Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Investigation of 12-tetradecanoyl phorbol 13-acetate (TPA)-resistant U937 cell clones has demonstrated that the normal sustained p42 mitogen-activated protein kinase (p42MAPK) activation produced by TPA treatment is absent. This is shown to be due to the inability of TPA to maintain activation of MAP/extracellular signal-regulated kinase kinase (MEK) and cRaf1. A direct relationship between sustained p42MAPK activation and differentiation is provided by the demonstration that blockade of MEK activation by PD098059 prevents TPA-induced morphological differentiation of wild type U937 cells. Using TPA-resistant clones, an involvement of microtubule reorganization and granule release is demonstrated by the ability of the microtubule depolymerizing agent nocodazole, to promote sustained p42MAPK activation in the presence of TPA. This response correlates with the lack of TPA-induced microtubule reorganization in these clones and the ability of nocodazole to partially bypass resistance to TPA. The results demonstrate a causal link between protein kinase C-dependent microtubule reorganization, sustained p42MAPK activation, and the induction of differentiation in U937 cells.
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PMID:Tetradecanoyl phorbol acetate-induced microtubule reorganization is required for sustained mitogen-activated protein kinase activation and morphological differentiation of U937 cells. 1031 97

The family of basic secretagogues of connective tissue mast cells act as receptor mimetic agents, which trigger exocytosis by directly activating G proteins. We now demonstrate that pertussis toxin (Ptx)-sensitive Gi proteins, activated by compound 48/80 (c48/80), a potent member of this family, also activate the p42/p44 MAP kinases (MAPKs). This activation was potentiated by the protein tyrosine phosphatase inhibitor vanadate, whereas the tyrphostin AG-18, a competitive inhibitor of protein tyrosine kinases (PTKs); the protein kinase C inhibitors K252a and GF109203X; the phosphatidylinositol-3-kinase (PI-3K) inhibitors wortmannin and LY294002; and EGTA have abolished this activation. These results suggest that c48/80 activated the p42/p44 MAPKs via a mechanism that involves PTKs, protein kinase C, phosphatidylinositol-3-kinase and Ca2+ as mediators. Protein tyrosine phosphorylation and activation of the p42/p44 MAPKs were closely correlated with stimulation of arachidonic acid (AA) release by c48/80 but not with histamine secretion. However, whereas PD98059, the inhibitor of the MAPK kinase has abrogated MAPK activation, this inhibitor failed to effect release of AA. We therefore conclude that by activating Ptx-sensitive Gi protein(s), the basic secretagogues of mast cells stimulate multiple signaling pathways, which diverge to regulate the production and release of the different inflammatory mediators. Whereas the signaling pathway responsible for triggering histamine release is PTK independent, the pathway responsible for the stimulation of AA release bifurcates downstream to PTKs but upstream to the activation of MAPKs.
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PMID:Gi-mediated activation of mitogen-activated protein kinase (MAPK) pathway by receptor mimetic basic secretagogues of connective tissue-type mast cells: bifurcation of arachidonic acid-induced release upstream of MAPK. 1033 65

An age-related dysfunction of the immune system, and especially of the T lymphocytes, is the most common feature observed during aging. It is well recognized by now that changes in the molecular mechanisms connecting the antigen receptor of the T cell with its nuclear machinery, commonly called 'signal transduction pathways' are the basis for this dysfunction. This paper is an up-to-date review of current literature of the problem, describing age-related changes in the functioning of three major, complementary pathways of signal transduction in murine and human T cell: IP3/Ca2+/calcineurin, DAG/protein kinase C (PKC) and Ras/MAP kinases, discovered so far.
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PMID:[Impaired signal transduction in T-lymphocytes of the aged]. 1035 1

Confluent AKR-2B fibroblasts rapidly disintegrate after serum deprivation.27 ATP or adenosine added immediately after serum removal afforded substantial protection against cell death even for a long period of 24 h. ED50 values were 14 and 110 microM for ATP and adenosine, respectively. In the presence of 5 microg/ml cycloheximide the protective effect of both substances was suppressed, indicating that protein synthesis is required. The protective effect of ATP was highly specific since among numerous tested derivatives only ATP-[gamma-S] exhibited a substantial protective effect. The ability of ATP and adenosine to modulate cell division was analyzed. Both substances did not exhibit any mitogenic effect. Adenosine completely blocked PDGF-BB induced cell division, whereas ATP had no effect. Unlike adenosine, ATP strongly stimulated Ca2+-release from intracellular stores. On the other hand, adenosine stimulated an increase in the intracellular concentration of cAMP from 0.4 - 1.5 microM, whereas ATP decreased the content below 0.1 microM. ATP stimulated the phosphorylation of MAP-kinase, RSK and p70S6-kinase; adenosine was inactive. After complexation of [Ca2+]i the protective effect of ATP was greatly lost while adenosine was still active. Surprisingly neither ATP nor adenosine caused an activation of PKC-isoforms. After incubation with pertussis toxin, the protection by ATP was reduced indicating an involvement of Gi-proteins in the signal transduction induced by ATP. Our results indicate that ATP as well as adenosine are potent inhibitors of cell death caused by serum deprivation and that this protective effect apparently occurs via distinct pathways. However, both pathways must converge at the point of caspase activation, since the stimulation of DEVDase- and VEIDase-activities, respectively, are suppressed by either ATP or adenosine.
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PMID:ATP and adenosine prevent via different pathways the activation of caspases in apoptotic AKR-2B fibroblasts. 1038 45

1. Intradermal (i.d.) injection of cytokines, IL-1beta and TNFalpha (5 ng, 60 and 30 min prior) produces a rapid onset up-regulation of des-Arg9-BK-mediated rat paw oedema. Here we analyse the mechanisms involved in des-Arg9-BK-induced oedema in animals pre-treated with IL-1beta or TNFalpha. 2. Co-injection of anti-IL-1beta, anti-TNFalpha and anti-IL-8 (50 ng) significantly inhibited des-Arg9-BK-induced oedema in animals pre-treated with IL-1beta (65, 37 and 42%) or TNFalpha (39, 64, 25%). IL-1 receptor antagonist (IRA, 100 microg) or IL-10 (10 ng) inhibited the oedema caused by des-Arg9-BK, in rats that had received either IL-1beta (67 and 63%) or TNFalpha (46 and 35%). 3. Co-injection of the PKC inhibitors, staurosporine (10 nmol) or RO 318220 (30 nmol) inhibited des-Arg9-BK-induced paw oedema (44 and 42% for IL-1beta and, 53 and 30% for TNFalpha, respectively). Genistein (tyrosine kinase inhibitor, 2.5 mg kg-1, s.c.) or PD 098059 (MAP-kinase inhibitor, 30 nmol) produced marked inhibition of des-Arg9-BK-induced oedema (58 and 39% for IL-1beta and 31 and 35% for TNFalpha respectively). 4. The NF-kappaB inhibitors TLCK (2 mg kg-1, i.p.) and PDCT (100 mg kg-1, i.p.) significantly inhibited the oedema of des-Arg9-BK in IL-1beta (27 and 83%) or TNFalpha (28 and 80%) pre-treated animals. 5. It is concluded that up-regulation of B1 receptors modulated by IL-1beta or TNFalpha involves the release of other cytokines, activation of PKC and tyrosine kinase pathways, co-ordinated with the activation of MAP-kinase and nuclear factor kappaB, reinforcing the view that B1 receptors may exert a pivotal role in modulating chronic inflammatory processes.
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PMID:In vivo B1 kinin-receptor upregulation. Evidence for involvement of protein kinases and nuclear factor kappaB pathways. 1048 16

Platelet activation results in shape change, release of granule contents, aggregation and clot retraction. An intense intracellular 'machinery' is engaged to achieve these functions. Thrombin is one of the most important agonists for platelet recruitment and aggregation which is mediated by the binding of fibrinogen to its adhesive receptor: the glycoprotein (GP) IIb/IIIa complex or integrin alphaIIbbeta(3). The numerous biological processes consecutive to thrombin binding to platelet membrane are mainly controlled by phosphorylation mechanisms organized into signalling pathways. Schematically, the phospholipase Cbeta pathway activated by G protein coupled to the seven transmembrane thrombin receptors, provides the first intracellular relay and would generate regulators such as protein kinase C, phosphorylated pleckstrin but also modifications of the intracellular domain of beta(3). This inside-out signalling would lead to some changes in the extracellular domain of GPIIb/IIIa increasing access of fibrinogen to the receptor. Ligand interaction with GPIIb/IIIa induced reorganization of the cytoskeleton and would mediate the outside-in signals which involve a series of intracellular events including tyrosine kinases, phosphatidylinositol 3 kinases, MAP kinases and phosphatases. Some of these pathways and/or signalling metabolites could be associated to some well-characterized platelet functions: cortactin phosphorylation is involved in platelet shape change, phosphatidylinositol 3 kinase (p85) in the stabilisation of platelet aggregates and MAP kinase (p44) in postaggregation events. But in fact the sequence of events which has been described has to be viewed as integrated networks. At least three biochemical processes govern the highly integrated organization to send just the appropriate quanta of signal for a specific need: the reorganisation of the cytoskeleton following the binding of fibrinogen to alphaIIbbeta(3), the structure of the signal transducers that contain SH2, SH3, and PH domains leading to the formation of macromolecules of signalling and the crosstalk phenomena between the different pathways. Elucidating the mechanisms of such networks becomes an increasingly exciting project.
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PMID:Platelet signal transduction pathways: could we organize them into a 'hierarchy'? 1049 30

The authors hypothesized that certain PKC isoforms play an important role in the induction of pro-inflammatory cytokine (TNF-alpha, IL-1beta, IL-6) synthesis. To test this hypothesis, the cytosol-to-membrane translocation of select PKC isoforms with tested cytokine production in human monocytes cultured in vitro was correlated. It is reported that in monocytes treated with phorbol ester (PMA), translocation of PKC isoforms alpha, betaII, delta and epsilon precede cytokine synthesis. Moreover, specific inhibition of PKC translocation that occurs in the presence of Calphostin C is reflected in downstream events: lack of MAP kinases phosphorylation, loss of DNA binding ability by AP-1 transcription factor, and the reduction of pro-inflammatory cytokine synthesis. Thus, the cytosol-to-membrane translocation of PKC isoforms alpha, betaII, delta and epsilon with the subsequent activation of: (1) MAP kinases; and (2) AP-1 transcription factor, may represent critical steps in the induction of signalling cascade leading to TNF-alpha, IL-1beta, IL-6 synthesis in human monocytes.
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PMID:Protein kinase c-dependent pathway is critical for the production of pro-inflammatory cytokines (TNF-alpha, IL-1beta, IL-6). 1054 71

The damaging effects of glucose on the cells which contribute to the development of diabetic complications are ill-understood. There are three major hypotheses - the sorbitol pathway, non-enzymatic glycation of proteins and increased oxidative stress - and many examples illustrate inter-connections between the three. It is suggested that these pathways, together with other biochemical anomalies arising from hyperglycaemia, can synergise by sharing the capacity to activate mitogen-activated protein kinases (MAP kinases) and that these enzymes in actual fact form glucose transducers. The more recent hypothesis, namely that activation of a specific isoform of protein kinase C (PKC) underpin damaging changes in retinopathy and neuropathy, can also be related because protein kinase C is an effective activator of mitogen-activated protein kinases. These latter kinases phosphorylate transcription factors, which in turn alter the balance of gene expression. In this way they can alter cellular phenotype, promote division or increase production of extracellular material. In short, mitogen-activated protein kinases have the capacity to trigger all the cellular events necessary for the development of diabetic nephropathy, retinopathy and neuropathy and it is suggested that their pharmacological modulation might provide therapeutic control of these conditions. [Diabetologia (1999) 42: 1271-1281]
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PMID:Mitogen-activated protein kinases as glucose transducers for diabetic complications. 1055 Apr 10

A novel peptide with multiple phosphorylation sites, which we designated as multide, was developed to detect a wide variety of protein kinases in crude cell extracts. Multide, KKRKSSLRRWSPLTPRQMSFDC, has been designed to contain consensus sequences for various Ser/Thr protein kinases including cAMP-dependent protein kinase, protein kinase C, MAP kinases, and Ca(2+)/calmodulin-dependent protein kinases in a single peptide. In-gel protein kinase assay using multide was found to be very useful for analyzing the activities of protein kinases that are altered in response to various extracellular stimuli. The substrate specificities of the protein kinases thus detected were further determined by using five multide analogs with different phosphorylation sites.
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PMID:Detection of a variety of Ser/Thr protein kinases using a synthetic peptide with multiple phosphorylation sites. 1057 48

The participation of phosphatidylinositol 3-kinase (PI3-kinase), protein kinase C, and mitogen-activated protein kinase (MAP-kinase) in the inhibition by interleukin 6 (IL-6) and insulin of phosphoenolpyruvate carboxykinase (PCK) gene expression was investigated in cultured rat hepatocytes. IL-6 or insulin inhibited the glucagon-stimulated increase in PCK messenger RNA (mRNA) by about 70%. In the presence of either the PI3-kinase inhibitor, wortmannin, or the protein kinase C inhibitor, GF109203x, the inhibition by IL-6 was only about 40%, although it was abolished with both inhibitors in combination. Wortmannin alone but not GF109203x prevented the inhibition by insulin of glucagon-stimulated PCK gene expression. The MAP-kinase pathway inhibitor, PD98059, did not affect IL-6 or insulin inhibition of PCK mRNA increase. When chlorophenylthio-cyclic 3',5' adenosine monophosphate (CPT-cAMP) was used instead of glucagon, IL-6 or insulin inhibited the increase in PCK mRNA by 75% and 85%, respectively. The inhibition by IL-6 was only about 50% in the presence of either wortmannin or GF109203x alone but was abolished with the combination of both inhibitors. The inhibition by insulin was only about 50% in the presence of GF109203x and was abolished by wortmannin. The inhibitors did not affect the inhibition by IL-6 or insulin of the glucagon-stimulated increase in cAMP. It is concluded that the inhibition by IL-6 of PCK gene expression involved both PI3-kinase and protein kinase C, whereas the inhibition by insulin required only PI3-kinase. The inhibition occurred downstream from cAMP formation. Hence, IL-6 and insulin may share, in part, common signal transduction pathways in the inhibition of PCK gene expression.
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PMID:Phosphatidylinositol 3-kinase and protein kinase C contribute to the inhibition by interleukin 6 of phosphoenolpyruvate carboxykinase gene expression in cultured rat hepatocytes. 1065 71


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