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)

To understand the signalling mechanisms involved in the dual stimulatory effects of endothelin-1 (ET-1) on DNA synthesis and melanization in cultured human melanocytes, we analysed the biological profile of ET-1 receptor and determined the effects of ET-1 on the protein kinase C, cyclic AMP system and mitogen-activated protein kinase (MAP kinase) in comparison with their relevant stimulants. The photoaffinity labelling of ET-1 receptors with Denny-Jaff reagents revealed an ET-1 receptor with a molecular mass of 51 kDa in human melanocytes. The ET(A) receptor subtype-sensitive antagonist BQ123(50 nM) or pertussis toxin (100 ng/ml) significantly suppressed the ET-1-induced intracellular calcium mobilization, indicating the presence of pertussis toxin-sensitive G-protein-coupled ET(A) receptors. An assay of protein kinase C activity revealed that 10nM ET-1 translocated cytosolic protein kinase C to membrane-bound protein kinase C within 5 min of the start of incubation. In contrast, receptor-mediated melanocyte activation by ET-1 was accompanied by an elevated level of cyclic AMP (4-fold over control) after 10-60 min of incubation, whereas 60 min of incubation of human melanocytes with c-Kit or c-Met ligands such as stem cell factor (10 nM) or basic fibroblast growth factor (10 nM) did not elevate the cyclic AMP level. We have also demonstrated that a specific tyrosine kinase inhibitor, tyrphostin B-42 (10 microM), inhibited the ET-1-induced growth stimulation, suggesting the involvement of the tyrosine kinase pathway in growth stimulation. Consistently, an assay of MAP kinase revealed that ET-1 caused a 10-fold activation of MAP kinase after 5 min of incubation with human melanocytes in a similar way to tyrosine kinase ligands such as stem cell factor and hepatocyte growth factor. Further, the DNA synthesis stimulated by the c-Kit ligand stem cell factor at a concentration of 1 nM was synergistically enhanced by 5 nM ET-1. These results suggest that ET-induced dual cellular events in human melanocytes are closely associated with cross-talk between the protein kinase C and A and tyrosine kinase pathways.
 ...
PMID:Signalling mechanisms of endothelin-induced mitogenesis and melanogenesis in human melanocytes. 866 Feb 99

In the course of screening for inhibitors of tumorigenic phenotype of K-ras-transformed NIH3T3 cells (DT cells), we found a novel compound, oxamflatin, an aromatic sulfonamide hydroxamate derivative, which induces flat phenotype in these cells and suppresses their anchorage-independent growth. In contrast to DT cells, in v-raf-transformed NIH3T3 cells, no change in their morphology and no specific inhibition of their anchorage-independent growth was observed. Interestingly, oxamflatin was effective to NIH3T3 cells transformed by constitutively activated mutant of MEK, indicating the possibility that oncogene-induced morphological change is not necessarily induced by common signaling pathway such as MAP kinase cascade. In oxamflatin-treated DT cells, the expression of transcription factor junD was highly augmented, resulting in trans-activation of fibronectin gene by junD via cyclic AMP responsive element in its promoter. This behavior of junD was confirmed to correlate well with partial blocking of malignant phenotype in DT cells. Thus, oxamflatin can be categorized as the first reagent which induces genes whose products can interfere with oncogene-dependent transformation.
 ...
PMID:Oxamflatin: a novel compound which reverses malignant phenotype to normal one via induction of JunD. 870 May 40

The effects of cyclic AMP on mitogen-activated protein (MAP) kinase activation were investigated in 3T3-F442A preadipocytes. Several agents, which raise intracellular cyclic AMP levels by distinct mechanisms, induced a transient activation of the p42 and p44 isoforms of MAP kinase and of a MAP kinase kinase. Activation of MAP kinase by cyclic AMP was prevented by two distinct inhibitors of cyclic AMP-dependent protein kinase and by PD 098059, a specific inhibitor of the activation of the MAP kinase kinase MEK 1. Therefore, in contrast to most cell types studied, cyclic AMP exerts a positive influence on the MAP kinase pathway in 3T3-F442A preadipocytes at a level upstream of the activation of MAP kinase kinase.
 ...
PMID:Cyclic AMP stimulates the phosphorylation and activation of p42 and p44 mitogen-activated protein kinases in 3T3-F442A preadipocytes. 871 15

Extracellular signal-regulated protein kinases (ERKs) are members of the mitogen-activated protein kinase family that are rapidly phosphorylated and activated in response to various extracellular stimuli, including growth factors. Of these, the ERK1 and ERK2 forms are by far the most abundant and the most studied. Much less is known about other ERK forms, including one previously designated ERK4 on the basis of its cross-reactivity with ERK1 and ERK2. We report here that ERK4 in rat PC12 pheochromocytoma cells can be immunoprecipitated by anti-ERK antiserum R2 and have used this re-agent to characterize this species further. We find that ERK4 rapidly becomes tyrosine-phosphorylated in response to nerve growth factor (NGF) and epidermal growth factor (EGF) and, to a lesser degree, in response to insulin and a permeant cyclic AMP analogue. As in the case of ERK1 and ERK2, tyrosine phosphorylation of ERK4 occurs by a ras-dependent pathway in response to NGF and EGF and shows prolonged kinetics for NGF but not EGF treatment. Recognition by multiple antisera directed against various domains of ERK1 supports classification of ERK4 within the ERK family; however, two-dimensional gel analysis clearly distinguishes ERK4 from isoforms of ERK1. These findings thus reveal an additional member of the ERK family that is responsive to growth factors and that could play a distinct role in intracellular signaling.
 ...
PMID:Tyrosine phosphorylation of extracellular signal-regulated protein kinase 4 in response to growth factors. 876 83

The expression of cytokine-induced neutrophil chemoattractants (CINC-1 and CINC-2) mRNA was studied in rat peritoneal cells stimulated with insoluble IgG/ovalbumin immune complexes. A dose- and time-dependent induction was observed in adherent cells, which was more prominent than that induced by the lipid mediator platelet-activating factor (PAF), comparable to that observed in response to 10 micrograms endotoxin in the absence of lipopolysaccharide (LPS)-binding protein, but lower than that produced by 1 mM dibutyryl cyclic AMP, a compound which stabilized transiently expressed genes containing AU-rich sequences in the 3' untranslated region. Analysis of CINC-1 protein by specific enzyme-linked immunosorbent assay confirmed the presence of CINC-1 in the supernatants at concentrations of approximately 4 nM, 4 h after addition of 100 micrograms/ml immune complexes. CINC-2 beta protein was detectable at a lower concentration (approximately 0.3 nM) under the same conditions. Attempts to relate CINC-1 induction with the pathways for cytoplasmic signaling showed a dissociation of Ca2+ mobilization and protein kinase C activation as judged from the small effect of thapsigargin and the lack of effect of phorbol ester. In contrast, these agents produced a marked mobilization of arachidonate linked to the MAP kinase-dependent activation of cytosolic phospholipase A2. The possible dependence of CINC-1 induction on the autocrine generation of lipid mediators was ruled out by a set of experiments including the use of the PAF receptor antagonist BB823, and the analysis of the effect of free arachidonate and leukotriene B4 on CINC-1 induction. Surprisingly, the inhibitor of leukotriene synthesis MK-886 in the range of concentration 1-10 microM inhibited CINC-1 induction by a mechanism that appears to be independent of its effect on eicosanoid production. Interestingly, CINC-1 induction appeared to be related to protein tyrosine phosphorylation reactions on the basis of both the appearance of several tyrosine-phosphorylated protein bands in lysates from adherent peritoneal cells treated with immune complexes and the complete blockade of CINC-1 induction by treatment with 1 microM herbimycin A, an inhibitor of src protein tyrosine kinases.
 ...
PMID:The expression of cytokine-induced neutrophil chemoattractants (CINC-1 and CINC-2) in rat peritoneal macrophages is triggered by Fc gamma receptor activation: study of the signaling mechanism. 881 63

The wis1 protein kinase of Schizosaccharomyces pombe is a member of the MAP kinase kinase family. Loss of wis1 function has previously been reported to lead to a delay in the G2-mitosis transition, loss of viability in stationary phase, and hypersensitivity to osmotic shock. It acts at least in part by activating the MAP kinase homologue sty1; loss-of-function sty1 mutants share many phenotypes with wis1 deletion mutants. We show here that, in addition, loss of wis1 function leads to defective conjugation, and to suppression of the hyperconjugation phenotype of the pat1-114 mutation. Consistent with this, the induction of the mei2 gene, which is normally induced by nitrogen starvation, is defective in wis1 mutants. In wild-type cells, nitrogen starvation leads to mei2 induction through a fall in intracellular cyclic AMP (cAMP) level and activity of the cAMP-dependent protein kinase. We show here that wis1 function is required for mei2 induction following nitrogen starvation. Expression of the fbp1 gene is negatively regulated by cAMP in response to glucose limitation: induction of fbp1 also requires wis1 and sty1 function. Loss of wis1 is epistatic over increased fbp1 expression brought about by loss of adenylate cyclase (git2/cyr1) or cAMP-dependent protein kinase (pka1) function. These observations can be explained by a model in which the pka1 pathway negatively regulates the wis1 pathway, or the two pathways might act independently on downstream targets. The latter explanation is supported, at least as regards regulation of cell division, by the observation that loss of function of the regulatory subunit of the cAMP-dependent protein kinase (cgs1) brings about a modest increase in cell length at division in both wis1+ and wis1 delta genetic backgrounds.
 ...
PMID:The wis1 signal transduction pathway is required for expression of cAMP-repressed genes in fission yeast. 883 15

The agents which increase intracellular cyclic AMP (cAMP) or cyclic GMP (cGMP) have been found to counteract the effects of the vasoconstrictive agents such as endothelin-1 (ET-1). To clarify the mechanism of this interaction, we evaluated the activities of mitogen-activated protein kinase (MAPK) cascade, one of the important signal transduction system of ET-1. Beraprost sodium, an analogue of PGI2, and adrenomedullin, a cAMP-raising agent, inhibited ET-1-induced activation of MAPK. Dibutyryl cAMP (Bt2-cAMP) and 8-bromo-cGMP (8-Br-cGMP), cell permeable analogues of cAMP and cGMP, were also able to inhibit the activation of MAPK and MAPK kinase (MAPKK) by ET-1 without interfering basal activities. In contrast, phorbol 12, 13-dibutylate (PDBu)-induced activation of MAPK and MAPKK was inhibited by Bt2-cAMP but not by 8-Br-cGMP. Interestingly, atrial natriuretic peptide (ANP) partially inhibited PDBu-induced activation of MAPK and MAPKK. These results indicate that cAMP and cGMP inhibit ET-1-induced activation of MAPK in cultured mesangial cells at different steps; the former might inhibit at a step downstream of PKC and the latter prior to PKC. The data also suggest that ANP might have cGMP-independent effect on MAPK.
 ...
PMID:Differential inhibition of mesangial MAP kinase cascade by cyclic nucleotides. 884 Feb 64

Recent experiments have shown that the inactivation of a protein kinase, pat1, and the activation of an RNA-binding protein, mei2, commit fission yeast cells to enter meiosis. Both the cyclic AMP cascade and the mitogen-activated protein kinase cascade seem to be involved in this activation/inactivation. An RNA molecule that cooperates with mei2 to play a critical role in the promotion of meiosis I has also been identified.
 ...
PMID:The molecular control mechanisms of meiosis in fission yeast. 884 33

The mitogenic effect of extracellular ATP was examined in cultured rat aortic smooth muscle cells (VSMCs). ATP, 2-methylthio-ATP, and ADP stimulated [3H]thymidine and [3H]leucine incorporation and cell growth. AMP, adenosine, UTP, and P2x agonists showed little of these effects. Reactive blue 2, a P2Y purinoceptor antagonist, was effective in suppressing the mitogenic effect of ATP and 2-methylthio-ATP, indicating that extracellular ATP-induced VSMC proliferation is mediated by P2Y purinoceptors. The P2Y purinoceptor activation was coupled to a pertussis toxin (PTX)-insensitive G protein (Gq) and triggered phosphoinositide hydrolysis with subsequent activation of protein kinase C (PKC), Raf-1, and mitogen-activated protein kinase (MAPK) in VSMCs. In response to ATP, both 42-and 44-kDa MAPKs were activated, and tyrosine was phosphorylated. Western blot analysis using PKC isozyme-specific antibodies indicated that VSMCs express PKC-alpha, PKC-delta, and PKC-zeta. A complete down-regulation of PKC-alpha and PKC-delta was seen after 24-hr treatment with 12-O-tetradecanoylphorbol-13-acetate. When cells were pretreated with 12-O-tetradecanoyl-phorbol-13-acetate for 24 hr and subsequently challenged with ATP, Raf-1 activation and 42-kDa as well as 44-kDa MAPK tyrosine phosphorylation failed to be induced. These results demonstrate that ATP-induced Raf-1 and MAPK activations involve the activation of PKC-alpha and PKC-delta. P2Y purinoceptor stimulation with ATP also caused accumulation of c-fos and c-myc mRNAs. Both Reactive blue 2 and staurosporine significantly blocked this increase by ATP. In conclusion, the mitogenic effect of ATP seemed to be triggered by activation of the Gq protein-coupled P2Y purinoceptor that led to the formation of inositol trisphosphate and activation of PKC. PKC and, in turn, Raf-1 and MAPK were then activated, leading eventually to DNA synthesis and cell proliferation.
 ...
PMID:Mechanism of extracellular ATP-induced proliferation of vascular smooth muscle cells. 949 67

Fibroblast growth factor (FGF) activates a protein kinase cascade in SK-N-MC cells that regulates gene expression at a cyclic-AMP response element (CRE) by stimulating the transcriptional activity of CREB. The activation of CREB is prevented by a dominant negative mutant of Ras and triggered via the same site (Ser133) that becomes phosphorylated in response to cyclic AMP and Ca2+. However, the effect of FGF is not mediated by cyclic AMP-dependent protein kinase, TPA-sensitive isoforms of protein kinase-C, p70S6K or p90rsk (all of which phosphorylate CREB at Ser133 in vitro). Instead, we identify the FGF-stimulated CREB kinase as MAP kinase-activated protein (MAPKAP) kinase-2, an enzyme that lies immediately downstream of p38 MAP kinase, in a pathway that is also stimulated by cellular stresses. We show that MAPKAP kinase-2 phosphorylates CREB at Ser133 in vitro, that the FGF- or stress-induced activation of MAPKAP kinase-2 and phosphorylation of CREB and ATF-1 are prevented by similar concentrations of the specific p38 MAP kinase inhibitor SB 203580, and that MAPKAP kinase-2 is the only detectable SB 203580-sensitive CREB kinase in SK-N-MC cell extracts. We also show that transfection of RK/p38 MAP kinase in SK-N-MC cells, but not transfection of p44 MAP kinase, activates Gal4-CREB-dependent transcription via Ser133. These findings identify a new growth factor and stress-activated signaling pathway that regulates gene expression at the CRE.
 ...
PMID:FGF and stress regulate CREB and ATF-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2. 888 54


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