma membrane, thereby providing a new perspective for adaption of cell function to alterations of the environment.
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PMID:Activation of extracellular signal-regulated kinases Erk-1 and Erk-2 by cell swelling in H4IIE hepatoma cells. 761 47

The receptors for insulin-like growth factor 1 (IGF1) and insulin are related heterotetrameric proteins which, like the epidermal growth factor (EGF) receptor, possess intrinsic ligand-stimulated tyrosine protein kinase activity. In Rat 1 fibroblasts, stimulation of mitogen-activated protein (MAP) kinase via the IGF1 receptor and the Gi-coupled receptor for lysophosphatidic acid (LPA), but not via the EGF receptor, is sensitive both to pertussis toxin treatment and to cellular expression of a specific G beta gamma subunit-binding peptide. The IGF1, LPA, and EGF receptor-mediated signals are all sensitive to inhibitors of tyrosine protein kinases, require p21ras activation, and are independent of protein kinase C. These data suggest that some tyrosine kinase growth factor receptors (e.g. IGF1 receptor) and classical G protein-coupled receptors (e.g. LPA receptor) employ a similar mechanism for mitogenic signaling that involves both tyrosine phosphorylation and G beta gamma subunits derived from pertussis toxin-sensitive G proteins.
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PMID:G beta gamma subunits mediate mitogen-activated protein kinase activation by the tyrosine kinase insulin-like growth factor 1 receptor. 762 49

The novel 38-amino acid neuropeptide PACAP (pituitary adenylate activating peptide) has recently been shown to induce the pancreatic acinar tumour AR4-2J cell growth. This growth promoting effect of PACAP was, however, independent of adenylate cyclase activation but suppressed by pertussis toxin and the somatostatin analog SMS 201-995. This study was undertaken to search for potential cell signalling pathways involved in the growth promoting effect of PACAP on AR4-2J cells. The AR4-2J cells were grown in Dulbecco's Modified Eagle's Medium containing 10% foetal calf serum. For studies on cell signalling pathways, all experiments were carried out on cells which have reached 50 to 75% confluency. At that point, they were transferred to serum free medium overnight with or without 1 microCi/ml myristic acid. The next morning, cells were harvested, washed and used for tyrosine kinase and phospholipase D (PLD) activities. For studies on growth, cells were grown for 2 days in the presence of 1 nM PACAP +/- the different inhibitors of tyrosine kinase and PLD. PACAP-38 and -27 caused a dose-dependent and parallel activation of tyrosine kinase and PLD an effect prevented by the antagonist PACAP 7-38. PACAP-38-stimulated tyrosine kinase and PLD activation are both dose-dependently inhibited by SMS 201-995. Finally, PACAP-stimulated tyrosine kinase and PLD activities are both inhibited by cell's preincubation with genistein and pertussis toxin. After 2 days, the PACAP-induced increase in AR4-2J cell growth was significantly inhibited by increasing concentrations of genistein and wortmannin, inhibitors of tyrosine kinase, PLD and phosphatidylinositol 3-kinase, respectively. PACAP can induce concomitant activation of tyrosine kinase and PLD; this finding and the observation that inhibition of these two enzymes inhibited PACAP-induced AR4-2J cell growth strongly suggests that they are intimately involved in the overall process of PACAP-induced AR4-2J cell proliferation.
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PMID:Cell signalling pathway involved in PACAP-induced AR4-2J cell proliferation. 766 8

Some agonists of G protein-coupled receptors, such as thrombin and lysophosphatidic acid (LPA), can promote cell proliferation via a pertussis toxin (PTX)-sensitive signaling pathway. While these agonists stimulate phospholipase C and inhibit adenylate cyclase, it appears that other, as-yet-unidentified, effector pathways are required for mitogenesis. Here we report that LPA and a thrombin receptor agonist peptide rapidly activate the protooncogene product p21ras in quiescent fibroblasts. This activation is inhibited by PTX and yet not attributable to known PTX-sensitive G protein pathways, including stimulation of phospholipases, inhibition of adenylate cyclase, or modulation of ion channels. LPA- and peptide-induced p21ras activation is inhibited by the tyrosine kinase inhibitor genistein, at doses that do not affect epidermal growth factor-induced p21ras activation. Thus, a heterotrimeric G protein of the Gi subfamily regulates activation of p21ras by LPA and thrombin, possibly through an intermediary tyrosine kinase. This pathway may critically participate in mitogenic signaling downstream from certain G protein-coupled receptors.
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PMID:Pertussis toxin-sensitive activation of p21ras by G protein-coupled receptor agonists in fibroblasts. 767 95

Stimulation of division of Balb/c3T3 cells by epidermal growth factor (EGF) and/or insulin is inhibited by pertussis toxin. The G-protein involvement in this response includes the growth factor receptor-induced translocation of the alpha-subunit of Gi (Gi alpha) to the nucleus, where Gi alpha binds specifically to chromatin of dividing cells. This paper reports the first data of studies on the mode of interaction of tyrosine kinase growth factor receptors with Gi alpha, and the mechanism by which Gi affects cell proliferation. When Gi alpha was immunoprecipitated from Triton X-100 extracts of Balb/c3T3 cells, several other proteins were co-precipitated. The major proteins, of 110,000, 60,000 and 36,000 M(r), were not directly recognized by the Gi alpha antibody, showing that Gi alpha was in a complex with these proteins. The 36,000 M(r) protein was recognized by G beta-common antiserum, so confirming its identity as Gi beta. The 36,000 M(r) protein was phosphorylated in cells activated for 20 h with platelet-derived growth factor, epidermal growth factor and insulin, but not after 3 min or 1 h of stimulation. Both Gi alpha and G beta-common antibodies precipitated the phosphorylated 36,000 protein. Gi beta phosphorylation was similarly observed in response to activation by EGF alone for 20 h, but to a lesser extent. Phosphotyrosine antibodies also precipitated a 36,000 M(r) phosphorylated protein from growth factor-activated cells, suggesting that Gi beta may be phosphorylated on tyrosine. Therefore, Gi beta phosphorylation appears to represent a late event after activation of cells by tyrosine kinase growth factor receptors. We are currently examining the role of this event in signal transduction, particularly in relation to control of nuclear responses.
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PMID:Gi alpha and Gi beta are part of a signalling complex in Balb/c3T3 cells: phosphorylation of Gi beta in growth-factor-activated fibroblasts. 768 Aug 79

A431 cells, a human epidermoid carcinoma, possess specific [3H]platelet-activating factor (PAF) and [3H]WEB 2086 binding sites indicating the presence of PAF receptors. PAF-stimulated PLC as determined by the increase in inositol phosphate levels. Pretreatment of A431 cells with genistein, a putative tyrosine kinase inhibitor, abolished the ability of PAF to activate PLC, whereas pretreatment with staurosporine, a protein kinase C inhibitor, potentiated the ability of PAF to activate PLC. Pretreatment of A431 cells with phorbol-12-myristate-13-acetate, a protein kinase C activator, blocked PAF-stimulated PLC. Overnight exposure of cells to pertussis toxin (PT) partially blocked the ability of PAF to stimulate PLC. Based on these observations the involvement of PT-sensitive and -insensitive guanine nucleotide-binding protein(s) (G-protein) as well as the role of tyrosine kinase in the activation of PLC by PAF was considered further. PT treatment of A431 cell membranes obliterated PAF-stimulated GTPase and indicated that PT-insensitive membrane-associated G-proteins were not involved in PAF actions. In alpha-toxin permeabilized cells, PT blocked GTP-gamma-S potentiation of PLC activation by PAF, thus suggesting that PT-insensitive G-proteins were not involved in PAF activation of PLC in A431 cells. PAF stimulated tyrosine kinase activity as observed with the increase in radioactivity associated with proteins immunoprecipitated with polyclonal antibodies to phosphotyrosine residues. This increase was blocked by PAF receptor antagonists, CV 6209 and TCV 309, and by pretreatment with genistein. PAF also activated the phosphorylation of pp60c-src and Src associated proteins in A431 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of guanine nucleotide-binding protein and tyrosine kinase in platelet-activating factor activation of phospholipase C in A431 cells: proposal for dual mechanisms. 768

Tyrosine phosphorylation is known to regulate the formation of focal adhesions in cells adhering to extracellular matrix (ECM). We have investigated the possible involvement of tyrosine phosphorylation and the focal adhesion kinase (FAK) in the cytoskeletal changes induced by serum or lysophosphatidic acid (LPA) in quiescent Swiss 3T3 fibroblasts. As shown previously by others, quiescent cells stimulated with serum or LPA reveal a rapid reappearance of focal adhesions and stress fibers. Here we show that this is accompanied by an increase in phosphotyrosine in focal adhesions and specifically an increase in the tyrosine phosphorylation of FAK. The LPA-stimulated reappearance of focal adhesions and stress fibers is blocked by inhibitors of phospholipase C but not by pertussis toxin (PTX), indicating that this LPA signaling pathway is mediated by phospholipase C activation and does not involve PTX-sensitive G proteins. In the absence of serum or LPA, these cytoskeletal effects and the tyrosine phosphorylation of FAK can be mimicked by sodium orthovanadate in conjunction with hydrogen peroxide, agents that inhibit protein tyrosine phosphatases and thereby elevate levels of phosphotyrosine. Two tyrosine kinase inhibitors, erbstatin and genistein block both the serum-induced tyrosine phosphorylation of FAK and the assembly of focal adhesions and stress fibers. Two other tyrosine kinase inhibitors, tyrphostins 47 and 25, previously shown to inhibit FAK, failed to prevent FAK phosphorylation or the reassembly of focal adhesions and stress fibers in response to serum. However, these inhibitors did prevent FAK phosphorylation and cytoskeletal assembly in response to lysophosphatidic acid (LPA), one component of serum previously shown to stimulate assembly of focal adhesions and stress fibers. Our findings suggest that the response to serum is complex and that although FAK phosphorylation is important, other tyrosine kinases may also be involved.
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PMID:Tyrosine phosphorylation is involved in reorganization of the actin cytoskeleton in response to serum or LPA stimulation. 770 13

We investigated the role of three different signal transduction systems adenylate-cyclase (AC), protein kinase C (PKC) and tyrosine kinase (TK) for growth and invasion of a human follicular (FTC133) and a human papillary thyroid cancer cell line (PTC-UC1). Cyclic AMP stimulators and inhibitors had no effect at any concentration. The PKC agonist TPA enhanced both growth and invasion of FTC133 by 15%, whereas staurosporine, a PKC antagonist, inhibited growth by 47% and invasion by 32%. The latter also reversed thyrotropin (TSH) stimulation, but not epidermal growth factor (EFG) stimulation. EGF-stimulated growth and invasion of both cell lines were abolished by EGF-receptor antagonism using a monoclonal antibody. The tyrosine kinase antagonist genistein reversed EGF, but not TSH, stimulation. Pertussis toxin inhibited growth (FTC133: 22%) and invasion (FTC133: 18%). Cholera toxin was less inhibitory. Obviously, signal transduction of differentiated thyroid cancer is complex and systems other than adenylate cyclase are crucial for basal invasion and growth of follicular thyroid cancer cells in culture.
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PMID:[Growth and invasion of differentiated thyroid gland carcinoma: importance of signal transduction]. 776 Jun 57


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