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)

Neutrophils express several receptors for the Fc region of IgG molecules. Specific cross-linking of the type II receptor (Fc gamma RII) can be achieved by treating neutrophils with the Fab fragment of a specific monoclonal antibody IV.3 against the receptor followed by goat anti-mouse IgG F(ab')2 fragment. Such treatment initiates a number of neutrophil responses including the release of O2-. and increased protein tyrosine phosphorylation. The increase in tyrosine phosphorylation is rapid and transient and correlates with O2-. release. Both responses are inhibited by pretreatment of neutrophils with a protein tyrosine kinase inhibitor, genistein. The increase in protein tyrosine phosphorylation is not inhibited by pretreatment of neutrophils with pertussis toxin or an intracellular Ca2+ chelator, but is enhanced by a phosphoprotein phosphatase inhibitor, okadaic acid. The activity of a neutrophil Ca2+/calmodulin-dependent protein kinase II (CAMPKII) is also stimulated by cross-linking Fc gamma RII. The increase in CAMPKII activity is inhibited by pretreatment with either genistein or Ca2+ chelator. The results suggest that the increase in protein tyrosine phosphorylation induced by cross-linking of Fc gamma RII requires neither pertussis-toxin-sensitive G-proteins nor a rise in intracellular Ca2+ but can be regulated by protein phosphatases. Furthermore, protein tyrosine phosphorylation may be an early signal functionally linked to Fc gamma RII-mediated signal transduction leading to CAMPKII activation and O2-. release in human neutrophils.
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PMID:Tyrosine phosphorylation induced by cross-linking of Fc gamma-receptor type II in human neutrophils. 753 66

We have recently described an alpha 2-macroglobulin (alpha 2M) signalling receptor which is distinct from the low-density lipoprotein-related protein/alpha 2M receptor (LRP/alpha 2MR). Ligation of the macrophage signalling receptor by alpha 2M-methylamine stimulates production of several second messengers and involves a pertussis toxin-insensitive G-protein. We now report that binding of alpha 2M-methylamine, or the cloned M(r) = 20,000 receptor-binding fragment from rat alpha 1M, to macrophage alpha 2M signalling receptors induces protein phosphorylation. By use of a monoclonal antibody to phospholipase C gamma l (PLC gamma l) we were able to identify it as one target for protein phosphorylation. Phosphorylation was time and concentration dependent, being optimal at about 60 s of incubation and a 100-200 nM ligand concentration. By use of a second monoclonal antibody directed against phosphotyrosine, we were able to demonstrate that at least a portion of the label was incorporated into one or more tyrosine residues. PLC gamma l phosphorylation was then studied in membrane preparations at 4 degrees C in order to minimize serine or threonine modification. Preincubation of macrophage membranes with genistein, a tyrosine kinase inhibitor, drastically reduced phosphorylation of PLC gamma l. Receptor-associated protein, which blocks alpha 2M binding to LRP/alpha 2MR but not to the alpha 2M signalling receptor, had no effect on alpha 2M-methylamine-induced tyrosine phosphorylation of PLC gamma l. Binding of lactoferrin to LRP/alpha 2MR failed to induce phosphorylation of PLC gamma l, further supporting the hypothesis that the alpha 2M signalling receptor and LRP/alpha 2MR are distinct entities. Growth factors which induce tyrosine phosphorylation typically cause a rise in cytosolic pH. Binding of a2M-methylamine to macrophages also gradually increased the intracellular pH in a concentration-dependent manner, being optimal at a 200 nM ligand concentration. The increase in pH was amiloride sensitive. We propose that receptor-recognized forms of a2M may function like growth factors with regard to macrophage regulation.
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PMID:Ligation of the alpha 2-macroglobulin signalling receptor on macrophages induces protein phosphorylation and an increase in cytosolic pH. 754 45

Nonopsonized Bordetella pertussis bind to human monocytes by means of the virulence factors filamentous hemagglutinin (FHA), pertactin, and the minor fimbrial subunit FimD. Receptors on monocytes that mediate binding of B. pertussis to these cells include complement receptor type 3 (CR3), which binds to FHA of B. pertussis, and very late antigen-5 (VLA-5), which binds to an, as yet, unknown ligand on these bacteria. In the present study, the possibility that FimD acts as a ligand for VLA-5 was investigated. Soluble fibronectin, which is the natural ligand for VLA-5, or mAbs against VLA-5 inhibited binding to monocytes of B. pertussis strains that express FimD but not of mutant strains that lack FimD. Beads that were coated with the fusion protein maltose-binding protein-FimD bound to adherent monocytes, and this binding was inhibited by soluble fibronectin or mAb against the alpha- or beta-chain of VLA-5, while soluble collagen or mAb against VLA-4, VLA-6, CR3, or HLA class II had no effect. Down-modulation of VLA-5 on the apical surface of monocytes by plating the cells onto surfaces precoated with anti-VLA-5 mAb also inhibited binding of beads coated with maltose-binding protein-FimD to monocytes, while precoating of the surfaces with mAb against VLA-6 or CR3 had no effect. These results indicate that VLA-5 on monocytes serves as a receptor for FimD on B. pertussis. Binding of C3bi-coated erythrocytes to monocytes, which is a measure of the binding activity of CR3, was enhanced when monocytes were adhered onto plates precoated with purified fimbriae of B. pertussis, while precoating with fimbriae lacking FimD had no effect. Precoating of the plates with FimD-containing fimbriae also enhanced binding of B. pertussis, which express FHA, but not of strains that lack FHA, to monocytes. The enhanced binding of C3bi-coated erythrocytes and B. pertussis to monocytes could be markedly inhibited by tyrphostin-47, a protein tyrosine kinase inhibitor. These results demonstrate that interaction of FimD of B. pertussis with VLA-5 on monocytes activates CR3, which requires protein tyrosine kinases and results in enhanced binding of B. pertussis to the latter receptor via FHA.
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PMID:Binding of FimD on Bordetella pertussis to very late antigen-5 on monocytes activates complement receptor type 3 via protein tyrosine kinases. 756 Nov 5

The mechanism of mitogen-activated protein (MAP) kinase activation by pertussis toxin-sensitive Gi-coupled receptors is known to involve the beta gamma subunits of heterotrimeric G proteins (G beta gamma), p21ras activation, and an as-yet-unidentified tyrosine kinase. To investigate the mechanism of G beta gamma-stimulated p21ras activation, G beta gamma-mediated tyrosine phosphorylation was examined by overexpressing G beta gamma or alpha 2-C10 adrenergic receptors (ARs) that couple to Gi in COS-7 cells. Immunoprecipitation of phosphotyrosine-containing proteins revealed a 2- to 3-fold increase in the phosphorylation of two proteins of approximately 50 kDa (designated as p52) in G beta gamma-transfected cells or in alpha 2-C10 AR-transfected cells stimulated with the agonist UK-14304. The latter response was pertussis toxin sensitive. These proteins (p52) were also specifically immunoprecipitated with anti-Shc antibodies and comigrated with two Shc proteins, 46 and 52 kDa. The G beta gamma- or alpha 2-C10 AR-stimulated p52 (Shc) phosphorylation was inhibited by coexpression of the carboxyl terminus of beta-adrenergic receptor kinase (a G beta gamma-binding pleckstrin homology domain peptide) or by the tyrosine kinase inhibitors genistein and herbimycin A, but not by a dominant negative mutant of p21ras. Worthmannin, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K) inhibited phosphorylation of p52 (Shc), implying involvement of PI3K. These results suggest that G beta gamma-stimulated Shc phosphorylation represents an early step in the pathway leading to p21ras activation, similar to the mechanism utilized by growth factor tyrosine kinase receptors.
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PMID:G protein beta gamma subunits stimulate phosphorylation of Shc adapter protein. 756 18

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

Thrombin is known to evoke numerous inflammatory and proliferative responses in a wide variety of its target cells. Recent studies have demonstrated morphoregulatory and mitogenic effects of thrombin on astroglial cells (astrocytes). The present study deals with thrombin-induced activation of mitogen-activated protein (MAP) kinase in primary cultures of rat astrocytes. Treatment of serum-starved astrocytes with thrombin resulted in a rapid activation of tyrosine (Tyr) phosphorylation of a set of proteins including a prominent one with a molecular mass of 42 kDa (p42). The identity of p42 with MAP kinase was confirmed by MAP kinase-immunoreactivity of isolated [i.e., immunoprecipitated with anti-phosphotyrosine (PY) antibodies] p42 and by increased myelin basic protein (MBP) kinase activity present in MAP kinase immunoprecipitates of thrombin-treated cultures. Pertussis toxin (PTX) pretreatment failed to inhibit thrombin stimulation of p42 phosphorylation, indicating the lack of involvement of PTX sensitive G proteins in the mechanism of activation of MAP kinase by thrombin. Chronic exposure of cultures to phorbol 12-myristate 13-acetate to down-regulate PKC resulted in an attenuation of thrombin-induced p42 Tyr phosphorylation, although H-7, a known PKC inhibitor, failed to block thrombin effect. However, staurosporine, a nonspecific protein kinase inhibitor, prevented the activation of p42 phosphorylation. It is concluded that thrombin induces MAP kinase activation in astrocytes by a mechanism involving a staurosporine-sensitive pathway.
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PMID:Thrombin activates mitogen-activated protein kinase in primary astrocyte cultures. 759 20

Upon binding to their receptors on the surface of neutrophils, chemotactic peptides elicit a burst of metabolic activity. The excess acid generated by this burst must be rapidly extruded in order to maintain intracellular pH and preserve normal microbicidal responses. Recently, H(+)-pumping vacuolar-type ATPases (V-pumps) and a H(+)-selective conductance were described in the membrane of neutrophils. However, these systems are virtually quiescent in resting cells. In this report, we analyzed whether the V-pumps and the conductance become active and contribute to pH regulation following cell activation by chemoattractants. Formyl-Met-Leu-Phe (fMLP) was found to stimulate V-pumps, as assessed by the appearance of bafilomycin-sensitive H+ extrusion. Concomitantly, the chemoattractant also activated the H+ conductance, detected as a voltage-dependent and Zn(2+)-sensitive net H+ efflux. In both cases, activation was prevented by treatment with competing antagonistic peptides or with pertussis toxin, implying mediation by a receptor coupled to a heterotrimeric G protein. The signalling pathways downstream of the G proteins were also investigated. Stimulation of neither the V-pump nor the conductance required activation of protein kinase C. An elevation of cytosolic calcium ([Ca2+]i) comparable to that induced by fMLP did not suffice to trigger either transporter. Moreover activation of the conductance remained unaffected when the chemoattractant-induced increase in [Ca2+]i was precluded. In contrast, stimulation of the V-pump was substantially (approximately 50%) depressed when [Ca2+]i was prevented from rising. Tyrosine phosphorylation of several polypeptides accompanies stimulation by fMLP. Prevention of phosphotyrosine accumulation resulted in a pronounced inhibition of H(+)-pumping and of the H+ conductance. Together, these data indicate that engagement of surface receptors by chemotactic peptides can lead to stimulation of two voltage-sensitive pH regulatory pathways, a pump and a conductance, by a pathway that requires tyrosine phosphorylation. Both pathways are capable of sizable H+ extrusion, thereby contributing to pH regulation during the metabolic burst.
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PMID:Chemoattractant-induced activation of vacuolar H+ pumps and of an H(+)-selective conductance in neutrophils. 759 38

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

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

In pre-labelled A549 cells epidermal growth factor (EGF) (10 nM) stimulates the release of [5,6,8,9,11,12,14,15-3H(N)]-arachidonic acid (3H-AA) by approximately 70%. Increasing Ca2+i with thapsigargin (50 nM) stimulates 3H-AA release by approximately 120%. However, the combined use of these two agents results in a synergistic stimulation of 3H-AA release by over 700%. The EGF stimulated release is sensitive to pertussis toxin (10 ng/mL) and guanosine 5'-O-(2-thiodiphosphate) suggesting a G protein-mediated event. This is supported by the fact that the G protein activators AlF-4 and guanosine 5'-O-(2-thiotriphosphate) both stimulate 3H-AA release. The stimulation of 3H-AA release by both EGF or direct G protein activation is completely blocked following pre-treatment for 3 hr with 1 nM dexamethasone. This effect is reversed with a neutralizing antibody to lipocortin-1 (1 microgram/mL) suggesting that this protein mediates the inhibitory effects of glucocorticoids on agonist activated 3H-AA release. Thapsigargin stimulation of 3H-AA release is insensitive to dexamethasone treatment. A peptide fragment from the N-terminus of lipocortin-1-Lc13-25 (20-200 micrograms/mL) mimics the effect of glucocorticoid in suppressing both EGF and G protein activated 3H-AA release. A peptide with Me-Tyr substituting Tyr21 is much reduced in activity suggesting that the presence of this residue is essential. As peptide Lc13-25 is not derived from the Ca2+/phospholipid binding domain of the native protein then sequestration of phospholipid substrate for PLA2 remains an unlikely mechanism of action for this peptide.
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PMID:Lipocortin-1 and the control of arachidonic acid release in cell signalling. Glucocorticoids (changed from glucorticoids) inhibit G protein-dependent activation of cPLA2 activity. 764 51


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