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: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A questionnaire was mailed out to member states of the European Union (EU) plus Switzerland, Norway, and Iceland, to inquire about the type of information routinely recorded in national pertussis surveillance systems. Information was requested on surveillance methods, type of information recorded for cases of pertussis, vaccination schedule, type of vaccine used, and methods for estimating vaccination coverage. Local surveillance methods, vaccination strategies, and methods to estimate vaccination coverage were found to differ widely across the participating countries. The results of the questionnaire survey show, however, that there are comparable subsets of variables common to many countries. Future activities of the EUVAC-NET project will include defining the homogeneous elements in national systems and to group appropriately those countries with common surveillance features.
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PMID:The EUVAC-NET survey: national pertussis surveillance systems in the European Union, Switzerland, Norway, and Iceland. 1167 37

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) promotes its function primarily by activating two receptor tyrosine kinases, Flt-1 (VEGFR-1) and KDR (VEGFR-2). Recently, it has been shown that KDR is responsible for VPF/VEGF-stimulated endothelial cell (EC) proliferation and migration, whereas Flt-1 activation down-modulates KDR-mediated EC proliferation. Although KDR-mediated EC proliferation and migration have been extensively studied, much less is known about Flt-1-mediated antiproliferation. Here, we demonstrate that Flt-1-mediated antiproliferative activity can be blocked completely by the dominant negative mutant of CDC42 (CDC42-17N) and partially by a Rac1 dominant negative mutant (Rac1-17N) but is not affected by a RhoA dominant negative mutant (RhoA-19N). Both CDC42-17N and Rac1-17N increase the intracellular Ca(2+) mobilization in response to VPF/VEGF but have no effect on KDR and MAPK phosphorylation. Using the chimeric-receptor EGLT in which the extracellular domain of epidermal growth factor receptor was fused to the transmembrane and intracellular domains of Flt-1, we also demonstrate that CDC42 and Rac1 are activated by EGLT. Previously, we showed that phosphatidylinositol 3-kinase is required for Flt-1-mediated antiproliferative activity, but phospholipase C is not required. As expected, CDC42 and Rac1 activation mediated by EGLT can be completely inhibited by PI3K inhibitors, wortmannin and LY294002, and the p85 dominant negative mutant but not by either the phospholipase C inhibitor, or an intracellular Ca(2+) chilator BAPTA/AM. Surprisingly, pertussis toxin and overexpression of the free Gbetagamma-specific sequestering minigene hbetaARK1(495) also inhibit EGLT-mediated CDC42 and Rac1 activation completely. Moreover, pertussis toxin treatment also increases the intracellular Ca(2+) mobilization and inhibits the antiproliferation activity, thus suggesting that pertussis toxin-sensitive G proteins and the Gbetagamma subunits are involved in the signaling pathway of Flt-1 that down-regulates EC proliferation. Taken together, these results further expand our understanding of Flt-1-mediated antiproliferative activity in VPF/VEGF-stimulated endothelium.
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PMID:Flt-1-mediated down-regulation of endothelial cell proliferation through pertussis toxin-sensitive G proteins, beta gamma subunits, small GTPase CDC42, and partly by Rac-1. 1172 72

Regulation of the PI3K-protein kinase B/Akt (serine/threonine kinase) cascade by PRL-releasing peptide (PrRP) and insulin in GH3 rat pituitary tumor cells was investigated. PrRP and insulin rapidly and transiently stimulated the activation of Akt, and the PI3K inhibitor wortmannin blocked the PrRP- or insulin-induced activation of Akt. Both pertussis toxin (10 ng/ml), which inactivates Gi/Go proteins, and expression of a peptide derived from the carboxyl terminus of the beta-adrenergic receptor kinase I, which specifically blocks signaling mediated by the betagamma subunits of G proteins, completely blocked the PrRP-induced Akt activation, suggesting that Gi/Go proteins are involved in PrRP-induced Akt activation, as they are in the activation of ERK by PrRP. Moreover, to determine whether a PI3K-Akt cascade regulates rat PRL (rPRL) promoter activity, we transfected the intact rPRL promoter ligated to the firefly luciferase reporter gene into GH3 cells. PrRP and insulin activated the rPRL promoter activity. Pretreatment with wortmannin or cotransfection with a dominant-negative Akt partially but significantly inhibited the induction of the rPRL promoter by PrRP or insulin. Cotransfection with a constitutively active Akt induced the rPRL promoter activity and cotransfection with a dominant-negative cAMP response element-binding protein (CREB) completely abolished the response of the rPRL promoter to the constitutively active Akt. Furthermore, either treatment with PrRP and insulin or transfection with the constitutively active Akt induced the phosphorylation of CREB. These results suggest that PrRP and insulin activate a PI3K-Akt cascade that is necessary to elicit rPRL promoter activity via a CREB-dependent mechanism.
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PMID:Regulation of the PRL promoter by Akt through cAMP response element binding protein. 1175 85

Previously, we have demonstrated age-associated alterations in transmembrane signaling. One of the most reproducible alterations found in the immune response with aging is the decrease of lymphocyte proliferation on stimulation with various different mitogens. Here, we confirm that proliferative responses to stimulation with phytohaemagglutin (PHA), recombinant human IL-2, or anti-CD3 monoclonal antibody are all greater in the young (20-25 years) than old (60-87 years) population. We attempted to modulate the proliferative response using various agents acting at different levels of transmembrane signaling (pertussis toxin, cholera toxin, isoproterenol, PMA, Ca ionophore A23187), as well as at the level of the lymphocyte plasma membrane (methyl-beta-cyclodextrin, MBCD), or by using antioxidant vitamins (Vitamin E or C). None of these agents was able to restore effectively the proliferative response of lymphocytes from the aged to the level of young subjects. Even the combination of A23187 and PMA acting directly on calcium metabolism and protein kinase C activity was insufficient to restore the decreased mitogenic capacity of T cells from elderly subjects. Cyclodextrin, which decreases the cholesterol content of the membrane, increased the proliferative response of lymphocytes of elderly subjects, but not to the level of the young. Vitamin E had a very strong inhibitory effect on lymphocyte stimulation in both the age groups, except in combination with MBCD in T cells of the elderly, while Vitamin C had no significant modulatory effect. MAPK ERK and p38 activation was found to be decreased with aging in T cells after anti-CD3 mAb stimulation. Vitamin E but not Vitamin C strongly inhibited MAPK ERK or p38 activation. The direct activation of certain molecules or the modulation of the cholesterol content of the membrane seems to be effective immunomodulatory interventions with aging.
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PMID:Modulation of human lymphocyte proliferative response with aging. 1177 24

Neuropeptide Y (NPY), 36-amino acid amidated peptide expressed in central and peripheral neurons, regulates a variety of physiological activities, including food intake, energy expenditure, vasoconstriction, anxiolysis, nociception and ethanol consumption. NPY binds to a family of G-protein coupled receptors whose activation results in inhibition of adenylyl cyclase activity. To more fully characterize the signal transduction pathways utilized by the NPY receptor subtypes, the pathways leading to phosphorylation of the extracellular signal regulated protein kinases 1 and 2 (ERK) have been compared in CHO cells expressing each of the four cloned human NPY receptor subtypes, Y(1), Y(2), Y(4) and Y(5). NPY Y(1), Y(2), Y(4) and Y(5) receptor-mediated ERK phosphorylation was blocked by pertussis toxin (PTX) exposure, indicating that all four receptors are coupled to inhibitory G(i/o) proteins. Exposure to the protein kinase C (PKC) inhibitor GF109203X diminished Y(1), Y(2) and Y(4) receptor-mediated ERK phosphorylation but completely blocked Y(5) receptor-mediated ERK phosphorylation. Additionally, Y(5) receptor-mediated ERK phosphorylation was inhibited by the phosphatidylinositol 3-kinase inhibitors LY294002 and wortmannin to a greater extent than was Y(1)-mediated ERK phosphorylation. These results demonstrate that in CHO cells, the Y(5) receptor and the Y(1), Y(2) and Y(4) receptors utilize different pathways to activate ERK.
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PMID:Activation of extracellular signal regulated protein kinase by neuropeptide Y and pancreatic polypeptide in CHO cells expressing the NPY Y(1), Y(2), Y(4) and Y(5) receptor subtypes. 1185 73

Cd(2+) exposure increases the risk of cancer in humans and animals. In this report, we have studied the effect of Cd(2+) on signal transduction and Ca(2+) mobilization in murine macrophages. At micromolar concentrations, Cd(2+) significantly increased cell division as judged by [3H]thymidine uptake and cell counts. Cd(2+)-treated cells continued to proliferate even after more than 4 weeks in culture. Cd(2+) (1 microM) treatment induced a 1.5- to 2-fold increase in cytosolic free Ca(2+), [Ca(2+)](i), which was transitory and/or oscillatory. The sources of this Ca(2+) included both inositol 1,4,5-trisphosphate (IP(3))-sensitive and -insensitive stores. Macrophage treatment with 1-(6-((17beta-3-methoxyestra-1,2,5(10)-triene-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (U73122), an inhibitor of phosphatidylinositol-specific phospholipase C (PLC), decreased Cd(2+)-induced formation of IP(3) in a concentration-dependent manner (K(d) about 2 microM). This caused a concomitant, partial decrease in the effect of Cd(2+) on [Ca(2+)](i). Cd(2+) itself crosses the macrophage membrane in part via L-type Ca(2+) channels, but it also interacts with a cell surface membrane protein(s) coupled to a pertussis toxin-sensitive G protein. Use of selective inhibitors of signal transduction and the quantitation of the levels of phosphorylated MAPK/ERK-activating kinase-1 (MEK1), extracellular signal-regulated kinase-1 (ERK1), and p38 mitogen-activated protein kinase (MAPK) suggests that the effects of Cd(2+) are mediated by the p21(ras)-dependent MAPK, but not the phosphoinositide 3 (PI 3)-kinase signalling pathway. The effect of activating these pathways includes increased availability of the transcription factor NFkappaB as well as activation of the early genes c-fos and c-myc.
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PMID:Cadmium-induced DNA synthesis and cell proliferation in macrophages: the role of intracellular calcium and signal transduction mechanisms. 1185 40

Amyloid beta-peptide (Abeta) is implicated as the toxic agent in Alzheimer's disease and is the major component of brain amyloid plaques. In vitro, Abeta causes cell death, but the molecular mechanisms are unclear. We analyzed the early signaling mechanisms involved in Abeta toxicity using the SH-SY5Y neuroblastoma cell line. Abeta caused cell death and induced a 2- to 3-fold activation of JNK. JNK activation and cell death were inhibited by overexpression of a dominant-negative SEK1 (SEK1-AL) construct. Butyrolactone I, a cdk5 inhibitor, had an additional protective effect against Abeta toxicity in these SEK1-AL-expressing cells suggesting that cdk5 and JNK activation independently contributed to this toxicity. Abeta also weakly activated ERK and Akt but had no effect on p38 kinase. Inhibitors of ERK and phosphoinositide 3-kinase (PI3K) pathways did not affect Abeta-induced cell death, suggesting that these pathways were not important in Abeta toxicity. Insulin-like growth factor I protected against Abeta toxicity by strongly activating ERK and Akt and blocking JNK activation in a PI3K-dependent manner. Pertussis toxin also blocked Abeta-induced cell death and JNK activation suggesting that G(i/o) proteins were upstream activators of JNK. The results suggest that activation of the JNK pathway and cdk5 may be initial signaling cascades in Abeta-induced cell death.
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PMID:Signaling events in amyloid beta-peptide-induced neuronal death and insulin-like growth factor I protection. 1188 52

The matricellular protein thrombospondin (TSP) stimulates stress fiber and focal adhesion disassembly through a sequence (hep I) in its heparin-binding domain. TSP/hep I signals focal adhesion disassembly by binding cell surface calreticulin (CRT) and activating phosphoinositide 3-kinase (PI3K). However, other components of this signaling pathway have not been identified. We now show that TSP induces focal adhesion disassembly through activation of pertussis toxin (PTX)-sensitive G proteins and ERK phosphorylation. PTX pretreatment inhibits TSP/hep I-mediated focal adhesion disassembly as well as PI3K activation. In addition, membrane-permeable Galpha(i2)- and Gbetagamma-blocking peptides inhibit hep I-mediated focal adhesion disassembly. Hep I stimulates a transient increase in ERK activation, which is abrogated by both PTX and PI3K inhibitors. Inhibiting ERK activation with MEK inhibitors blocks hep I-mediated focal adhesion disassembly, indicating that ERK activation is required for cytoskeletal reorganization. G protein signals and ERK phosphorylation are induced by TSP binding to cell surface CRT, because CRT null mouse embryonic fibroblasts (MEF) fail to stimulate ERK phosphorylation in response to TSP/hep I treatment. These data show that G(i) protein and ERK, in concert with PI3K, are stimulated by TSP.CRT interactions at the cell surface to induce de-adhesive changes in the cytoskeleton.
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PMID:Thrombospondin stimulates focal adhesion disassembly through Gi- and phosphoinositide 3-kinase-dependent ERK activation. 1192 91

Platelet activating factor (PAF) interacts with cell surface G protein-coupled receptors on leukocytes to induce degranulation, leukotriene C(4) (LTC(4)) generation, and chemokine CCL2 production. Using a basophilic leukemia RBL-2H3 cell line expressing wild-type PAF receptor (PAFR) and a phosphorylation-deficient mutant (mPAFR), we have previously demonstrated that receptor phosphorylation mediates desensitization of PAF-induced degranulation. Here, we sought to determine the role of receptor phosphorylation on PAF-induced LTC(4) generation and CCL2 production. We found that PAF caused a significantly enhanced LTC(4) generation in cells expressing mPAFR when compared with PAFR cells. In contrast, PAF-induced CCL2 production was greatly reduced in mPAFR cells. Pertussis toxin and U0126, which inhibit G(i) and p44/42 mitogen-activated protein kinase (ERK) activation, respectively, caused very little inhibition of PAF-induced CCL2 production (approximately 20% inhibition). In contrast, these inhibitors almost completely blocked both PAF-induced ERK phosphorylation and LTC(4) generation in PAFR cells. However, in mPAFR cells pertussis toxin only partially inhibited PAF-induced ERK phosphorylation. A Ca(2+)/calmodulin inhibitor had no effect on PAF-induced ERK phosphorylation in PAFR cells but completely blocked the response in mPAFR cells. These data demonstrate that receptor phosphorylation, which serves to desensitize PAF-induced LTC(4) generation, is required for chemokine CCL2 production. They also indicate a previously unrecognized selectivity in G protein usage and ERK activation for PAF-induced responses. Whereas PAF-induced CCL2 production is, in large part, mediated independently of G(i) activation or ERK phosphorylation, LTC(4) generation requires ERK phosphorylation, which is mediated by different G proteins depending on the phosphorylation status of the receptor.
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PMID:Distinct roles of receptor phosphorylation, G protein usage, and mitogen-activated protein kinase activation on platelet activating factor-induced leukotriene C(4) generation and chemokine production. 1193 80

The hypothalamic hormone gonadotropin-releasing hormone (GnRH) stimulates the synthesis and release of the pituitary gonadotropins. GnRH acts through a plasma membrane receptor that is a member of the G protein-coupled receptor (GPCR) family. These receptors interact with heterotrimeric G proteins to initiate downstream signaling. In this study, we have investigated which G proteins are involved in GnRH receptor-mediated signaling in L beta T2 pituitary gonadotrope cells. We have shown previously that GnRH activates ERK and induces the c-fos and LH beta genes in these cells. Signaling via the G(i) subfamily of G proteins was excluded, as neither ERK activation nor c-Fos and LH beta induction was impaired by treatment with pertussis toxin or a cell-permeable peptide that sequesters G beta gamma-subunits. GnRH signaling was partially mimicked by adenoviral expression of a constitutively active mutant of G alpha(q) (Q209L) and was blocked by a cell-permeable peptide that uncouples G alpha(q) from GPCRs. Furthermore, chronic activation of G alpha(q) signaling induced a state of GnRH resistance. A cell-permeable peptide that uncouples G alpha(s) from receptors was also able to inhibit ERK, c-Fos, and LH beta, indicating that both G(q/11) and G(s) proteins are involved in signaling. Consistent with this, GnRH caused GTP loading on G(s) and G(q/11) and increased intracellular cAMP. Artificial elevation of cAMP with forskolin activated ERK and caused a partial induction of c-Fos. Finally, treatment of G alpha(q) (Q209L)-infected cells with forskolin enhanced the induction of c-Fos showing that the two pathways are independent and additive. Taken together, these results indicate that the GnRH receptor activates both G(q) and G(s) signaling to regulate gene expression in L beta T2 cells.
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PMID:Involvement of both G(q/11) and G(s) proteins in gonadotropin-releasing hormone receptor-mediated signaling in L beta T2 cells. 1205 Jan 61


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