Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Incubation of Swiss 3T3 or L929 cells with tumor necrosis factor (TNF) leads to the rapid stimulation of several cytosolic Ser/Thr kinases active toward myelin basic protein, the S6 peptide (RRLSSLR), the G peptide (SPQPSRRGSESSEE), and Kemptide (LRRASLG). This confirms the hypothesis that kinases other than protein kinases A and C may be involved in the TNF signal transduction. Chromatography on Mono Q resolved multiple kinase peaks with each substrate tested and moreover revealed a TNF-mediated casein kinase-2 activation in both cell lines, measurable with the specific RRREEESEEE peptide or with the G peptide. The TNF-stimulated myelin basic protein kinases-1 and -2 were identified as extracellular signal-regulated kinases-2 and -1, respectively, based on their elution pattern on Mono Q chromatography, their inactivation by protein phosphatase action, their reaction with phosphothreonine and phosphotyrosine antibodies, and by their migration on sodium dodecyl sulfate-polyacrylamide gel electrophoresis as 42- and 44-kDa proteins recognized by anti-extracellular signal-regulated kinase antibodies.
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PMID:Tumor necrosis factor stimulates multiple serine/threonine protein kinases in Swiss 3T3 and L929 cells. Implication of casein kinase-2 and extracellular signal-regulated kinases in the tumor necrosis factor signal transduction pathway. 128 78

The pleiotropic cytokine tumor necrosis factor-alpha (TNF alpha) controls the expression of multiple gene products in macrophages and plays an important role in host defense. TNF alpha is recognized by the receptors, CD120a (p55) and CD120b (p75). Ligation of CD120a (p55) by TNF alpha or by anti-receptor agonistic antibodies initiates signal transduction leading to the activation of mitogen-activated protein kinases (MAPKs) (p42mapk/erk2 and p44mapk/erk1). Phosphorylation and activation of MAPK are mediated by MAPK kinase (MEK), a family of Thr/Tyr kinases. In this study, we investigated the preferential involvement of the MEK isoforms MEK1 and MEK2 in the activation of p42mapk/erk2 in mouse macrophages stimulated with TNF alpha. Exposure of macrophages to TNF alpha stimulated a time-dependent increase in the activity of MEK1 as measured by an in vitro kinase assay using kinase-inactive p42mapk/erk2 (rMAPKkd) as substrate in the presence of gamma-[32P]ATP. Maximal activation of MEK1 was detected at 10 min poststimulation and coincided with maximal transphosphorylation of Tyr and Thr residues of rMAPKkd. By contrast, there was no evidence of MEK2 activation in macrophages in response to TNF alpha. These data suggest that MEK1 is the preferred substrate for MEK kinase, the upstream kinase implicated in activation of the MAPK pathway in macrophages by TNF alpha.
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PMID:Preferential involvement of MEK1 in the tumor necrosis factor-alpha-induced activation of p42mapk/erk2 in mouse macrophages. 749 90

Mechanisms involved in tumor necrosis factor (TNF)-alpha signal transduction are incompletely understood. In some circumstances, TNF may use a signal transduction pathway involving hydrolysis of sphingomyelin to ceramide and stimulation of a ceramide-activated protein kinase. In HL-60 cells, TNF rapidly activates this pathway and induces monocytic differentiation. Here, we demonstrate that treatment of HL-60 cells with TNF selectively increases tyrosine phosphorylation of p42 mitogen-activated protein kinase (p42mapk) and stimulates its enzymatic activity. Induction of p42mapk phosphorylation was time- and dose-dependent and closely paralleled activation of sphingomyelin hydrolysis. Direct engagement of the sphingomyelin signal transduction pathway by addition of bacterial sphingomyelinase led to MAP kinase activation. The time course of p42mapk phosphorylation in the sphingomyelinase-treated cells was similar to that of TNF, with maximal response occurring at 5 min. A maximal concentration of sphingomyelinase (0.01 unit/ml) was more potent than TNF at inducing MAP kinase enzymatic activity (2.6-fold) and phosphorylation of MAP kinase and tyrosine. The cell-permeable ceramide analogs, C2- and C6-ceramide, which mimic effects of TNF, also induced p42mapk phosphorylation within seconds. These studies indicate that the sphingomyelin pathway can regulate MAP kinase activity and suggest that MAP kinase activation by this mechanism may be involved in TNF-induced signal transduction.
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PMID:Sphingomyelinase and ceramide activate mitogen-activated protein kinase in myeloid HL-60 cells. 768 98

Although tumor necrosis factor (TNF)-alpha stimulation of human neutrophils does not result in a significant release of arachidonic acid, it primes the cell for arachidonic acid release when cells are further stimulated by agents that induce an intracellular calcium increase. We demonstrate that TNF-alpha stimulation of neutrophils induces the phosphorylation of cytosolic phospholipase A2 (cPLA2) and also increases its activity. These results indicate that although TNF-alpha, by itself, does not cause the release of arachidonic acid in intact cells, it increases the phosphorylation and activation of the enzyme cPLA2. Since we recently found that TNF-alpha stimulation of neutrophils does not increase the tyrosine phosphorylation or activation of the p42erk2 and p44erk1 mitogen-activated protein kinases (MAPKs), the present studies demonstrate the involvement of a MAPK independent pathway in the phosphorylation and activation of cPLA2.
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PMID:A mitogen-activated protein kinase independent pathway involved in the phosphorylation and activation of cytosolic phospholipase A2 in human neutrophils stimulated with tumor necrosis factor-alpha. 772 46

The activation of MAPKAP kinase 2 was investigated under heat-shock conditions in mouse Ehrlich ascites tumor cells and after treatment of human MO7 cells with tumor necrosis factor-alpha (TNF-alpha). MAPKAP kinase 2 activity was determined using the small heat-shock proteins (sHsps) Hsp25 and Hsp27 as substrates. In both cell types, about a threefold increase in MAPKAP kinase 2 activity could be detected in a time interval of about 10-15 min after stimulation either by heat shock or TNF-alpha. Phosphorylation of MAPKAP kinase 2, but not the level of MAPKAP kinase 2 mRNA, was increased after heat shock in EAT cells. It is further shown that activation of MAPKAP kinase 2 in MO7 cells is accompanied by increased MAP kinase activity. These data strongly suggest that increased phosphorylation of the sHsps after heat shock or TNF-alpha treatment results from phosphorylation by MAPKAP kinase 2, which itself is activated by phosphorylation through MAP kinases. Hence, we demonstrate that MAPKAP kinase 2 is responsible not only for phosphorylation of sHsps in vitro but also in vivo. The findings link sHsp phosphorylation to the MAP kinase cascade, explaining the early phosphorylation of sHsp that is stimulated by a variety of inducers such as mitogens, phorbol esters, thrombin, calcium ionophores, and heat shock.
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PMID:MAPKAP kinase 2 is activated by heat shock and TNF-alpha: in vivo phosphorylation of small heat shock protein results from stimulation of the MAP kinase cascade. 775 69

Taxol, a unique antimitotic drug, is thought to exert its antitumor activity by binding to and promoting the assembly of microtubules. Studies on the mechanism of action of Taxol have focused mainly on this ability to induce microtubule polymerization. Recent evidence suggests that Taxol affects novel intracellular targets within macrophages and neutrophils. To investigate further the mechanism of action of Taxol on macrophages, we have examined the pattern of tyrosine protein phosphorylation, using antiphosphotyrosine monoclonal antibodies (MAbs) in a RAW 264.7 (RAW) macrophage cell line. We found that Taxol, like lipopolysaccharides (LPS), caused a marked increase in tyrosine phosphorylation of three proteins having M(r) of 40 (p40), 41 (p41), and 43 (p43) kd in RAW cells. Immunoprecipitation of these tyrosine phosphoproteins followed by Western blotting with a microtubule-associated protein-2 (MAP-2) kinase MAb revealed that both Taxol and LPS induced the tyrosine phosphorylation of a MAP-2 kinase-like protein. In addition, MAP-2 kinase-like activity was stimulated in the presence of Taxol or LPS. Examination of cellular mRNA levels in LPS and Taxol-activated macrophages by Northern blot analysis revealed increased expression of Interleukin-1 beta, and tumor necrosis factor-alpha cytokine mRNAs. Because Taxol promotes tubulin assembly, we examined the effect of LPS on microtubule polymerization. LPS had no polymerizing activity over Taxol alone. We conclude that Taxol and LPS have a common target in macrophages that is a critical component of the signal transduction pathway that mediates LPS cellular responses.
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PMID:Taxol and lipopolysaccharide activation of a murine macrophage cell line and induction of similar tyrosine phosphoproteins. 791 36

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

Previous studies have shown that macrophages play an important role in both the initiation of protective responses and the effector mechanism of immunity to Toxoplasma gondii. The purpose of this investigation was to characterize the responses of macrophages to a soluble antigen extract of T. gondii tachyzoites (STAg) in comparison with a prototypic macrophage-activating agent, lipopolysaccharide (LPS), and to determine whether STAg-induced signaling requires a functional Lps gene. Toward this end, tumor necrosis factor (TNF) secretion, a panel of six LPS-inducible genes, and protein tyrosine phosphorylation were examined to gain insights into macrophage responses to STAg. STAg stimulated both C3H/OuJ (Lpsn) and C3H/HeJ (Lpsd) macrophages to secrete bioactive TNF-alpha and to express a subset of LPS-inducible genes (encoding TNF-alpha, TNF receptor 2, and interleukin-1 beta). In contrast to LPS, STAg failed to stimulate Lpsn or Lpsd macrophages to express genes encoding IP-10, D3, or D8. STAg also induced a pattern of tyrosine phosphorylation identical to that induced by LPS; mitogen-activated protein kinase 47-kDa and 43-kDa isoforms and a 41-kDa protein of undetermined identity were inducibly phosphorylated. The ability of STAg to induce TNF-alpha, encoded by a subset of LPS-inducible genes, and tyrosine phosphoproteins was not affected by LPS inhibitors, confirming that the macrophage response to the parasite extract could not be attributed to LPS contamination. We propose that STAg, while differing from LPS in the pattern of macrophage genes induced, may share with LPS two signaling pathways that are intact in Lpsd macrophages.
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PMID:Toxoplasma gondii soluble antigen induces a subset of lipopolysaccharide-inducible genes and tyrosine phosphoproteins in peritoneal macrophages. 803 14

B chronic lymphocytic leukemia (B-CLL) and hairy cell leukemia (HCL) cells are refractory to many of the signals which activate normal B cells but are stimulated to proliferate by tumor necrosis factor (TNF). Cell signalling by TNF is mediated in part by the induction of the transcription factor families AP-1 and NF-kappa B. In some cellular contexts, these factors play a role in regulating cell cycle transit. AP-1 binds DNA as dimers of jun and fos family proteins and is regulated by a cascade of protein kinases which eventually activate a mitogen-activated protein kinase (MAP kinase) and also by protein kinase C. Three pathways have been implicated in the activation of NF-kappa B by extracellular ligands. 1, the activation of protein kinase C by diacylglycerol generated by ligand-mediated activation of phosphatidylcholine hydrolysis, 2, stimulation of specific protein kinases by ceramide generated following activation of a sphingomyelinase by diacylglycerol and 3, a novel pathway involving ligand-induced generation of free radical species. In B-CLL and HCL cells, the generation of nuclear-localized c-jun and c-fos proteins (components of AP-1) in response to TNF or PMA appears to be blocked. Whereas PMA failed to induce NF-kappa B in these cells, this factor was readily induced by TNF. TNF induction of NF-kappa B was abolished by antioxidants, suggesting involvement of the free radical pathway. The data discussed here suggest defects in coupling of some protein kinase C-dependent pathways in B-CLL and HCL cells and that TNF is able to bypass these blocks by the activation of NF-kappa B via a free radical-dependent pathway which is independent of protein kinase C.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Defects in signal transduction pathways in chronic B lymphocytic leukemia cells. 858 Aug 20

A new member of the mitogen-activated protein kinase family, alternatively termed CSBP, p38, or RK, has been identified independently by several laboratories recently. Activation of this novel protein kinase via dual phosphorylation has been observed in different cell systems upon stimulation by a wide spectrum of stimuli, such as physicochemical stress and treatment with lipopolysaccharide or proinflammatory cytokines such as interleukin-1 and tumor necrosis factor. Furthermore, CSAID cytokine biosynthesis inhibitors have now been determined to be potent and selective inhibitors of CSBP/p38/RK kinase activity. These inhibitors will help to dissect signaling pathways involved in inflammatory responses. In particular, for the first time a definitive signal transduction pathway can be prescribed to the action of lipopolysaccharide in cytokine production in macrophages.
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PMID:Role of CSB/p38/RK stress response kinase in LPS and cytokine signaling mechanisms. 860 87


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