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

We have investigated the activation of mitogen-activated protein kinase (MAP-kinase) in KB human epidermoid carcinoma cells treated with interleukin 1 (IL-1). MAP-kinase activity was transient; the time required for activity to reach a maximal level was dependent upon the dose of IL-1, ranging from 15 minutes to 45 minutes. The level of kinase induction correlated well with dose-response curves for two characteristic IL-1-induced responses, PGE2 and IL-6 production. MAP-kinase activity returned to basal levels within 2 hours regardless of the amount of IL-1 added to the system. Exposure of KB cells to free IL-1 was accordingly restricted to periods of 2 hours or less, by replacing IL-1 with an excess of IL-1 receptor antagonist. Even after 2 hours exposure, the ability of IL-1 to induce IL-6 or PGE2 was still IL-1ra-inhibitable by more than 80%, suggesting that events downstream of, or parallel to MAP-kinase activation, requiring the continual formation of new IL-1 receptor complexes, are needed to fully elicit these responses. Two general serine/threonine kinase inhibitors, K252a and quercetin, were found to strongly inhibit MAP kinase in vivo with ED50s of c. 100 nM and 30 microM, respectively. At these concentrations, both compounds effectively inhibited IL-1-driven PGE2 and IL-6 induction without affecting general protein synthesis or secretion. Other non-selective kinase inhibitors had less effect on MAP-kinase activation or IL-1-induced biological responses. The transient activation of MAP-kinase induction correlated strikingly with activation of the transcription factor NF-kappa B. IL-1-induced NF-kappa B activation was, however, relatively insensitive to inhibition by K252a or quercetin. We suggest that MAP-kinase is likely to be a necessary, but not sufficient, intermediate in some (IL-6, PGE2 induction) but not all (NF-kappa B activation) IL-1 responses in these cells.
 ...
PMID:Evidence that MAP (mitogen-activated protein) kinase activation may be a necessary but not sufficient signal for a restricted subset of responses in IL-1-treated epidermoid cells. 133 84

We examined the molecular mechanism of DT-5461-induced LPS antagonism in human peripheral blood monocytes. Dose-response studies revealed that LPS-induced IL-1 and TNF-alpha production was apparently totally suppressed in a competitive manner by a 10-fold excess of DT-5461. A 10-fold excess of DT-5461 significantly blocked the binding of FITC-LPS to the monocytes. DT-5461 suppressed IL-1 and TNF-alpha mRNA expression in LPS-activated monocytes. Western blots showed that DT-5461 suppressed the LPS-induced tyrosine phosphorylation of p42mapk/ERK2. These results suggested that the competitive binding inhibition and repression of early intracellular signaling involved in DT-5461-mediated LPS antagonism.
 ...
PMID:Endotoxin antagonism by a synthetic lipid A analogue, DT-5461, with low endotoxicity in human peripheral blood monocytes. 748 14

Interleukin (IL)-1 plays a central role in human host defense. Binding of IL-1 to its receptor is associated with phosphorylation of various cellular target proteins, most of which are unidentified. The kinases responsible for target protein phosphorylation after IL-1 stimulation are also still not completely understood. We report here that IL-1 induced activation of mitogen-activated protein (MAP) kinase in primary monocytes and in the human monocytic leukemia cell line U-937. Activation of MAP kinase was followed by activation of MAP kinase-activated protein (MAPKAP) kinase 2, a serine/threonine kinase, leading to subsequent phosphorylation of the small heat shock protein [27-kDa heat shock protein (Hsp27)]. Phosphorylation of Hsp27 triggered by IL-1 was both dose and time dependent. IL-1 failed to phosphorylate Hsp27 when cells had been previously deactivated with tyrosine kinase inhibitors such as genistein. In those cells, however, Hsp27 phosphorylation could be reconstituted when activated immunoprecipitated MAP kinase or purified MAPKAP kinase 2 was added. Phosphorylation of Hsp27 could also be inhibited when NaF, a serine/threonine phosphatase inhibitor, was omitted. Taken together, our findings indicate that IL-1-induced intracellular signaling pathways converge in the activation of MAP kinase and MAPKAP kinase 2 and the subsequent phosphorylation of Hsp27.
 ...
PMID:Interleukin-1-induced intracellular signaling pathways converge in the activation of mitogen-activated protein kinase and mitogen-activated protein kinase-activated protein kinase 2 and the subsequent phosphorylation of the 27-kilodalton heat shock protein in monocytic cells. 780 27

Increases (5-fold) in the rate of phosphorylation of beta-casein were observed in extracts of human gingival fibroblasts that had been stimulated by interleukin 1 (IL-1) or tumour necrosis factor (TNF). The induced kinase was cytosolic and had little activity on alpha-casein. Its chromatographic behaviour on anion-exchange and gel-filtration columns was similar to that of beta-casein kinase, an enzyme detected originally in MRC-5 cells stimulated by IL-1 and TNF. Phosphopeptide maps of beta-casein confirmed that the kinase activated in gingival fibroblasts had the same substrate specificity as beta-casein kinase. In gingival fibroblasts, beta-casein kinase activity was maximum after 15 min of stimulation by IL-1 or TNF, and remained activated for several hours. Activations of small heat-shock protein (hsp27) kinase and mitogen-activated protein (MAP) kinase were also maximum 15 min after stimulation, but decreased to background levels within the next 30 min. Study of the effects of 21 agents other than IL-1 or TNF showed that none activated beta-casein kinase, whereas several activated MAP kinase or hsp27 kinase. beta-Casein kinase was also detected in extracts of bovine articular chondrocytes and human endothelial cells stimulated by IL-1 or TNF. Semi-purified preparations of fibroblast beta-casein kinase were not inactivated by phosphatases in vitro. Our results suggest that it may be involved in responses specific to IL-1 and TNF in a wide range of cell types and that its activation probably involves mechanisms other than its phosphorylation.
 ...
PMID:Specific activation of beta-casein kinase by the inflammatory cytokines interleukin 1 and tumour necrosis factor. 781 78

Treatment of human diploid FS-4 fibroblasts with TNF or IL-1 led to a rapid increase in the phosphorylation of a approximately 28-kDa protein. Increased phosphorylation was seen after 5 min of TNF treatment, it reached a plateau between 10 and 30 min, and decreased thereafter. Immunoprecipitation with specific antibodies identified the 28-kDa protein as a member of the family of small heat shock proteins (Hsp28). Treatment of cells with different kinase inhibitors (staurosporine, H7, H8, HA-1004, or chelerythrine chloride) failed to inhibit TNF-induced Hsp28 phosphorylation, suggesting that neither protein kinase C nor other common protein kinases were involved. Treatment of FS-4 cells with sodium arsenite led to a very strong increase in the phosphorylation of Hsp28 demonstrable after 5 min and persisting for at least 4 h. Tyrosine phosphorylation of pp42 and pp44 MAP kinases was increased by TNF treatment, whereas arsenite produced a modest increase in tyrosine phosphorylation of pp44 while decreasing that of pp42 MAP kinase. The finding that sodium arsenite strongly increased Hsp28 phosphorylation, together with the resistance of TNF-induced phosphorylation to kinase inhibitors, supports the notion that increased serine phosphorylation of Hsp28 in this system involves inhibition of protein phosphatase activity.
 ...
PMID:Pathways of heat shock protein 28 phosphorylation by TNF in human fibroblasts. 785 64

An IL-1-stimulated protein kinase cascade resulting in phosphorylation of the small heat shock protein hsp27 has been identified in KB cells. It is distinct from the p42 MAP kinase cascade. An upstream activator kinase phosphorylated a 40 kDa kinase (p40) upon threonine and tyrosine residues, which in turn phosphorylated a 50 kDa kinase (p50) upon threonine (and some serine) residues. p50 phosphorylated hsp27 upon serine. p40 and p50 were purified to near homogeneity. All three components were inactivated by protein phosphatase 2A, and p40 was inactivated by protein tyrosine phosphatase 1B. The substrate specificity of p40 differed from that of p42 and p54 MAP kinases. The upstream activator was not a MAP kinase kinase. p50 resembled MAPKAPK-2 and may be identical.
 ...
PMID:Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27. 792 54

The dorsal (dl) nuclear gradient initiates the differentiation of the mesoderm, neuroectoderm, and dorsal ectoderm by activating and repressing gene expression in the early Drosophila embryo. This gradient is organized by a Toll signaling pathway that shares many common features with the mammalian IL-1 cytokine pathway. Here we present evidence that a second signaling pathway, controlled by the torso (tor) receptor tyrosine kinase, also modulates dl activity. Evidence is presented that the tor pathway selectively masks the ability of dl to repress gene expression but has only a slight effect on activation. Intracellular kinases that are thought to function downstream of tor, such as D-raf and the rolled MAP kinase, mediate this selective block in repression. Normally, the Toll and tor pathways are both active only at the embryonic poles, and consequently, target genes (zen and dpp) that are repressed in middle body regions are expressed at these sites. Constitutive activation of the tor pathway causes severe embryonic defects, including disruptions in gastrulation and mesoderm differentiation, as a result of misregulation of dl target genes. These results suggest that RTK signaling pathways can control gene expression by antirepression, and that multiple pathways can fine-tune the activities of a single transcription factor.
 ...
PMID:Regulation of the dorsal morphogen by the Toll and torso signaling pathways: a receptor tyrosine kinase selectively masks transcriptional repression. 792 28

We have identified in rabbits two hepatic forms of T669 peptide kinases that are very strongly activated after systemic injection with the inflammatory cytokine interleukin 1 (IL-1). The T669 peptide contains a major phosphorylation site of the epidermal growth factor receptor, threonine 699 and is a substrate for mitogen-activated protein (MAP) kinases. The kinases were purified to homogeneity and corresponded to 50- and 55-kD proteins on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Amino acid sequencing of 12 tryptic peptides of both kinases identified them as p54 MAP kinase alpha. This kinase belongs to the novel family of stress-activated protein kinases. This is the first evidence of IL-1 activating a specific protein kinase in vivo.
 ...
PMID:Interleukin 1 alpha activates two forms of p54 alpha mitogen-activated protein kinase in rabbit liver. 796 79

These studies were undertaken to investigate the therapeutic mechanism of saturated solutions of KI, used to treat infectious and inflammatory diseases. The addition of 12-50 mM KI to cultured human peripheral blood mononuclear cells resulted in 319-395 mosM final solute concentration and induced interleukin (IL)-8 synthesis. Maximal IL-8 production was seen when 40 mM salt was added (375 mosM) and was equal to IL-8 induced by endotoxin or IL-1 alpha. However, there was no induction of IL-1 alpha, IL-1 beta, or tumor necrosis factor to account for the synthesis of IL-8; the effect of KI was not due to contaminating endotoxins. Hyperosmolar NaCl also induced IL-8 and increased steady-state levels of IL-8 mRNA similar to those induced by IL-1 alpha. IL-8 gene expression was elevated for 96 hr in peripheral blood mononuclear cells incubated with hyperosmolar NaCl. In human THP-1 macrophagic cells, osmotic stimulation with KI, NaI, or NaCl also induced IL-8 production. IL-1 signal transduction includes the phosphorylation of the p38 mitogen-activated protein kinase that is observed following osmotic stress. Using specific blockade of this kinase, a dose-response inhibition of hyperosmolar NaCl-induced IL-8 synthesis was observed, similar to that in cells stimulated with IL-1. Thus, these studies suggest that IL-1 and osmotic shock utilize the same mitogen-activated protein kinase for signal transduction and IL-8 synthesis.
 ...
PMID:Osmotic regulation of cytokine synthesis in vitro. 861 75

CSBP p38 is a mitogen-activated protein kinase that is activated in response to stress, endotoxin, interleukin 1, and tumor necrosis factor. Using a catalytically inactive mutant (D168A) of human CSBP2 as the bait in a yeast two-hybrid screen, we have identified and cloned a novel kinase which shares approximately 70% amino acid identity to mitogen-activated protein kinase-activated protein kinase (MAPKAP kinase)-2, and thus was designated MAPKAP kinase-3. The binding of CSBP to MAPKAP kinase-3 was confirmed in vitro by the precipitation of epitope-tagged CSBP1, CSBP2, and CSBP2(D168A) and endogenous CSBP from mammalian cells by a bacterially expressed GST-MAPKAP kinase-3 fusion protein and in vivo by co-precipitation of the epitope-tagged proteins co-expressed in HeLa cells. MAPKAP kinase-3 was phosphorylated by both CSBP1 and CSBP2 and was then able to phosphorylate HSP27 in vitro. Treatment of HeLa cells with sorbitol or TNF resulted in activation of CSBP and MAPKAP kinase-3 and activation of MAPKAP kinase-3 could be blocked by preincubation of cells with SB203580, a specific inhibitor of CSBP kinase activity. These data suggest that MAPKAP kinase-3 is activated by stress and cytokines and is a novel substrate of CSBP both in vitro and in vivo.
 ...
PMID:Identification of mitogen-activated protein (MAP) kinase-activated protein kinase-3, a novel substrate of CSBP p38 MAP kinase. 862 50


1 2 3 4 5 6 7 8 9 10 Next >>