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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Porphyromonas gingivalis 381 lipid A possesses 1-phospho beta(1-6)-linked glucosamine disaccharide with 3-hydroxy-15-methylhexadecanoyl and 3-hexadecanoyloxy-15-methylhexadecanoyl groups at the 2- and 2'-positions, respectively. P. gingivalis lipid A indicated lower activities in inducing interleukin-1 beta (IL-1 beta) mRNA expression, pro-IL-1 beta protein synthesis and IL-1 beta production than those of synthetic Escherichia coli lipid A (compound 506) in human peripheral blood mononuclear cells (PBMC). The induction of IL-6 mRNA and IL-6 synthesis by P. gingivalis lipid A were comparable to those of compound 506. Herbimycin A, H-7 and H-8, inhibitors of tyrosine kinase, protein kinase C and cyclic nucleotide-dependent protein kinase, inhibited P. gingivalis lipid A- and compound 506-induced IL-1 beta and IL-6 synthesis. W-7, an inhibitor of calmodulin (CaM) kinase, inhibited only P. gingivalis lipid A-induced IL-1 beta production. The result suggests that the CaM kinase-dependent cascade is involved in the down-regulation of IL-1 beta production by P. gingivalis lipid A. P. gingivalis lipid A and compound 506 also functioned in the induction of tyrosine and serine/threonine phosphorylation of several proteins in PBMC. P. gingivalis lipid A inhibited specific binding of fluorescein-labelled E. coli LPS to the PBMC. The nontoxic lipid A of P. gingivalis, having a chemical structure different from toxic compound 506, appears to induce the up- and down-regulation of the differential cytokine-producing activities following the activation of various intracellular enzymes including the CaM kinase through the common receptor sites of LPS.
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PMID:Differential induction of IL-1 beta and IL-6 production by the nontoxic lipid A from Porphyromonas gingivalis in comparison with synthetic Escherichia coli lipid A in human peripheral blood mononuclear cells. 880 70

A short synthetic peptide (Pa) containing a structural motif ("2-6-11" motif) present in a number of human extracellular matrix proteins was found to stimulate the production of cytokines IL-1alpha, IL-1beta, IL-6, and TNFalpha by human peripheral blood mononuclear cells. We have now investigated the signal transduction pathway involved in the elicitation of these immunomodulating properties on isolated human monocytes. Our results show that active peptide Pa provoked phosphoinositide hydrolysis, intracellular calcium elevation, and cAMP accumulation. Herbimycin A, an inhibitor of protein tyrosine kinases (PTK), markedly reduced these effects of peptide Pa. We have also found that this peptide stimulated CREB, NF-kappaB, and AP-1 DNA-binding activity. With the help of inhibitors of PTK (herbimycin A), phospholipase C (neomycin sulfate), protein kinase C (bis-indolyl maleimide), protein kinase A (H89), and the calmodulin antagonist W-7, as well as cholera toxin, an agent that increases intracellular cAMP, we showed that cytokine (IL-1alpha, IL-1-beta, IL-6, and TNFalpha) production could be modified by the signal transduction pathway triggered by peptide Pa on monocytes.
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PMID:Signaling pathway triggered by a short immunomodulating peptide on human monocytes. 902 64

This study analyses the production of tumour necrosis factor (TNF)alpha and soluble TNF receptor (sTNF-R) before and after exposure to gamma irradiation and interferon gamma (IFN gamma) in 12 cell lines derived from Ewing's sarcoma (ES)/peripheral primitive neuroectodermal tumours (pPNET). Supernatants from ES/pPNET cell cultures were tested in a TNF alpha-specific amplified enzyme-linked immunosorbent assay (ELISA), a bioassay, and sTNF-Rp55 and sTNF-Rp75 ELISA. The tumour cell lines released minimal amounts of TNF alpha, prominent amounts of sTNF-Rp55 (7/12 cell lines) and no sTNF-Rp75. Exposure to gamma irradiation (5 Gy) either induced (3/12) cell lines) or up-regulated (3/12 cell lines) TNF alpha release without changing sTNF-Rp55 and sTNF-Rp75 levels. Priming of cultures with recombinant human IFN gamma (rhIFN gamma) markedly enhanced TNF alpha secretion in the radiation-responsive cell lines and had no influence on sTNF-Rp55 and sTNF-Rp75 levels. rhIFN gamma affected the magnitude rather than the sensitivity of the radiation response. The TNF alpha secreted was bioactive, as shown by its cytotoxic effect of WEHI-164 cells, and neutralization of its activity by anti-TNF alpha monoclonal antibody. Herbimycin A (a tyrosine-specific protein kinase inhibitor) but not calphostin C (a protein kinase C inhibitor), H89 (a protein kinase A inhibitor), AA-COCF3 (a specific inhibitor of phospholipase A2) and MK-886 (a specific inhibitor of 5-lipoxygenase) abrogated gamma-irradiation-stimulated TNF alpha release. The antioxidants N-acetylcysteine, nordihydroguaiaretic acid and mepacrine dose-dependently inhibited gamma-irradiation-mediated TNF alpha production. Collectively our findings indicate that IFN gamma priming potentiates the secretion of bioactive TNF alpha by ES/pPNET cells in response to gamma irradiation without affecting sTNF-R release. The data suggest a requirement for protein tyrosine kinase activity and a role for reactive oxygen species in the gamma-irradiation-mediated intracellular signalling pathway leading to TNF alpha production.
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PMID:Regulation of the release of tumour necrosis factor (TNF)alpha and soluble TNF receptor by gamma irradiation and interferon gamma in Ewing's sarcoma/peripheral primitive neuroectodermal tumour cells. 920 Dec 46

The middle T antigen (MTAg) encoded by polyomavirus plays an important role in virus-mediated tumorigenesis. The activated protein kinase activity of MTAg-associated pp60c-src has been shown to be necessary for cell transformation by polyomavirus. In this study, the effects of herbimycin A on the pp60c-src kinase activities in the polyomavirus- and MTAg-transformed cells were studied. Phosphorylation of src and MTAg is reduced in polyomavirus and MTAg- transformed cells pretreated with herbimycin A. Inactivation of the enzymatic activity by herbimycin A was found to be dependent on the time of incubation and the drug concentration. In contrast, src immunoprecipitates from untreated MTAg-transformed cells appeared to be resistant to inhibition by herbimycin A. Herbimycin A does not affect the synthesis of MTAg and pp60c-src in the MTAg-transformed cells. These results suggest that pp60c-src kinase activity in the drug-treated cell lysates is more sensitive to herbimycin A inhibition than the same activity in the immunoprecipitates.
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PMID:Inhibition of pp60c-src protein kinase by herbimycin A in polyomavirus middle tumor antigen-transformed cells. 941 59

Prostaglandin H2 synthase (PGHS)-1 and PGHS-2 expression was examined in primary cultures of human amnion cells, an in vitro model of amnion tissue. Epidermal growth factor (EGF), the protein kinase C (PKC) activating phorbol ester TPA, and the protein phosphatase inhibitor, okadaic acid (OA), stimulated PGHS activity and the level of PGHS-2 mRNA, but did not affect the level of PGHS-1 mRNA. In situ hybridization suggested that the same population of cells responded to EGF, TPA and OA. Okadaic acid promoted PGHS activity independently of PKC. EGF stimulated the activity of extracellular signal-regulated protein kinase (Erk) and N-terminal c-Jun kinase (Jnk). OA increased Jnk activity but had no effect on Erk activity, while TPA had no influence on either Erk or Jnk activity. PD098059, a selective inhibitor of the Erk-activating kinase MEK, blocked the stimulation of PGHS expression by EGF, but did not decrease stimulation in response to OA. Herbimycin A, a tyrosine kinase inhibitor, suppressed the stimulation of PGHS activity and PGHS-2 mRNA abundance by all three stimulants, and blocked signalling via the Erk and Jnk mitogen-activated protein kinase pathways. Thus, growth factor stimulation, PKC activation and protein phosphatase inhibition induced the expression of PGHS-2 in primary amnion cells by distinct regulatory mechanisms involving tyrosine kinase(s). Tyrosine kinase inhibitors may constitute a new category of PGHS-2 inhibitors that act by blocking the expression of the enzyme.
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PMID:Regulation of prostaglandin H2 synthase-2 expression in primary human amnion cells by tyrosine kinase dependent mechanisms. 951 44

The effect of stress on the production of cytokine-induced neutrophil chemoattractant (CINC) was examined in rat C6 glioma cells. We studied the production of CINC, an interleukin-8 (IL-8) family protein, with bacterial endotoxin, H2O2, and tumor necrosis factor-alpha (TNF-alpha). Each stress induced CINC mRNA in a concentration-dependent manner. Since stress activates the protein kinases regulating nuclear transcription factors, we examined the effects of protein kinase inhibitors and the over-expression of dominant-negative Ras on CINC mRNA expression. Neither over-expression of dominant-negative Ras nor pretreatment with PD98059 (MEK-1 inhibitor), SB203580 (p38MAPK inhibitor), or GF109203X (protein kinase C (PKC) inhibitor) altered stress-induced CINC mRNA expression. This suggests that the Ras-MAPK, p38MAPK, and PKC pathways are not involved in CINC mRNA expression in glial cells. On the other hand, pretreatment with herbimycin A, a potent tyrosine kinase inhibitor, or Ro31-8220, a non-selective serine/threonine kinase inhibitor, suppressed stress-induced CINC mRNA expression. This indicates that stress-induced CINC mRNA expression is mediated by herbimycin A-, or Ro31-8220-sensitive kinases in glial cells. Since stress activates NF-kappaB and NF-IL6, we examined that the effect of herbimycin A, which suppresses CINC mRNA expression, on NF-kappaB and NF-IL6 activation. Herbimycin A suppressed NF-kappaB but not NF-IL6. These results suggest that in rat glial cells, the factors that induce CINC mRNA expression are mediated by herbimycin A-sensitive NF-kappaB activation, but not through the PKC, Ras-MAPK or p38 MAPK pathways.
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PMID:Induction of cytokine-induced neutrophil chemoattractant in response to various stresses in rat C6 glioma cells. 959 44

In macrophages, bacterial lipopolysaccharide (LPS) has been noted to mimic certain effects of the sphingolipid ceramide, suggesting that ceramide may be involved in macrophage activation by LPS and/or that LPS utilizes ceramide-related signaling pathways. Putative downstream targets of ceramide include a ceramide-activated (serine/threonine) protein kinase (CAPK) and phosphatase (CAPP). However, the potential role of tyrosine phosphorylation pathways in macrophage response to ceramide has not been examined. Herein we report that cell-permeable analogs of ceramide up-regulate both inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF) production in RAW 264.7 murine macrophages. Herbimycin A and genistein, potent natural inhibitors of protein tyrosine (but not serine/threonine) phosphorylation, block ceramide-induced iNOS and TNF production. Furthermore, the highly src-family selective pyrazolopyrimidine inhibitor PP1 also blocks ceramide-induced iNOS and TNF production in RAW 264.7 cells. We found that PP1 also inhibits ceramide-mediated tyrosine phosphorylation of the src-family kinase hck. These data indicate that src-related tyrosine kinases play a critical role in macrophage activation by ceramide.
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PMID:Ceramide-mediated stimulation of inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF) accumulation in murine macrophages requires tyrosine kinase activity. 1081 Oct 15

Glial fibrillary acidic protein (GFAP) is expressed upon cAMP-mediated induction of differentiation of glial progenitor cells into type II astrocytes. The protein is regulated by hormones, growth factors and cytokines but the signal transduction pathways involved in the regulation of GFAP expression are largely unknown. Specific protein kinase inhibitors were used to study their effect on the expression of GFAP in rat C6 glioma cells. Herbimycin A, a selective protein tyrosine kinase inhibitor, reduced GFAP mRNA and protein expression upon cAMP analog or beta-adrenergic receptor-mediated induction of differentiation. The latter inhibitor attenuated the elevation of cAMP by adenylate cyclase and abolished the activity of phosphatidylinositol 3-kinase (PI 3-K). These data indicate that GFAP expression is regulated by protein tyrosine phosphorylations, modulating the cAMP concentration and PI 3-K activity in C6 glioma cells.
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PMID:Protein tyrosine kinase-dependent regulation of adenylate cyclase and phosphatidylinositol 3-kinase activates the expression of glial fibrillary acidic protein upon induction of differentiation in rat c6 glioma. 1140 34

Emedastine difumarate (emedastine) is an antiallergic drug found among the derivatives which has a series of benzimidazole frames. It has been reported that emedastine can significantly inhibit the migration of eosinophils elicited by classical chemoattractants, including LTB4 or PAF. However, the effect of emedastine on the selective migration of eosinophils that have been stimulated with CC chemokines has not been examined. Emedastine at concentrations of 10 nM or higher strongly inhibited the eosinophil migration elicited by CC chemokines, including eotaxin, RANTES and MCP-3. Preincubation of the eosinophils with emedastine did not alter the expression of the CCR3 receptor, although a decrease in the concentration of intracellular calcium ions was observed after stimulation with 100 ng/ml of eotaxin. Herbimycin A, genistein, staurosporin and emedastine were all able to inhibit the eotaxin-elicited migration. Tyrosine kinase activity in the cytosol supernatant of eosinophils obtained after stimulation with eotaxin significantly decreased when the eosinophils were preincubated with emedastine. In addition, protein kinase A and protein kinase C activities in eotaxin-stimulated EoL-1 cell supernatants decreased significantly with emedastine pretreatment. These findings suggest that emedastine inhibits CC chemokine-elicited eosinophil migration by decreasing the activities of tyrosine kinase or protein kinases but does not alter CCR3 expression.
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PMID:Effect of emedastine difumarate on CC chemokine-elicited eosinophil migration. 1140 68

Proliferation of astrocytes is a common response of the CNS to injury and disease. The mechanisms controlling the proliferation of astrocytes are of great interest. In this paper, the signaling pathways underlying glutamate-induced astrocyte proliferation are investigated. Glutamate stimulates the proliferation of non-synchronized, subconfluent cultures of rat cortical astrocytes. Glutamate-induced cell proliferation is not prevented by inhibitors of G protein, protein kinase A, protein kinase C, phosphatidylinositol 3 kinase, extracellular signal-regulated kinase, or phospholipase A2. However, the tyrosine kinase inhibitors Genistein and Herbimycin A inhibit the glutamate-induced proliferation. Moreover, this proliferation is mediated by the activation of glutamate metabotropic receptors. These results suggest that glutamate induces astrocyte proliferation through a tyrosine kinase pathway.
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PMID:Tyrosine kinase signaling involved in glutamate-induced astrocyte proliferation. 1173 3


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