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)

Microglia, the resident macrophages of the brain, secrete a number of mediators involved in neural-immune function. The cytokines, IL-1 alpha and TNF alpha, are two such factors which are stored as inactive precursor molecules requiring post-translational proteolytic processing prior to release. From investigations of second messenger pathways involved in regulating the secretion of these cytokines, we have demonstrated that the PKC inhibitor, H-7, blocks the induction of TNF alpha secretion induced by LPS. In contrast, H-89 and HA-1077, inhibitors of cyclic nucleotide-dependent protein kinases (PKA and PKG), did not alter LPS-stimulation of TNF alpha release. Consistent with these observations, the weak PKC activator, mezerein, induced TNF alpha secretion in an H-7-reversible manner. In marked contrast, PKC activation did not induce IL-1 alpha secretion and H-7 potentiated IL-1 alpha release. In the case of the protein phosphatase inhibitor, okadaic acid, secretion of both cytokines was induced, indicating that protein phosphorylation is important for the induction of cytokine secretion but only in the case of TNF alpha is PKC involved. In the case of IL-1 alpha, a tonic inhibitory regulation involving PKC activation may be present. We therefore conclude that alterations in phosphorylation-dephosphorylation cycles may be important triggers in the switching of microglial cellular function from a resting to an activated state.
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PMID:Differential regulation of IL-1 alpha and TNF alpha release from immortalized murine microglia (BV-2). 806 28

TNF is a pluripotent cytokine that mediates activities through two distinct receptors of 55 to 60 kDa (CD120a, known as TNFR60) and 75 to 80 kDa (CD120b, known as TNFR80). These receptors share homology in the extracellular ligand binding region; however, the cytoplasmic domains are distinct and lack any inherent enzymatic activity, which suggests that ligand binding and subsequent receptor clustering leads to the association of active signaling molecules with TNFRs. To test this hypothesis, we isolated TNFRs by immunoprecipitation and examined the immune complexes for the presence of associated phosphoproteins and protein kinase activity. In the U-937 monocytic cell line, prelabeled with 32PO4, TNF induces the association of several phosphoproteins with TNFR60, but not TNFR80. The TNFR60 immune complexes also contain a TNF-dependent serine protein kinase activity, which was detected by an in vitro kinase assay, that phosphorylates proteins of 125, 97, 85, and 60 kDa, which are of apparent molecular masses that are similar to those of TNF-induced phosphoproteins that coprecipitate with TNFR60. Association of serine protein kinase activity with TNFR60 is rapid and dependent on the concentration of TNF. Proteins of molecular mass similar to the 125- and 97-kDa protein kinase substrates seem to be associated with TNFR60 immune complexes only after exposure of U-937 cells to TNF. The TNFR60-associated protein kinase activity is inhibited by staurosporine, but not by the protein kinase A and C inhibitors, HA-1004 and H7. Staurosporine greatly enhanced the sensitivity of U-937 cells to the cytotoxic effect of TNF. These results suggest a serine protein kinase(s), and, possibly, other TNF-dependent TNFR60-associated proteins may be involved in mediating signals through TNFR60 in response to ligand binding.
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PMID:TNF receptor signal transduction. Ligand-dependent stimulation of a serine protein kinase activity associated with (CD120a) TNFR60. 808 85

1. Kinins exert a contractile effect on rabbit aortic rings via the stimulation of B1 receptors. Des-Arg9-bradykinin (BK) is more potent than BK on this receptor type. The mode of action of des-Arg9-BK on rabbit aortic tissue has been studied by both the aortic ring contractility assay and a cellular model using cultured aortic smooth muscle cells (SMCs). 2. The des-Arg9-BK-induced contractions in rabbit aortic rings were unaffected by pretreatments with nifedipine, indomethacin, REV-5901 (a 5-lipoxygenase blocker) and LY-83583 (a guanylyl cyclase inhibitor); however, the protein kinase inhibitors H-7 and H-9 significantly reduced the maximal effect of des-Arg9-BK. 3. The contractile responses to des-Arg9-BK in calcium-free Krebs solution were slightly but not significantly attenuated in amplitude, as compared to paired control tissues bathed in Krebs solution, and sustained plateaus of contraction were observed in the absence of Ca2+. However, Ca2+ replenishment further increased the kinin-induced contraction measured in Ca(2+)-free bathing fluid. 4. Despite the lack of evidence of a mediating role for prostaglandin in the mechanical response to des-Arg9-BK, the kinin stimulated the release of prostacyclin from rabbit aorta rings measured as immunoreactive 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha). 5. Smooth muscle cells (SMCs) derived from the rabbit aorta exhibit functional responses to des-Arg9-BK in acute release of 6-keto-PGF1alpha and of inositol phosphate turnover which were inhibited by pretreatment with the B1 receptor antagonist, Lys[Leu8]des-Arg9-BK, but not by the B2 receptor antagonist, Hoe-140. Preincubation of the cells with interleukin- 1 (IL-1) 20 h before stimulation with the kinin had no effect on basal inositol phosphate turnover, but potentiated the acute effect of des-Arg9-BK.6. These results suggest that second mesengers derived from the action of phospholipase C are produced by SMCs when B1 receptors are activated in rabbit aortic tissue. Intracellular calcium stores are primarily mobilized by des-Arg9-BK, although receptor-controlled calcium influx has not been ruled out, and may contribute to initiate the contractile responses. The maintenance of the contractile state involves protein kinase C activity and is consistent with a current model of SMC function. The cell model retains some of the cardinal properties of B1 receptor-mediated vascular responses: endothelium independent PGI2 release and up-regulation by the cytokine IL-1. PGI2 is not involved in the mechanical response, possible because the rabbit aorta is refractory to this prostaglandin.
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PMID:Vascular mode of action of kinin B1 receptors and development of a cellular model for the investigation of these receptors. 810 48

Interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have previously been reported to induce rapid phosphorylation of the mitogen-activated protein (MAP) kinase. However, little is known about signaling events initiated by both hematopoietins that occur downstream of the MAP kinase. MAP kinase has been shown to phosphorylate the AP-1 transcription factor and also to activate two kinases designated insulin-stimulated protein kinase-1 and MAP kinase-activated protein (MAP-KAP) kinase 2. We show here that IL-3 and GM-CSF induce MAPKAP kinase 2 activity in the human megakaryoblastic leukemia cell line MO7 and phosphorylate the human small heat shock protein Hsp 27 on serine residues in vitro. GM-CSF also induced Hsp 27 phosphorylation in neutrophils in a range similar to that observed in MO7 cells, suggesting that MAPKAP kinase 2-mediated Hsp 27 activation occurs independently of proliferation. Hsp 27 phosphorylation was dose-dependent, occurred as early as 5 minutes after factor exposure, and was inhibited by the tyrosine kinase inhibitors genistein and herbimycin A. Furthermore, the protein phosphatase A2 abolished IL-3- and GM-CSF-induced serine phosphorylation of Hsp 27. Taken together, our findings indicate that tyrosine phosphorylation of MAP kinase is a prerequisite for serine phosphorylation of Hsp 27, which is mediated by MAPKAP kinase 2. Hsp 27 has shown activation-dependent translocation from the cytosolic to the nuclear region and has been linked to the cellular stress response. However, its precise function is largely unknown. Our data identify Hsp 27 as a target of the IL-3/GM-CSF stimulation pathway that involves MAP kinase and MAPKAP kinase 2. In addition, our results indicate that Hsp 27 may be target of phosphorylation events not only in the stress response but also in unstressed cells responding to cytokine stimulation.
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PMID:Interleukin-3 and granulocyte-macrophage colony-stimulating factor induce activation of the MAPKAP kinase 2 resulting in in vitro serine phosphorylation of the small heat shock protein (Hsp 27). 1101 49

In T lymphocytes, intracellular Ca2+ concentration ([Ca2+]i) rises within seconds of T-cell antigen-receptor stimulation and initiates the synthesis and secretion of interleukin 2, a cytokine essential for T-cell proliferation and the immune response. Using video-imaging techniques, we tracked [Ca2+]i signals in individual T cells and measured subsequent expression of a beta-galactosidase reporter gene (lacZ) controlled by the NF-AT element of the interleukin 2 enhancer. [Ca2+]i spikes elicited by monoclonal antibody binding to the CD3 epsilon subunit of the T-cell receptor were positively correlated with gene expression, but varied widely between individual cells and were therefore difficult to relate quantitatively to lacZ expression. The [Ca2+]i dependence of NF-AT-regulated gene expression was determined by elevating [Ca2+]i with either thapsigargin or ionomycin and then "clamping" [Ca2+]i to various, stable levels by altering either extracellular [Ca2+] or extracellular [K+]. Raising [Ca2+]i from resting levels of 70 nM to between 200 nM and 1.6 microM increased the fraction of cells expressing lacZ, with Kd approximately 1 microM. Activation of protein kinase C enhanced the [Ca2+]i sensitivity of gene expression (Kd = 210 nM), whereas stimulation of protein kinase A inhibited [Ca2+]i-dependent gene expression. The experiments described here provide single-cell measurements linking a second messenger to gene expression in individual cells.
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PMID:Intracellular calcium dependence of gene expression in single T lymphocytes. 814 3

Using the human monocytic cell line Mono Mac 6 we studied the involvement of Ca2+, protein kinase A (PKA), and protein kinase C (PKC) dependent pathways in the regulation of M-CSF and IL-6 gene expression. The results demonstrate that on activation with the calcium ionophore A23187 both M-CSF and IL-6 mRNA are induced after 3 and 6 h respectively. Co-stimulation with A23187 plus PMA resulted in an up-regulation of M-CSF mRNA and a down-regulation of IL-6 mRNA. Conversely co-stimulation with A23187 plus DBcAMP resulted in a down-regulation of M-CSF mRNA and an up-regulation of IL-6 mRNA. Nuclear run-on and mRNA half-life studies showed that the effects on the M-CSF expression were related to changes at transcriptional and post-transcriptional level. In contrast, the effects on the IL-6 gene expression seems to be mediated at post-transcriptional level. With regard to the secretion of the IL-6 protein it was shown that it closely follows the accumulation of IL-6 mRNA. Taken together, the data show that several intracellular signalling pathways control strictly the cytokine expression in monocytic cells which gives the cells the opportunity to respond variably to external activation signals.
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PMID:Differential regulation of M-CSF and IL-6 gene expression in monocytic cells. 819 14

In this study we analyzed the involvement of the cyclic AMP (cAMP)-protein kinase A system in the regulation of interleukin 6 production by cultured cortical astrocytes. Vasoactive intestinal peptide strongly increased, in a dose-dependent manner, interleukin 6 production. This effect was reduced when protein kinase A was blocked by KT-5720; it was not affected by calphostin C, a protein kinase C inhibitor. Forskolin caused a concentration-dependent increase in interleukin 6 release that was also inhibited by KT-5720. Because prostaglandins are believed to play a role in interleukin 6 production, we tried to determine whether the stimulatory effects of vasoactive intestinal peptide and forskolin on cytokine release might be mediated by stimulation of prostaglandin production in cortical astrocytes. Vasoactive intestinal peptide did not increase the production of either prostaglandin E2 or F2 alpha. Conversely, forskolin concentration-dependently stimulated the production of both prostaglandins, an effect that was blocked by indomethacin. Indomethacin did not affect either vasoactive intestinal peptide- or forskolin-stimulated interleukin 6 production. To exclude the possibility that prostaglandins participate in interleukin 6 production induced by forskolin, we tested prostaglandins E2 and F2 alpha. The former was completely ineffective in eliciting the cytokine production, whereas prostaglandin F2 alpha slightly increased interleukin 6 production only at the highest concentrations. 8-Bromo-cAMP and dibutyryl-cAMP stimulated interleukin 6 production to a lesser extent than vasoactive intestinal peptide and forskolin. In conclusion, we provide evidence that vasoactive intestinal peptide increases interleukin 6 production by astrocytes through the stimulation of the cAMP-protein kinase A pathway, an effect that is reproduced by cAMP analogues.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vasoactive intestinal peptide and forskolin stimulate interleukin 6 production by rat cortical astrocytes in culture via a cyclic AMP-dependent, prostaglandin-independent mechanism. 820 38

The high-affinity receptors for granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin 3 (IL-3) and IL-5 consist of two subunits, alpha and beta. The alpha subunits are specific to each cytokine and the same beta subunit (beta c) is shared by these three receptors. Although none of these receptor subunits has intrinsic kinase activity, these cytokines induce protein tyrosine phosphorylation, activation of Ras, Raf-1 and MAP kinase, and transcriptional activation of nuclear proto-oncogenes such as c-myc, c-fos and c-jun. In this paper, we describe a detailed analysis of the signaling potential of the beta c subunit by using a series of cytoplasmic deletion mutants. The human beta c consists of 881 amino acid residues. A C-terminal deletion mutant of beta c at amino acid 763 (beta 763) induced phosphorylation of Shc and activation of Ras, Raf-1, MAP kinase and p70 S6 kinase, whereas a deletion at amino acid 626 (beta 626) induced none of these effects. The beta 763 mutant, as well as the full-length beta c, induced transcription of c-myc, c-fos and c-jun. Deletions at amino acid 517 (beta 517) and 626 (beta 626) induced c-myc and pim-1, but no induction of c-fos and c-jun was observed. GM-CSF increased phosphatidylinositol 3 kinase (PI3-K) activity in anti-phosphotyrosine immunoprecipitates from cells expressing beta 763 as well as beta c, whereas it was only marginally increased from cells expressing beta 517 or beta 626. Thus, there are at least two distinct regions within the cytoplasmic domain of beta c that are responsible for different signals, i.e. a membrane proximal region of approximately 60 amino acid residues upstream of Glu517 is essential for induction of c-myc and pim-1, and a distal region of approximately 140 amino acid residues (between Leu626 and Ser763) is required for activation of Ras, Raf-1, MAP kinase and p70 S6 kinase, as well as induction of c-fos and c-jun.
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PMID:Signal transduction by the high-affinity GM-CSF receptor: two distinct cytoplasmic regions of the common beta subunit responsible for different signaling. 822 33

Upon entering a cell the natural product rapamycin, like the structurally related immunosuppressant FK506, associates with members of the FKBP family of proteins. One or more of the resulting FKBP-rapamycin complexes blocks signaling pathways emanating from some growth factor receptors. Recently, the addition of rapamycin was shown to inhibit the phosphorylation and activation of a 70-kDa ribosomal S6 protein kinase, which normally occurs minutes after the activation of certain cytokine and growth factor receptors. We now report that rapamycin can be added 4 to 6 h after the addition of serum growth factors to quiescent human osteosarcoma cells and still arrest these cells in G1. This window of action correlates with the inducible appearance of a cyclin-dependent kinase (cdk) activity, and the induction of this activity is inhibited by the addition of rapamycin. Furthermore, p36cyclin D1 associates with this cdk protein complex in lysates of untreated cells, but does not associate with this cdk protein complex in lysates of rapamycin-treated cells. Together, these studies demonstrate that FKBP-rapamycin can modulate a cyclin-dependent kinase activity and a cyclin D1-cdk association during early G1 in MG-63 human osteosarcoma cells.
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PMID:FKBP-rapamycin inhibits a cyclin-dependent kinase activity and a cyclin D1-Cdk association in early G1 of an osteosarcoma cell line. 822 93

Bacterial LPS induce production of cytokines such as IL-1, IL-6, and TNF in mononuclear phagocytes, and this represents a central component in the pathogenesis of septic shock syndrome. However, the mechanisms by which LPS activates these cells to express cytokines are not completely characterized. The present study addressed the role of different protein kinases in the LPS induction of cytokines. It is shown that LPS induced a 12- to 16-fold increase in IL-1 beta, IL-6, and TNF-alpha mRNA levels, and this was completely or more than 80% blocked by the protein tyrosine kinase specific inhibitors herbimycin A and genistein at the concentrations of 1.7 and 37 microM, respectively. Protein kinase C inhibition by staurosporine reduced LPS induction of TNF-alpha, whereas it had no effects on IL-6 and IL-1 beta. Inhibition of protein kinase A by H89 reduced IL-6 mRNA levels but did not detectably change IL-1 beta or TNF-alpha mRNA levels. In contrast, LPS did not increase leukemia inhibitory factor mRNA, which was constitutively expressed and not significantly reduced by these inhibitors. In addition to cytokine mRNA levels, LPS-induced IL-6 protein synthesis and IL-6 bioactivity were also reduced to baseline levels by the PTK inhibitors herbimycin A and genistein. Both PTK inhibitors also reduced the LPS activation of nuclear factor-kappa B (NF-kappa B), which is a transcription factor involved in the expression of cytokine genes such as IL-6 and TNF-alpha. The activation of NF-kappa B was also reduced by H89, whereas staurosporine had no effect on this response. In summary, these findings suggest that protein kinase C and protein kinase A appear to have selective effects in the LPS induction of cytokines, whereas PTK is required for LPS induction of a broad spectrum of cytokines and NF-kappa B activation in monocytes.
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PMID:Protein tyrosine kinase activation is required for lipopolysaccharide induction of cytokines in human blood monocytes. 825 85


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