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

Thyroid hormone [L-thyroxine (T4)] rapidly induced phosphorylation and nuclear translocation (activation) of mitogen-activated protein kinase (MAPK) in HeLa and CV-1 cells in the absence of cytokine or growth factor. A pertussis toxin-sensitive and guanosine 5'-O-(3-thiotriphosphate)-sensitive cell surface mechanism responsive to T4 and agarose-T4, suggesting a G protein-coupled receptor, was implicated. Cells depleted of MAPK or treated with MAPK pathway inhibitors showed reduced activation of MAPK and of the signal transducer and activator of transcription STAT1alpha by T4; they also showed reduced T4 potentiation of the antiviral action of interferon-gamma (IFN-gamma). T4 treatment caused tyrosine-phosphorylated MAPK-STAT1alpha nuclear complex formation and enhanced Ser-727 phosphorylation of STAT1alpha, in the presence or absence of IFN-gamma. STAT1alpha-deficient cells transfected with STAT1alpha containing an alanine-for-serine substitution at residue 727 (STAT1alphaA727) showed minimal T4-stimulated STAT1alpha activation. IFN-gamma induced the antiviral state in cells containing wild-type STAT1alpha (STAT1alphawt) or STAT1alphaA727; T4 potentiated IFN-gamma action in STAT1alphawt cells but not in STAT1alphaA727 cells. T4-directed STAT1alpha Ser-727 phosphorylation is MAPK mediated and results in potentiated STAT1alpha activation and enhanced IFN-gamma activity.
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PMID:Thyroid hormone induces activation of mitogen-activated protein kinase in cultured cells. 1032 48

Diminished insulin action in the vasculature may contribute to the development of cardiovascular diseases in diabetes. We have studied insulin's effects on the phosphatidylinositol (PI) 3-kinase pathway in arterial smooth muscle cells (SMCs) and its inhibition by endothelin (ET)-1, a potent vasoactive hormone reported to be elevated in insulin resistance and other vascular diseases. ET-1 increased the level of serine phosphorylation of insulin receptor beta subunit but increased both tyrosine and serine phosphorylation of insulin receptor substrate (IRS)-2. Pretreatment of cells with ET-1 (10 nmol/l) inhibited insulin-stimulated PI 3-kinase activity associated with IRS-2 by 50-60% and inhibited the association of p85 subunit of PI 3-kinase to IRS-2. The inhibition of insulin-stimulated PI 3-kinase activity by ET-1 was prevented by BQ-123, a selective ET(A) receptor antagonist, but was not affected by pertussis toxin. Treatment of cells with phorbol 12-myristate 13-acetate, an activator of protein kinase C (PKC), reduced both insulin-stimulated PI 3-kinase activity by 57% and the association of IRS-2 to the p85 subunit of PI 3-kinase by 40%, whereas GF109203X, a specific inhibitor of PKC, partially prevented the inhibitory effect of ET-1 on insulin-induced PI 3-kinase activity. These results suggested that ET-1 could interfere with insulin signaling in SMCs by both PKC-dependent and -independent pathways.
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PMID:Endothelin-1 modulates insulin signaling through phosphatidylinositol 3-kinase pathway in vascular smooth muscle cells. 1033 19

The peptide hormone somatostatin exhibits antiproliferative activity by interacting with the G protein-coupled sst2 or sst5 receptor types. We show here that somatostatin at the human recombinant sst4 receptor induced a concentration-dependent increase in proliferation (EC50 20 nM) with a maximal response 5-fold greater than that produced by its synthetic analog, L-362,855. Analysis of the phosphorylation status of extracellular signal-regulated kinase (ERK)1 and ERK2 showed temporal differences in the changes evoked by the agonists. Phosphorylation induced by somatostatin (100 nM) peaked 10 min after the application and produced a response that continued for at least 4 h. In contrast, L-362,855 (1 microM) showed transient phosphorylation that had declined to basal levels by 1 h. However, both agonists induced rapid and sustained tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3) which was pertussis toxin-insensitive. Serine phosphorylation of STAT3 was only apparent after somatostatin treatment and was abolished by pertussis toxin or PD 98059, together with the associated increases in proliferation. Mitogen-activated protein/ERK kinase-1 inhibition also decreased the time interval over which somatostatin-induced ERK phosphorylation was observed (<2 h). We conclude that the difference in the magnitude of the proliferative response evoked by the two agonists at the sst4 receptor can be accounted for by their differential ability to phosphorylate STAT3 on serine residues and supports the concept that selective signaling can be achieved through pharmacological diversity.
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PMID:Activated G protein-coupled receptor induces tyrosine phosphorylation of STAT3 and agonist-selective serine phosphorylation via sustained stimulation of mitogen-activated protein kinase. Resultant effects on cell proliferation. 1034 3

The Ras-GRF exchange factor can activate Ras-dependent responses following the activation of heterotrimeric G-protein and calcium signalling. In stable lines of NIH-3T3 fibroblasts that express Ras-GRF, the agonist lysophosphatidic acid (LPA) increases the phosphorylation state and activity of Ras-GRF. The stimulation of Ras-GRF can be demonstrated in vitro, in an assay using recombinant Ras substrate, and in situ, by a selective increase in the ability of LPA to stimulate mitogen-activated protein (MAP) kinase. The increase in Ras-GRF phosphorylation state, which occurs on serine residues, and the increase in exchange factor activity are blocked by pretreatment with pertussis toxin. Activation of Ras-GRF by LPA can also be inhibited by chelation of intracellular calcium and treatment of the Ras-GRF with protein phosphatase 1 (PP1), supporting a model in which Ras-GRF serves to integrate signals from multiple transduction pathways.
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PMID:Activation of the Ras-GRF/CDC25Mm exchange factor by lysophosphatidic acid. 1043 21

Fibroblast growth factors (FGFs) stimulate proliferation, differentiation and motility of different cell types. The cellular effects of FGF are transduced by its interaction with any one of four members of a family of high affinity, cell surface FGF receptors (FGFRs) that have autophosphorylating tyrosine kinase activity. Activation of FGFR causes release of various low molecular weight signaling molecules which are required for the pleotropic effects of FGFs. We report here that basic FGF plays critical role in membrane phospholipid hydrolysis in NIH 3T3 cells that are stably transfected with FGFR1. Upon binding to FGFR1, basic FGF stimulates cytosolic form of phospholipase A2 (cPLA2), phospholipase C-gamma1 (PLC-gamma1) and phospholipase D (PLD), the key enzymes for the production of various lipid second messengers, in a tyrosine kinase-dependent manner. In addition to tyrosine phosphorylation, cPLA2 catalytic activation requires serine phosphorylation by p42 mitogen-activated protein (MAP) kinase and possibly pertussis toxin-sensitive G-protein coupling. On the other hand, phosphatidyl inositol 4,5 bisphosphate (PIP2) hydrolysis requires direct phosphorylation at tyrosine residue of the PLC-gamma1 isozyme. The activation of PLD needs direct or indirect receptor tyrosine kinase and protein kinase C (PKC) activities. Additionally, it also requires botulinum toxin C-sensitive Rho-like G-protein activation. All these results suggest that the pleotropic effects of FGF are exerted through its tyrosine kinase receptors and individual effectors are activated via distinguishable signaling mechanisms according to the cell's need.
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PMID:Basic fibroblast growth factor stimulates cytosolic phospholipase A2, phospholipase C-gamma1 and phospholipase D through distinguishable signaling mechanisms. 1049 74

Lysophosphatidic acid (LPA) is produced by a variety of activated cell types and acts as an intercellular mediator of processes associated with inflammation and repair including platelets aggregation, and smooth muscle and fibroblast proliferation. However no previous studies have examined the effects of LPA on endothelial cell leukocyte interactions. We have examined the ability of LPA to activate human aortic endothelial cells (HAEC) to bind monocytes, neutrophils, and HL60 cells (a neutrophil surrogate). Treatment of HAEC for 4 hours with 10 microM LPA caused an increase in the binding of monocytes, neutrophils, and HL60. LPA but not phosphatidic acid dose-dependently increased E-selectin and vascular cell adhesion molecule-1 (VCAM-1) cell surface expression. We performed several studies to characterize the receptor mediating the LPA effect. We demonstrate that at least five potential LPA receptors are expressed by HAEC: Edg-1, -3, -4, and -5 as well as PSP24. Cyclic phosphate-containing phosphatidic acid analogue, an agonist for the type 3 low affinity LPA receptor, was not effective in activating HAEC to bind leukocytes, excluding a role for this receptor. The selective receptor antagonists N-palmitoyl-serine and N-palmitoyl-tyrosine (which inhibits PSP24) completely inhibited LPA-induced VCAM expression; however these antagonists inhibited E-selectin expression by only 30%, suggesting a role for at least one additional LPA receptor mediating E-selectin expression. We propose that Edg-1 might be the second receptor, because this receptor, when expressed in HEK293 cells, similarly to the PSP24 receptor, caused ERK activation to nanomolar concentration of LPA. Exposure of HAEC to sphingosine-1-phosphate, another Edg-1 receptor agonist, increased surface expression of E-selectin and to a much smaller extent VCAM-1. The effects of both LPA and sphingosine-1-phosphate on the induction of both VCAM-1 and E-selectin expression was abolished by pretreatment with pertussis toxin suggesting that both LPA receptors in HAEC couple to a Gi pathway. These findings reveal an important and novel role for LPA and its receptors in inflammatory processes.
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PMID:Lysophosphatidic acid as a regulator of endothelial/leukocyte interaction. 1053 86

Pertussis toxin is a member of the AB(5) family of toxins and is composed of five subunits (S1 to S5) present in a 1:1:1:2:1 ratio. Secretion is a complex process. Each subunit has a secretion signal that mediates transport to the periplasm, where processing and assembly occur. Secretion of the assembled 105-kDa toxin past the outer membrane is mediated by the nine proteins encoded in the ptl operon. Previous studies have shown that S1, the catalytically active A subunit of pertussis toxin, is necessary for efficient secretion, suggesting that a domain on S1 may be required for interaction with the secretion apparatus. Previously, recombinant S1 from four different mutants (serine 54 to glycine, serine 55 to glycine, serine 56 to glycine, and arginine 57 to lysine) was shown to retain catalytic activity. We introduced these mutations into Bordetella pertussis and monitored pertussis toxin production and secretion. No pertussis toxin was detected in the serine 54-to-glycine mutant. The other S1 mutants produced periplasmic pertussis toxin, but little pertussis toxin secretion was observed. The arginine 57-to-lysine mutant had the most dramatic secretion defect. It produced wild-type levels of periplasmic pertussis toxin but secreted only 8% as much toxin as the wild-type strain. This phenotype was similar to that observed for strains with mutations in the ptl genes, suggesting that this region may have a role in pertussis toxin secretion.
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PMID:Mutations in the S1 subunit of pertussis toxin that affect secretion. 1067 38

Cannabinoids exert most of their effects in the central nervous system through the CB(1) cannabinoid receptor. This G-protein-coupled receptor has been shown to be functionally coupled to inhibition of adenylate cyclase, modulation of ion channels and activation of extracellular-signal-regulated kinase. Using Chinese hamster ovary cells stably transfected with the CB(1) receptor cDNA we show here that Delta(9)-tetrahydrocannabinol (THC), the major active component of marijuana, induces the activation of protein kinase B/Akt (PKB). This effect of THC was also exerted by the endogenous cannabinoid anandamide and the synthetic cannabinoids CP-55940 and HU-210, and was prevented by the selective CB(1) antagonist SR141716. Pertussis toxin and wortmannin blocked the CB(1) receptor-evoked activation of PKB, pointing to the sequential involvement of a G(i)/G(o) protein and phosphoinositide 3'-kinase. The functionality of the cannabinoid-induced stimulation of PKB was proved by the increased phosphorylation of glycogen synthase kinase-3 serine 21 observed in cannabinoid-treated cells and its prevention by SR141716 and wortmannin. Cannabinoids activated PKB in the human astrocytoma cell line U373 MG, which expresses the CB(1) receptor, but not in the human promyelocytic cell line HL-60, which expresses the CB(2) receptor. Data indicate that activation of PKB may be responsible for some of the effects of cannabinoids in cells expressing the CB(1) receptor.
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PMID:The CB1 cannabinoid receptor is coupled to the activation of protein kinase B/Akt. 1074 65

The present study demonstrates negative intracellular cross-talk between angiotensin II type 2 (AT2) and insulin receptors. AT2 receptor stimulation leads to inhibition of insulin-induced extracellular signal-regulated protein kinase (ERK2) activity and cell proliferation in transfected Chinese hamster ovary (CHO-hAT2) cells. We show that AT2 receptor interferes at the initial step of insulin signaling cascade, by impairing tyrosine phosphorylation of the insulin receptor (IR) beta-chain. AT2-mediated inhibition of IR phosphorylation is insensitive to pertussis toxin and is also detected in neuroblastoma N1E-115 and pancreatic acinar AR42J cells that express endogenous receptors. We present evidence that AT2 receptor inhibits the autophosphorylating tyrosine kinase activity of IR, with no significant effect on insulin binding properties. AT2-mediated inactivation of IR does not mainly involve tyrosine dephosphorylation by vanadate-sensitive tyrosine phosphatases nor serine/threonine phosphorylation by protein kinase C. As a consequence of IR inactivation, AT2 receptor inhibits tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and signal-regulatory protein (SIRPalpha1) and prevents subsequent association of both IRS-1 and SIRPalpha1 with Src homology 2 (SH2)-containing tyrosine phosphatase SHP-2. Our results thus demonstrate functional trans-inactivation of IR kinase by G protein-coupled AT2 receptor, illustrating a novel mode of negative communication between two families of membrane receptors.
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PMID:Functional trans-inactivation of insulin receptor kinase by growth-inhibitory angiotensin II AT2 receptor. 1084 82

Neutrophils dominate acute inflammatory responses that generally evolve into chronic inflammatory reactions mediated by monocyte/macrophages and lymphocytes. The latter cell types also serve as major targets for human immunodeficiency virus type 1 (HIV-1). In this study we have investigated the role of neutrophil products, particularly cathepsin G, in HIV infection. Cathepsin G induced chemotaxis and production of proinflammatory cytokines by macrophages but not CD4(+) T cells. Pretreatment with cathepsin G markedly increased susceptibility of macrophages but not CD4(+) T cells to acute HIV-1 infection. When macrophages were exposed to pertussis toxin prior to cathepsin G treatment, the cathepsin G-mediated effect was almost abrogated, suggesting that enhancement of HIV-1 replication by cathepsin G requires Gi protein-mediated signal transduction. Although prolonged exposure to cathepsin G suppressed HIV infection of macrophages, serine protease inhibitors, which are exuded from the bloodstream later during inflammatory processes, neutralized the inhibitory effect. Neutrophil extracts or supernatants from neutrophil cultures, which contain cathepsin G, had effects similar to purified cathepsin G. Thus, cathepsin G, and possibly other neutrophil-derived serine proteases, may have multiple activities in HIV-1 infection of macrophages, including chemoattraction of monocyte/macrophages (HIV-1 targets) to inflamed tissue, activation of target cells, and increase in their susceptibility to acute HIV-1 infection.
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PMID:Cathepsin G, a neutrophil-derived serine protease, increases susceptibility of macrophages to acute human immunodeficiency virus type 1 infection. 1088 24


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