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:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our previous work has demonstrated that the insulin-like growth factors (IGFs), acting through a single receptor, stimulate both proliferation and differentiation of L6A1 myoblasts. This unique model system has enabled us to closely examine the switch that regulates these two opposing responses. We have previously shown, using specific inhibitors of the IGF-I signal transduction pathway, that the mitogenic response is mediated by the Ras/Raf/MAP kinase pathway and the myogenic response by the PI 3-kinase/p70s6k pathway (Coolican SA, Samuel DS, Ewton DZ, McWade FJ, Florini JR, J Biol Chem 1997; 272: 6653-62). In that study we found that PD098059, an inhibitor of MEK activation, inhibited the proliferative response, but dramatically enhanced IGF-stimulated differentiation which was associated with elevation of p70s6k activity. Since there have been reports of elevation of Raf-1 activity in PD098059-treated L6 myoblasts, and stimulation of p70s6k activity in cells expressing an activated Raf-1, it was important to determine whether or not Raf-1 elevation plays a role in the myogenic response. To test this, we have transfected L6A1 myoblasts with delta Raf-1:ER, an estradiol-regulated form of oncogenic Raf-1. We found that activation of Raf-1 by estradiol resulted in increased phosphorylation of p42 and p44 MAP kinases and stimulation of proliferation. In contrast, Raf-1 activation inhibited all measured aspects of the myogenic response: myogenin expression, creatine kinase elevation, and fusion of myoblasts to form myotubes. In addition, we found no elevation of p70s6k activity upon Raf-1 activation. These results indicate the following: (1) stimulation of myogenic differentiation by PD098059 treatment is not simply due to the elevation of Raf-1, (2) Raf-1 has a positive role in the MAP kinase pathway and myoblast proliferation, and (3) Raf-1 activation inhibits myogenesis, possibly by forcing cells to remain in the proliferative state.
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PMID:Raf-1 activation stimulates proliferation and inhibits IGF-stimulated differentiation in L6A1 myoblasts. 1022 82

Granulocyte-macrophage colony-stimulating factor (GM-CSF) transmits anti-apoptotic signals in eosinophils and is involved in tissue eosinophilia at the site of allergic inflammation. We determined whether phosphatidylinositol 3-kinase (PI 3-kinase) and mitogen-activated protein kinase (MAP kinase) are involved in anti-apoptotic signals of GM-CSF in eosinophils. GM-CSF phosphorylated Akt, a downstream component of PI 3-kinase, and MAP kinases (ERK1 and ERK2) at 10 min after stimulation in eosinophils. GM-CSF prevented eosinophil apoptosis and sustained its survival during the 5-day culture. However, neither two PI-3 kinase inhibitors, wortmannin and LY294002, nor MEK inhibitor PD98059 inhibited GM-CSF-induced survival of eosinophils, although wortmannin and PD98059 inhibited GM-CSF-induced Akt phosphorylation and MAP kinase activation in eosinophils, respectively. In contrast, JAK2 inhibitor AG-490 inhibited both GM-CSF-induced JAK2 phosphorylation and cell survival in eosinophils. These results indicate that activation of JAK2, but not activation of PI 3-kinase/Akt and MAP kinase pathways, is critical for anti-apoptotic signals of GM-CSF in human eosinophils. Our findings suggest that manipulation of JAK2 activation would be useful for the treatment of allergic disorders.
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PMID:Involvement of JAK2, but not PI 3-kinase/Akt and MAP kinase pathways, in anti-apoptotic signals of GM-CSF in human eosinophils. 1033 1

In this study we show that platelet-derived growth factor (PDGF)-induced DNA binding as well as transcriptional activation of Stat5b are markedly increased by inhibition of the MAP (mitogen-activated protein) kinase kinase MEK. In addition to the previously demonstrated tyrosine phosphorylation, we show that serine and threonine phosphorylation of Stat5b is increased in response to PDGF stimulation. However, inhibition of MEK had no effect on the phosphorylation level of Stat5b or on the nuclear translocation of Stat5b. These observations indicate that MEK is a negative modulator of PDGF-induced Stat5b activation through a mechanism not involving direct phosphorylation of Stat5b.
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PMID:MEK is a negative regulator of Stat5b in PDGF-stimulated cells. 1035 46

In addition to important roles in the regulation of cell growth and cell restitution, both pro- and anti-inflammatory effects have been ascribed to TGFbeta in intestinal epithelial cells. However, the mechanisms involved in TGFbeta-dependent anti-inflammatory activities remain to be determined. In the rat intestinal epithelial cell line IEC-6, TGFbeta attenuated the glucocorticoid-dependent increases in mRNA levels of the acute phase protein gene haptoglobin, and of C/EBP isoforms beta and delta. Supershift assays demonstrated a TGFbeta-mediated decrease in the binding of C/EBP isoforms beta and delta to the haptoA and haptoC C/EBP DNA-binding sites from the haptoglobin promoter. Mutations of both HaptoA and HaptoC sites abolished the glucocorticoid-dependent activation and the TGFbeta-mediated attenuation of the haptoglobin promoter, as assessed by transient transfection assays. TGFbeta induced p42/p44 MAP kinase activities. Treatment with the MEK 1/2 inhibitor PD 98059 abolished TGFbeta attenuation. These results suggest that C/EBP isoforms are involved both in the glucocorticoid-dependent induction and in the TGFbeta-mediated attenuation of haptoglobin expression. Furthermore, p42/p44 MAP kinases may function in a TGFbeta-dependent signaling pathway leading to attenuation of haptoglobin expression.
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PMID:Attenuation of haptoglobin gene expression by TGFbeta requires the MAP kinase pathway. 1036 55

The mechanism of Taxol-induced apoptosis was investigated in MCF-7 human breast carcinoma cells. Taxol-induced apoptosis was associated with phosphorylation of both c-Raf-1 and Bcl-2 and activation of ERK and JNK MAP kinases. The serine protease inhibitor N-tosyl-L-phenylalanine chloromethyl ketone (TPCK) effectively blocked apoptosis, but N-p-tosyl-L-lysine chloromethyl ketone (TLCK), another serine protease inhibitor, was without effect. TPCK treatment also prevented phosphorylation of c-Raf-1 and Bcl-2 in response to Taxol treatment. The serine protease inhibitor did not alter JNK activity, but it enhanced Taxol-induced activation of ERK1/2. Treatment of cells with the inhibitor of MEK activation, PD98059, prevented Taxol-induced ERK activation both in the presence and absence of TPCK, but did not influence survival of either Taxol- or Taxol plus TPCK-treated cells. In addition, PD98059 had no effect on c-Raf-1 or Bcl-2 phosphorylation. Thus, while the Taxol-induced phosphorylations of c-Raf-1 and Bcl-2 proteins appear to be coupled, these events can be disassociated from ERK1/2 activation. In summary, these findings suggest that phosphorylation of c-Raf-1 and Bcl-2, but not ERK1/2, are important signaling events in Taxol-induced apoptosis of MCF-7 breast cancer cells and that a TPCK inhibitable protease(s) is required for these processes.
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PMID:Serine protease inhibitor TPCK prevents Taxol-induced cell death and blocks c-Raf-1 and Bcl-2 phosphorylation in human breast carcinoma cells. 1037 21

The implication of MAP kinases in the proliferation control of pancreatic cancer cells is still unknown. This study was undertaken to examine the contribution of the p44/p42 and p38 MAP kinases in the mitogenic response to epidermal growth factor (EGF) and bombesin in human pancreatic cancer cells, MIA PaCa-2 and PANC-1. Data indicate that EGF and bombesin stimulated growth of both cell lines. In MIA PaCa-2 cells, EGF and bombesin stimulated the in gel activation of p38 while p44/p42 kinases exhibited high basal activity and no response to stimuli. Growth and p38 activation were inhibited by genistein, wortmannin, PD98059 and SB203580, specific inhibitors of tyrosine kinase, phosphatidylinositol 3-kinase, MEK-1 and p38 kinases, respectively. In PANC-1 cells, EGF and bombesin stimulated p42 in gel activation; p44 remained highly activated and unresponsive to stimuli and p38 did not respond. Stimulated growth and p42 activation were inhibited by genistein, wortmannin and PD98059. Estimation of MAPK activities with a specific anti-active MAP kinase antibody indicated, however, that EGF increased the intensity of the bands corresponding to p42 and p44 MAP kinases in both cell lines, indicating that the mitogenic factor can regulate MAP kinase activity. Data also pointed out that ATP is sufficient to increase MAP kinase activity within the in gel assay technique and may thus explain the discrepancies existing between the in gel assay data and those obtained with the anti-active MAP kinase antibody.
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PMID:Activation of MAP kinases in growth responsive pancreatic cancer cells. 1043 20

Mn(2+) treatment has been shown to promote neurite outgrowth in rat pheochromocytoma (PC12) cells in a time- and dose-dependent manner. This process is mediated through the interactions of extracellular matrix (ECM) proteins and integrin receptors. Studies were performed to determine whether the phosphorylation of the MAP kinases, ERK1 and 2, is required for Mn(2+)-induced neurite outgrowth. A time- and dose-dependent increase in phosphorylation of both ERK1 and 2 was observed upon treatment of PC12 cells with Mn(2+). Phosphorylation of the ERKs occurred as early as 2 hr after initiating treatment, with a maximum increase occurring at approximately 24 hr. Inhibition of MEK with the specific inhibitor, PD98059, blocked the phosphorylation of ERK1 and 2 and increased Mn(2+) toxicity. When cells were grown in serum-free defined medium, Mn(2+)-induced phosphorylation of ERK1 and ERK2 occurred in cells grown on surfaces treated with growth serum or fibronectin but not on surfaces treated with poly-L-lysine. In addition, the pentapeptide GRGDS, which blocks RGD-mediated interactions, inhibited Mn(2+)-induced phosphorylation of ERK1 and 2. The Mn(2+)-induced increase in phosphorylated ERK1 and 2 was not seen in a PC12 cell line that does not respond to Mn(2+). These data support the hypothesis that integrin-mediated activation of the MAPK signal transduction pathway leading to the activation of ERK1 and 2 is required for Mn(2+)-induced PC12 differentiation and neurite outgrowth.
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PMID:Activation of ERK1 and ERK2 is required for manganese-induced neurite outgrowth in rat pheochromocytoma (PC12) cells. 1046 56

Interleukin 1 (IL-1) activates p42/p44 and p38 mitogen-activated protein kinases (MAP kinases) in target cells. Here we have used two specific inhibitors, PD98059 which inhibits MAP kinase kinase (MEK), and SB203580 which inhibits p38 MAP kinase to explore the involvement of these kinases in the induction of IL-2 by IL-1 in the murine thymoma cell line EL4.NOB-1. Both kinase inhibitors suppressed IL-1-stimulated IL-2 production. PD98059 blocked IL-2 mRNA accumulation and the induction of a reporter gene linked to the IL-2 promoter. In contrast, SB203580 only marginally inhibited IL-2 promoter-linked reporter gene expression and had no inhibitory effect on IL-2 mRNA levels. Neither PD98059 nor SB203580 had an inhibitory effect on NFkappaB-driven reporter gene expression in response to IL-1. Surprisingly, higher concentrations of SB203580 (30 microM) potentiated the IL-1 responses. PD98059 also inhibited induction of IL-2 by phorbol 12-myristate 13-acetate (PMA), and AP1-linked reporter gene expression in response to PMA but not IL-1. These results indicate that p42/p44 MAP kinase is involved in the regulation of IL-2 gene transcription by IL-1, whilst p38 MAP kinase has a post-transcriptional target. Additional IL-1 signalling pathways can clearly compensate for the lack of p38 MAP kinase which result in potentiation of the IL-1 responses observed at high-dose SB203580.
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PMID:Distinct roles for p42/p44 and p38 mitogen-activated protein kinases in the induction of IL-2 by IL-1. 1047

Neuregulin is a neural factor implicated in upregulation of acetylcholine receptor (AChR) synthesis at the neuromuscular junction. Previous studies have demonstrated that the extracellular signal-regulated kinase (ERK) subgroup of MAP kinases is required for neuregulin-induced AChR gene expression. We report here that the neuregulin-mediated increase in AChR epsilon-subunit mRNA was a delayed response in C2C12 muscle cells. Neuregulin induced expression of immediate early genes c-jun and c-fos, which followed and depended on the ERK activation. Treatment of muscle cells with cycloheximide to inhibit c-JUN synthesis at the protein level and suppression of c-JUN function by a dominant-negative mutant blocked neuregulin-induced expression of the epsilon-subunit gene, indicating an essential role of c-JUN in neuregulin signaling. Furthermore, neuregulin activated c-JUN N-terminal kinase (JNK) in C2C12 muscle cells. Blockade of JNK activation by overexpressing dominant-negative MKK4 inhibited epsilon-promoter activation. Moreover, overexpression of the JNK dominant-negative mutant inhibited neuregulin-mediated expression of the epsilon-transgene and endogenous epsilon-mRNA. Taken together, our results demonstrate important roles of c-JUN and JNK in neuregulin-mediated expression of the AChR epsilon-subunit gene and suggest that neuregulin activates multiple signaling cascades that converge to regulate AChR epsilon-subunit gene expression.
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PMID:Essential roles of c-JUN and c-JUN N-terminal kinase (JNK) in neuregulin-increased expression of the acetylcholine receptor epsilon-subunit. 1049 50

The MAP-kinase pathways are intracellular signaling modules that are likely to exist in all eukaryotes. We provide an evolutionary model for these signaling pathways by focusing on the gene duplications that have occurred since the divergence of animals from yeast. Construction of evolutionary trees with confidence assessed by bootstrap clearly shows that the mammalian JNK and p38 pathways arose from an ancestral hyperosmolarity pathway after the split from yeast and before the split from C. elegans. These coduplications of interacting proteins at the MAPK and MEK levels have since evolved toward substrate specificity, thus giving distinct pathways. Mammalian duplications since the split from C. elegans are often associated with divergent tissue distribution but do not appear to confer detectable substrate specificity. The yeast kinase cascades have undergone similar fundamental functional changes since the split from mammals, with duplications giving rise to central signaling components of the filamentous and hypoosmolarity pathways. Experimentally defined cross-talk between yeast pheromone and hyperosmolarity pathways is mirrored with corresponding cross-talk in mammalian pathways, suggesting the existence of ancient orthologous cross-talk; our analysis of gene duplications at all levels of the cascade is consistent with this model but does not always provide significant bootstrap support. Our data also provide insights at different levels of the cascade where conflicting experimental evidence exists.
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PMID:The evolution of the MAP kinase pathways: coduplication of interacting proteins leads to new signaling cascades. 1055 38


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