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)

Heat-shock protein 27 (HSP27) is a major target of phosphorylation upon cell stimulation with a variety of agents and has been suggested to have a phosphorylation-regulated function at the level of actin filaments. Here we investigated comparatively the mechanisms of HSP27 phosphorylation by oxidative stresses, exposures to tumor necrosis factor (TNF), heat shock and growth factors. Extracts of Chinese hamster or human cells exposed to H2O2, xanthine/xanthine oxidase, menadione or TNF contained up to 15-fold more HSP27 kinase activity than comparable extracts obtained from control cells. Induction of HSP27 kinase activity by TNF or H2O2 was completely inhibited by first treating the cells with the antioxidant N-acetyl-L-cysteine, suggesting that generation of reactive oxygen metabolites was the key triggering element of this induction. In contrast, prior treatment with acetylcysteine had no or little effect on the induction by thrombin, serum and heat shock. The kinase activity in extracts of cells stimulated by heat shock, H2O2, sodium arsenite, TNF or growth factors was identified by in-gel renaturation and purified approximately 8000-fold by sequential chromatography. In all cases, the induced kinase activity was entirely associated with two polypeptides of 45 kDa and 54 kDa, identified as mitogen-activated-protein kinase-activated protein (MAPKAP) kinase-2 based on its reactivation in vitro by 42/44-kDa MAP kinases, its antigenic properties and its substrate specificity. The 45/54-kDa HSP27 kinase may play an important role in the cell response to oxidative stress. Overexpression of the wild-type HSP27 but not of a nonphosphorylatable form of human HSP27 in Chinese hamster cells conferred resistance to actin fragmentation by oxidative stress generated by H2O2. It is concluded that activation of the 45/54-kDa HSP27 kinase is a common mechanism of HSP27 phosphorylation to which converge both oxyradical-dependent and oxyradical-independent pathways and which may participate in a homeostatic response to stress at the level of actin microfilament.
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PMID:Characterization of 45-kDa/54-kDa HSP27 kinase, a stress-sensitive kinase which may activate the phosphorylation-dependent protective function of mammalian 27-kDa heat-shock protein HSP27. 785 16

For "leaky" epithelia the transepithelial resistance (Rt) is an electrophysiological measure of the paracellular pathway within the epithelial barrier. The Rt across a monolayer of LLC-PK1 porcine renal epithelial cells is specifically an inverse measure of paracellular transepithelial permeability and displays a multiphasic and reversible response to the cytokine tumor necrosis factor-alpha (TNF). The Rt response to TNF can be inhibited by the nonhydrolyzable adenosine 3',5'-cyclic monophosphate (cAMP) analogue, dibutyryl-cAMP. In addition, activation of adenylate cyclase (forskolin) or inhibition of phosphodiesterase (3-isobutyl-1-methylxanthine, Ro-20-1724, and pentoxifylline), each of which have been reported to elevate cellular cAMP levels, also inhibited the Rt response to TNF. Incubation of the LLC-PK1 cell sheet with N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide, an inhibitor of cAMP-dependent protein kinase (PKA), potentiated the Rt response to TNF. The Rt response to TNF was completely prevented by preincubation of the cultures with cholera toxin, whereas pertussis toxin pretreatment had a slight but significant potentiating effect on the response. Pretreatment with cholera toxin was associated with an approximately 18-fold elevation in cAMP levels in both control and TNF-treated cultures. Measurements of cellular cAMP content at selected intervals after TNF administration showed a significant elevation (P < 0.01) of 140% above time-matched controls at 1 h after the administration of TNF to the cell sheet. The level of cAMP then declined to approximate control level within 2.5 h of TNF administration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:cAMP modulates transepithelial resistance response of LLC-PK1 renal epithelia to tumor necrosis factor. 786 72

The two tumor necrosis factor (TNF) receptors (TNF-R55 and TNF-R75) can release soluble TNF-binding proteins (TNF-R55-BP and TNF-R75-BP) by proteolytic cleavage. The proteolytic processing of the TNF receptors was investigated in monoblastic THP-1 and promyelocytic HL-60-10 leukemic cell lines. The release of soluble forms of both receptors was rapidly stimulated by staurosporine-sensitive protein kinase C activation by phorbol myristate acetate (PMA) and more slowly stimulated by TNF. No receptor release was seen below a temperature of 16 degrees C. NH4Cl (10 mmol/liter) and monensin (1 mumol/liter), known to increase intracellular pH, inhibited to some extent PMA- and TNF-induced release of both TNF-R55-BP and TNF-R75-BP. The inhibitory effect of monensin might be explained by a diminished translocation of newly synthesized receptor to the plasma membrane. The weak inhibitory effect of NH4Cl on PMA-induced release of soluble receptor forms could be due to effects on a pH-sensitive compartment. PMA-induced down-regulation of receptors was not dependent on acidity as it occurred also in the presence of monensin and NH4Cl when the release of TNF-BPs is partially blocked. Dibutyryl cAMP inhibited the PMA-induced release of TNF-R55-BP but not of TNF-R75-BP in both cell lines investigated. In addition, dibutyryl cAMP alone stimulated the release of both receptors but only in THP-1 cells. Our data show that the generation of soluble forms of both TNF receptors can be regulated by both PKC and PKA.
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PMID:Mechanisms involved in the processing of the p55 and the p75 tumor necrosis factor (TNF) receptors to soluble receptor forms. 794 29

JNK protein kinases are distantly related to mitogen-activated protein kinases (ERKs) and are activated by dual phosphorylation on Tyr and Thr. The JNK protein kinase group includes the 46-kDa isoform JNK1. Here we describe the molecular cloning of a second member of the JNK group, the 55-kDa protein kinase JNK2. The activities of both JNK isoforms are markedly increased by exposure of cells to UV radiation. Furthermore, JNK protein kinase activation is observed in cells treated with tumor necrosis factor. Although both JNK isoforms phosphorylate the NH2-terminal activation domain of the transcription factor c-Jun, the activity of JNK2 was approximately 10-fold greater than that of JNK1. This difference in c-Jun phosphorylation correlates with increased binding of c-Jun to JNK2 compared with JNK1. The distinct in vitro biochemical properties of these JNK isoforms suggest that they may have different functions in vivo. Evidence in favor of this hypothesis was obtained from the observation that JNK1, but not JNK2, complements a defect in the expression of the mitogen-activated protein kinase HOG1 in the yeast Saccharomyces cerevisiae. Together, these data indicate a role for the JNK group of protein kinases in the signal transduction pathway initiated by proinflammatory cytokines and UV radiation.
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PMID:Signal transduction by tumor necrosis factor mediated by JNK protein kinases. 796 72

The macrophage-like cell line, J774, was found to respond to immobilized mouse monoclonal IgG2a proteins, but not to soluble forms of IgG2a or IgG2b or to immobilized F(ab')2 of IgG2a, by the increase in the nuclear proteins of two different types of NF-kappa B proteins which differed in their electrophoretic mobilities. Fc gamma 2a receptor-mediated activation of NF-kappa B was blocked by the presence of pyrrolidinedithiocarbamate, neutralizing anti-tumor necrosis factor (TNF)-alpha antibodies, various protein kinase inhibitors (H-89, genistein, or heparin) or intracellular calcium chelator (1,2-bis(O-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetra-(acetoxymethyl)-ester, BAPTA/AM) during stimulation. J774 cells were also found to respond to immobilized IgG2a, but not IgG2b, by the increased production of superoxide, H2O2, and TNF-alpha. Fc gamma 2aR-induced production of H2O2 was inhibited by pretreatment of the cells with pyrrolidinedithiocarbamate, H-89, genistein, heparin, or BAPTA/AM, but not with anti-TNF-alpha antibody. Fc gamma 2aR-induced production of TNF-alpha was, on the other hand, not inhibited by pretreatment of the cells with BAPTA/AM. Although J774 cells responded to exogenously added rTNF-alpha, but not to H2O2, by activation of NF-kappa B, the recombinant TNF-alpha-mediated NF-kappa B activation was enhanced by simultaneous presence of H2O2. These results thus suggest that macrophages respond to the stimulation of Fc gamma 2aR by the production of both reactive oxygen intermediates and TNF-alpha and that endogenous TNF-alpha activates NF-kappa B via the pathway involving reactive oxygen intermediates.
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PMID:The binding of immobilized IgG2a to Fc gamma 2a receptor activates NF-kappa B via reactive oxygen intermediates and tumor necrosis factor-alpha 1. 798 75

In the present study, we examined the ontogeny of the type 1 receptor for basic fibroblast growth factor (FGFR-1) in whole rat testis, its cellular localization, and its in vitro regulation in 20-day-old rat Sertoli cells. Gene expression of FGFR-1 was developmentally regulated; expression was higher in prepubertal testes and decreased with sexual maturity. The transcript was found to be expressed in Leydig-enriched fractions, peritubular cells, Sertoli cells, and, to a lesser extent, germ cells. FSH as well as (Bu)2cAMP enhanced FGFR-1 messenger RNA (mRNA) levels in cultured Sertoli cells, suggesting an involvement of the protein kinase-A pathway. Addition of basic FGF (bFGF), tumor necrosis factor-alpha (TNF alpha), or interleukin-1 alpha resulted in a dose- and time-related increase in FGFR-1 mRNA levels. The effect of bFGF was specific, because it was neutralized by cotreatment with an anti-bFGF. We tested medium conditioned by germ cells and found a stimulation of the Sertoli cell FGFR-1 mRNA levels, which was abolished by immunodepletion of the conditioned medium with anti-TNF alpha antibodies. It is suggested that in Sertoli cells, bFGF action, when mediated by FGFR-1, is under a complex hormonal (FSH) and paracrine and/or autocrine control exerted at least by bFGF, TNF alpha, and interleukin-1 alpha.
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PMID:Fibroblast growth factor receptor type 1 expression during rat testicular development and its regulation in cultured Sertoli cells. 798 24

Bacterial lipopolysaccharide (LPS), tumor necrosis factor (TNF)-alpha and interleukin-1 beta (IL-1 beta) stimulate similar cellular responses. TNF-alpha and IL-1 beta are known to initiate signaling through a pathway involving hydrolysis of sphingomyelin to ceramide (Kolesnick, R. N., and Golde, D. W. (1994) Cell 77, 325-328). In this system, ceramide acts as a second messenger stimulating a ceramide-activated serine/threonine protein kinase. The present studies demonstrate that LPS, like TNF and IL-1, stimulates ceramide-activated protein kinase activity in human leukemia (HL-60) cells and in freshly isolated human neutrophils. Lipid A, the biologically active core of LPS, enhanced kinase activity in a time- and concentration-dependent manner. As little as 10 nM lipid A was effective, and a maximal effect occurred with 500 nM lipid A, increasing kinase activity 5-fold. Native LPS similarly induced kinase activation. This effect of LPS was markedly enhanced by LPS binding protein and required the LPS receptor CD14. In contrast to TNF and IL-1, LPS did not cause sphingomyelin hydrolysis and thus stimulates ceramide-activated protein kinase without generating ceramide. Molecular modeling showed strong structural similarity between ceramide and a region of lipid A. Based on these observations, we propose that LPS stimulates cells by mimicking the second messenger function of ceramide.
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PMID:Bacterial lipopolysaccharide has structural similarity to ceramide and stimulates ceramide-activated protein kinase in myeloid cells. 802 Dec 69

Two-dimensional (2-D) gel electrophoresis has been used to map proteins from various cell types in an effort to eventually link such maps to the sequencing of the entire human genome. While this analysis indicates the cellular disposition and expression of proteins, another application of 2-D gels, the analysis of phosphoproteins, can provide much information as to the assembly and "wiring" of the signal transduction circuits within cells which appear to be enervated by phosphate exchange. The preparation and separation of 32P-labeled proteins is described, as well as various analytical methods, including: the variety of gel systems available for specialist types of analyses, comparing 33P- and 32P-labeling of proteins, imaging techniques, phosphoamino analysis, phosphopeptide separation, identifying the amino acid groups that are phosphorylated, and the identification of phosphoproteins on 2-D gels by immunoprecipitation, corunning of purified proteins, comparative mapping and microsequencing, and by Western blotting. Examples (in brackets) are given of applications in which 2-D phosphogels can be applied, which offer advantages over other techniques. These include: (i) identifying in vivo substrates for kinases (protein kinase C activated by phorbol myristate acetate), (ii) investigating cytokine signaling pathways (tumor necrosis factor and interleukin-1), (iii) investigating the effects of drugs on signaling pathways (okadaic acid, menadione and cyclooxygenase inhibitors), (iv) characterization of specific phosphoproteins (heat-shock protein Hsp27 and stathmin), (v) comparing normal and transformed cells (MRC-5 human lung fibroblasts and their SV-40-transformed counterparts, MRC-5 SV1 cells), (vi) purifying phosphoproteins, (vii) investigating the relationship of protein phosphorylation to stages in the cell cycle (stathmin), (viii) investigating protein/protein interactions, (ix) mapping in vitro kinase substrates (protein kinase C, protein kinase A, and mitogen activated protein kinase activated protein kinase 2), and (x) locating and identifying cellular phosphatases (Hsp27 phosphatase). It is possible that the mapping of phosphoproteins can be linked to other 2-D gel databases and that information derived from these can be used in the future to better understand the signaling mechanisms of normal and cancerous cells.
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PMID:Analysis of cellular phosphoproteins by two-dimensional gel electrophoresis: applications for cell signaling in normal and cancer cells. 805 70

Using an in vitro experimental model, we have recently demonstrated that Candida albicans in its hyphal form (H-Candida), similarly to lipopolysaccharide (LPS), enhances tumor necrosis factor (TNF) secretory response in the cloned macrophage (M phi) population ANA-1. Here we show that H-Candida and LPS each differ in their requirements for intact protein kinase functions, susceptibility to 0.4-microns micropore-size membranes, and sensitivity to polymyxin B. These results, together with the synergistic effect occurring between H-Candida and LPS in inducing TNF response, indicate the existence of different receptor(s) and/or signal-transduction pathway(s) through which the two stimuli act.
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PMID:Different events involved in the induction of macrophage tumor necrosis factor by Candida albicans and lipopolysaccharide. 806 29

The sphingomyelin pathway is a new signal transduction system initiated by hydrolysis of plasma membrane sphingomyelin to ceramide by the actin of a neutral sphingomyelinase. Ceramide serine/threonine protein kinase termed ceramide-activated protein kinase. This kinase belongs to a family of proline-directed protein kinases that recognize substrates containing the minimal motif, X-Thr/Ser-Pro-X, where the phosphoacceptor site is followed on the carboxyl terminus by a proline residue and X may be any amino acid. Three lines of evidence, rapid kinetics of activation of the sphingomyelin pathway by tumor necrosis factor (TNF) alpha, the ability of cell-permeable ceramide analogs to bypass receptor activation and mimic the effect of TNF alpha, and reconstitution of this cascade in a cell-free system, support the concept that the sphingomyelin pathway serves to signal TNF alpha-induced monocytic differentiation. Hence, the sphingomyelin pathway may represent a signaling system analogous to more well-defined systems such as the cyclic adenosine monophosphate and phosphoinositide pathways.
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PMID:Signal transduction through the sphingomyelin pathway. 808 39


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