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)

Exposure of plasma membranes isolated from high density resting murine B cells to recombinant IL-4 in the presence of gamma-[32P]-ATP promoted phosphorylation of a protein of Mr = 42,000. The 42 Kd protein kinase substrate could be detected in membranes prepared from low density B cells following a 24 h culture with lipopolysaccharide, but not in membranes prepared from B cells exposed to LPS for 48 h. Treatment of the cells with LPS resulted in the appearance of a number of new membrane-associated phosphoproteins. Treatment with the cytokine also resulted in the disappearance of a protein kinase substrate of Mr = 30,000 from phosphoprotein profiles of membranes prepared from cells exposed to LPS for 24 h. The 42 Kd structure appears to be a protein kinase substrate rather than possessing intrinsic phosphotransferase activity as judged from experiments employing 8-azido-gamma-[32P]-ATP as a photoaffinity label. No 42 Kd species was detectable using this reagent. Experiments employing identical protocols failed to reveal any enhanced or diminished phosphorylation of membrane-associated proteins in human peripheral blood B cells or in human B lymphoma cell lines.
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PMID:The effect of recombinant interleukin 4 upon protein kinase activities associated with murine and human B lymphocyte plasma membranes. 264 82

The gene for human granulocyte/macrophage colony-stimulating factor (GM-CSF) is expressed in a tissue-specific as well as an activation-dependent manner. The interaction of nuclear proteins with the promoter region of the GM-CSF gene that is likely to be responsible for this pattern of GM-CSF expression was investigated. We show that nuclear proteins interact with DNA fragments from the GM-CSF promoter in a cell-specific manner. A region spanning two cytokine-specific sequences, cytokine 1 (CK-1, 5' GAGATTCCAC 3') and cytokine 2 (CK-2, 5' TCAGGTA 3') bound two nuclear proteins [nuclear factor (NF)-GMa and NF-GMb] from GM-CSF-expressing cells in gel retardation assays. NF-GMb was inducible with phorbol 12-myristate 13-acetate and accompanied induction of GM-CSF message. NF-GMb was absent in cell lines not producing GM-CSF, some of which had other distinct binding proteins. NF-GMa and NF-GMb eluted from a heparin-Sepharose column at 0.3 and 0.6 M KCl, respectively. We hypothesize that the sequences CK-1 and CK-2 bind specific proteins and regulate GM-CSF transcription.
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PMID:Nuclear proteins interacting with the promoter region of the human granulocyte/macrophage colony-stimulating factor gene. 325 71

Interleukin 1 (IL1) or tumour necrosis factor (TNF) stimulated phosphorylation of a triad of 27 kDa phosphoproteins (pI 6.0, 5.7 and 5.5) in human dermal fibroblasts. The change was dependent on the dose of cytokine in the range 0.1-20 ng, was detectable between 3 and 5 min after stimulation and was maximal by 10 min. The proteins were found in the cytosol after subcellular fractionation. The 32P was removed from them by alkali, indicating the presence of phosphoserine and/or phosphothreonine. The results suggest that early changes in serine/threonine protein kinase activity may be involved in responses of fibroblasts to IL1 and TNF.
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PMID:Interleukin 1 and tumour necrosis factor increase phosphorylation of fibroblast proteins. 326 52

We assessed the role of cyclic nucleotides in modulating lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-alpha) generation in human peripheral blood monocytes. Exposure of monocytes to LPS (3 ng/ml) evoked a delayed, time-dependent generation of TNF-alpha that reached a maximum level 5-6 hr after LPS challenge and remained constant for up to 24 hr. This effect was concentration dependent and resulted in a 20-40-fold increase in the release of TNF-alpha that was sensitive to actinomycin D and cycloheximide. Treatment of monocytes with agents reputed to activate the cAMP/cAMP-dependent protein kinase (PKA) cascade in general inhibited LPS-induced TNF-alpha generation. Thus, the beta 2-adrenoceptor agonists albuterol and procaterol partially (approximately 40%) suppressed TNF-alpha generation in a propranolol-sensitive manner. Furthermore, 8-bromo-cAMP, cholera toxin, prostaglandin E2, and a number of drugs (i.e., rolipram (ZK 62711), denbufylline (BRL 30892), Ro 20-1724, benafentrine (AH 21-132), that inhibit the phosphodiesterase (PDE) 4 isoenzyme family abolished cytokine generation. In contrast, forskolin, inhibitors of PDE3 and PDE5, and activators of soluble and particulate guanylyl cyclase were essentially inactive. Interestingly, rolipram failed to potentiate the inhibitory effect of albuterol on LPS-induced TNF-alpha biosynthesis but, paradoxically, synergized with albuterol in the generation of cAMP and in the activation of PKA. When PGE2 was used to activate adenylyl cyclase, however, rolipram potentiated cAMP accumulation, PKA activation, and inhibition of TNF-alpha generation. In contrast, forskolin did not increase the cAMP content of monocytes in the absence or presence of rolipram. Collectively, these data suggest that LPS-induced TNF-alpha generation by human peripheral blood monocytes is due to increased transcription and subsequent translation of the TNF-alpha gene and that these effects are suppressed by a range of agents that activate the cAMP/PKA cascade. However, the failure of rolipram to potentiate the inhibitory effect of albuterol and procaterol on TNF-alpha generation suggests that beta 2-adrenoceptor agonists may affect gene expression and/or post-transcriptional regulatory processes by, at least in part, a cAMP-independent mechanism(s).
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PMID:Suppression of lipopolysaccharide-induced tumor necrosis factor-alpha generation from human peripheral blood monocytes by inhibitors of phosphodiesterase 4: interaction with stimulants of adenylyl cyclase. 747 3

Ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), oncostatin M (OSM), and interleukin-6 (IL6) compose a family of distantly related cytokines that initiate signaling by inducing either homodimerization of the "beta" signal transducing receptor component gp130 (in the case of IL6) or heterodimerization between gp130 and the gp130-related LIFR beta (in the case of CNTF, LIF, and OSM); dimerization of beta receptor components in turn activates members of the Jak/Tyk family of receptor-associated tyrosine kinases. Here we report that CNTF, LIF, OSM, and IL6 induce most of the same protein tyrosine phosphorylations, regardless of the cell type assayed or whether they initiate signaling by inducing homo- or heterodimerization of beta components. Although several of the protein tyrosine phosphorylations induced by the CNTF/LIF/OSM/IL6 family of factors may correspond to novel tyrosine kinase targets, we have been able to demonstrate the involvement of known signaling molecules, such as phospholipase C gamma, phosphoinositol 3-kinase, phosphotyrosine phosphatase (PTP1D), pp120, SHC, GRB2, STAT91, Raf-1, and the mitogen-activated protein kinases ERK1 and ERK2, revealing substantial convergence not only between the pathways activated by this cytokine family and other cytokines, but with pathways previously known to be activated only by factors that utilize receptor tyrosine kinases. Our data suggest the beta receptor components can form complexes with some of the signaling proteins identified and may play some role in their recruitment.
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PMID:Ciliary neurotrophic factor/leukemia inhibitory factor/interleukin 6/oncostatin M family of cytokines induces tyrosine phosphorylation of a common set of proteins overlapping those induced by other cytokines and growth factors. 751 71

Steel factor (SF) synergizes with a variety of hemopoietins to support the growth and differentiation of human progenitor cells. The human factor-dependent cell line MO7 has been used as a model to study the interaction of SF with other growth factors such as GM-CSF, because both factors support the proliferation of this cell line and are synergistic in combination. Previous studies have shown that this effect is not readily explained by the synergistic activation of early, cytosolic signal transduction intermediates such as tyrosine kinases, Raf-1, MAP2 kinase, or phospholipase C gamma. In an attempt to further explore the biological and biochemical mechanisms of the synergy between SF and GM-CSF, we examined the effects of these growth factors on the regulation of nuclear proto-oncogenes, cell cycle control genes, and G1-->S transition of MO7 cells. Individually, GM-CSF was a much more potent growth factor for MO7 cells than SF, particularly under serum-free conditions. Only GM-CSF, but not SF, was able to stimulate G1-->S transition of MO7 cells after factor deprivation for 24 h. Northern blot analyses showed also differential effects of GM-CSF and SF on the expression of some nuclear proto-oncogenes and G1 cyclins. GM-CSF (10 ng/ml), but not SF (20 ng/ml) increased the expression of c-myc and cyclin D2 mRNA, whereas both factors caused transient increases of c-fos and cyclin D3 mRNAs. When added simultaneously, GM-CSF and SF induced an at least additive increase of c-fos mRNA expression; this effect required the presence of fetal calf serum. No additive effects of GM-CSF and SF on c-myc, cyclin D2 or D3 mRNA expression were observed. C-jun and c-myb mRNAs were constitutively expressed in the MO7 cell line, but not further increased after stimulation with GM-CSF or SF for 15 min to 48 h. The inability of SF to induce growth promoting genes such as c-myc and cyclin D2 may explain why this cytokine does not support sustained proliferation of MO7 cells. These observations suggest that SF and GM-CSF exert different effects on the expression of genes involved in regulatory pathways of cell proliferation, but the molecular mechanism of synergy remains to be elucidated.
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PMID:Signal transduction of steel factor and granulocyte-macrophage colony-stimulating factor: differential regulation of transcription factor and G1 cyclin gene expression, and of proliferation in the human factor-dependent cell line MO7. 751 43

Peripheral blood T lymphocytes require two sequential mitogenic signals to reenter the cell cycle from their natural, quiescent state. One signal is provided by stimulation of the T-cell antigen receptor, and this induces the synthesis of both cyclins and cyclin-dependent kinases (CDKs) that are necessary for progression through G1. Antigen receptor stimulation alone, however, is insufficient to promote activation of G1 cyclin-Cdk2 complexes. This is because quiescent lymphocytes contain an inhibitor of Cdk2 that binds directly to this kinase and prevents its activation by cyclins. The second mitogenic signal, which can be provided by the cytokine interleukin 2, leads to inactivation of this inhibitor, thereby allowing Cdk2 activation and progression into S phase. Enrichment of the Cdk2 inhibitor from G1 lymphocytes by cyclin-CDK affinity chromatography indicates that it may be p27Kip1. These observations show how sequentially acting mitogenic signals can combine to promote activation of cell cycle proteins and thereby cause cell proliferation to start. CDK inhibitors have been shown previously to be induced by signals that negatively regulate cell proliferation. Our new observations show that similar proteins are down-regulated by positively acting signals, such as interleukin 2. This finding suggests that both positive and negative growth signals converge on common targets which are regulators of G1 cyclin-CDK complexes. Inactivation of G1 cyclin-CDK inhibitors by mitogenic growth factors may be one biochemical pathway underlying cell cycle commitment at the restriction point in G1.
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PMID:Inactivation of a Cdk2 inhibitor during interleukin 2-induced proliferation of human T lymphocytes. 751 74

The rat insulinoma beta-cell line RINm5F, which shares some homology with pancreatic islets, was used to study nitric oxide synthase induction. Nitric oxide is involved during beta-cell destruction and possibly in propagation of insulin-dependent diabetes mellitus. The cytokine interleukin-1 (IL-1) turned out to be the ultimate inducer, whereas tumour necrosis factor-alpha (TNF) and unexpectedly the phorbol ester TPA (12-O-tetradecanoylphorbol-13-acetate; 10 nM) synergistically promoted nitrite accumulation. Besides employing TPA directly, the synergistic effect of TNF could be traced back to protein kinase C activation since protein kinase C inhibitors (IC50 value for staurosporine: 4 nM) potently suppressed nitrite production in the case of IL-1/TNF administration. Further experiments using anti-TNF antibodies aimed to an autocrine loop following IL-1 addition to RINm5F cells, possibly involved in nitrite generation. Moreover, the nitric oxide synthase inductive IL-1 signal was antagonized by lipophilic cAMP analogues. Our results for nitrite accumulation in RINm5F cells point to activating protein kinase C and inhibitory protein kinase A signalling pathways.
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PMID:Modulation of inducible nitric oxide synthase in RINm5F cells. 751 91

Bacterial LPS stimulates human monocytes to secrete inflammatory cytokines, which are involved in several disease processes. However, the mechanism of LPS activation of cytokine expression and secretion is not completely understood. In this study, we investigated the signal transduction pathways involved in LPS-stimulated TNF-alpha and IL-1 beta secretion. TNF-alpha and IL-1 beta secretion were completely blocked by protein kinase C (PKC) and cyclic nucleotide-dependent protein kinase inhibitor, H-7, but were not affected by H-89, a specific cyclic nucleotide-dependent protein kinase inhibitor. In addition, LPS was found to induce activation of PKC, reaching maximal activity at 30 min and returning to unstimulated levels after 60 min. LPS stimulation only slightly increased intracellular levels of diacylglycerol, the natural activator of PKC, and pretreatment of monocytes with the diacylglycerol-kinase inhibitor, R59022, did not affect LPS-stimulated TNF-alpha secretion. LPS-induced PKC activation was found not to be affected by blocking of the LPS receptor, CD14, with mAb or by inhibition of protein tyrosine kinase with herbimycin A. However, these agents suppressed LPS-induced TNF-alpha secretion and TNF-alpha mRNA accumulation. The results suggest that TNF-alpha and IL-1 beta secretion after LPS stimulation of human monocytes requires the activation of protein tyrosine kinase and PKC, upstream to the activation of gene transcription. The activation of PKC by LPS is probably mediated by a diacylglycerol-independent pathway.
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PMID:Involvement of protein kinase C and protein tyrosine kinase in lipopolysaccharide-induced TNF-alpha and IL-1 beta production by human monocytes. 751 14

Regulation of the functional status of integrin receptors plays a critical role in inflammation and tissue remodeling, as it affects cell adherence and cytokine secretion. We have previously shown that in monocytes the binding of collagen to the alpha 2 beta 1 integrin induces the release of IL-1, an event that is potentiated by binding of fibronectin (Fn) to the alpha 5 beta 1 integrin. In this study, we have investigated the mechanisms leading to this phenomenon. Fn binding to alpha 5 beta 1 induced intracellular signals which increased the alpha 2 beta 1-dependent adhesiveness of monocytes to collagen without modifications of alpha 2 beta 1 expression. By using Abs against the intracellular region of the alpha 5 subunit of the alpha 5 beta 1 receptor, and specific inhibitors of protein kinase C (PKC), we found that the potentiation effect of Fn on monocyte IL-1 production and their adherence to collagen was dependent on an intact alpha 5 subunit cytoplasmic domain, and required PKC activation. Although the alpha 2 beta 1 could be activated by several intracellular second messengers, including protein kinase A and intracellular calcium, the potentiating effect of Fn was mediated only by PKC. These data provide an example of a novel regulatory mechanism: potentiation of beta 1 integrin-mediated events as a result of ligand binding to another integrin of the same class. They also show that the intracellular region of alpha 5 beta 1 plays a critical role in transducing signals generated by ligand binding to alpha 5 beta 1.
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PMID:Ligand binding to monocyte alpha 5 beta 1 integrin activates the alpha 2 beta 1 receptor via the alpha 5 subunit cytoplasmic domain and protein kinase C. 751 45


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