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)

It has previously been argued that the repressor of protein synthesis initiation factor 4E, 4E-BP1, is a direct in vivo target of p42mapk. However, the immunosuppressant rapamycin blocks serum-induced 4E-BP1 phosphorylation and, in parallel, p70s6k activation, with no apparent effect on p42mapk activation. Consistent with this finding, the kinetics of serum-induced 4E-BP1 phosphorylation closely follow those of p70s6k activation rather than those of p42mapk. More striking, insulin, which does not induce p42mapk activation in human 293 cells or Swiss mouse 3T3 cells, induces 4E-BP1 phosphorylation and p70s6k activation in both cell types. Anisomycin, which, like insulin, does not activate p42mapk, promotes a small parallel increase in 4E-BP1 phosphorylation and p70s6k activation. The insulin effect on 4E-BP1 phosphorylation and p70s6k activation in both cell types is blocked by SQ20006, wortmannin, and rapamycin. These three inhibitors have no effect on p42mapk activation induced by phorbol 12-tetradecanoate 13-acetate, though wortmannin partially suppresses both the p70s6k response and the 4E-BP1 response. Finally, in porcine aortic endothelial cells stably transfected with either the wild-type platelet-derived growth factor receptor or a mutant receptor bearing the double point mutation 740F/751F, p42mapk activation in response to platelet-derived growth factor is unimpaired, but increased 4E-BP1 phosphorylation is ablated, as previously reported for p70s6k. The data presented here demonstrate that 4E-BP1 phosphorylation is mediated by the FRAP-p70s6k pathway and is independent of mitogen-activated protein kinase.
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PMID:4E-BP1 phosphorylation is mediated by the FRAP-p70s6k pathway and is independent of mitogen-activated protein kinase. 863 19

PHAS-I or the eIF4E-binding protein 1 regulates the cap-binding activity of eIF4E by sequestering eIF4E. Binding of elF4E to PHAS-I is regulated by phosphorylation of PHAS-I. PC12 cells were used to study the signal transduction pathway leading to phosphorylation of PHAS-I. Both EGF and NGF induced phosphorylation of PHAS-I. Wortmannin, a PI-3 kinase inhibitor, staurosporine, a PKC inhibitor, and rapamycin, a FRAP inhibitor all blocked the phosphorylation of PHAS-I. Of the three inhibitors, only wortmannin was able to inhibit MAPK phosphorylation. This excludes a role for MAPK in NGF- and EGF-induced PHAS-I phosphorylation in PC12 cells. Apparently, PHAS-I was phosphorylated in a PI-3 kinase-, PKC-, and FRAP-dependent manner after EGF or NGF stimulation. Only PI-3 kinase and FRAP are involved in the regulation of the basal level of PHAS-I phosphorylation.
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PMID:Phosphorylation of the eIF4E-binding protein PHAS-I after exposure of PC12 cells to EGF and NGF. 891 81

Glucose-6-phosphate dehydrogenase (G6PDH) controls the flow of carbon through the pentose phosphate pathway and also produces NADPH needed for maintenance of reduced glutathione and reductive biosynthesis. Hepatic expression of G6PDH is known to respond to several dietary and hormonal factors, but the mechanism behind regulation of this expression has not been characterized. We show that insulin similarly induces expression of endogenous hepatic G6PDH and a reporter construct containing 935 base pairs of the G6PDH promoter linked to luciferase in transient transfection assays. Using well tested and structurally distinct inhibitors of Ras farnesylation, lovastatin and B581, and a specific inhibitor of mitogen-activated protein kinase kinase activation, PD 98059, we show that the Ras/Raf/mitogen-activated protein kinase pathway is not utilized for the insulin-induced stimulation of G6PDH gene expression in primary rat hepatocytes. Similarly, using well characterized inhibitors of phosphatidylinositol 3-kinase, wortmannin and LY 294002, we show that PI 3-kinase activity is necessary for the induction of G6PDH expression by insulin. Rapamycin, an inhibitor of FRAP protein, which is involved in the activation of pp70 S6 kinase, blocks the insulin induction of G6PDH, suggesting that S6 kinase is also necessary for the insulin induction of G6PDH expression.
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PMID:Insulin regulation of glucose-6-phosphate dehydrogenase gene expression is rapamycin-sensitive and requires phosphatidylinositol 3-kinase. 961 3

An increase in the level of active, GTP-bound Ras is not necessary for transformation of chicken embryo fibroblasts (CEF) by v-Src. This suggests that other Ras-independent pathways contribute to transformation by v-Src. To address the possibility that activation of phosphatidylinositol-3-kinase (PI3K) and the mammalian target of rapamycin (mTOR/FRAP), represents one of these pathways, we have examined the effect of simultaneous inhibition of the Ras-MAPK and PI3K-mTOR pathways on transformation of CEF by v-Src. Transformation was assessed by the standard parameters of morphological alteration, increased hexose uptake, loss of density inhibition, and anchorage-independent growth. Inhibition of the Ras-MAPK pathway by expression of the dominant-negative Ras mutant HRasN17 or by addition of the MAPK kinase (MEK) inhibitor PD98059 reduced several of these parameters but failed to block transformation. Similarly, inhibition of the PI3K-mTOR pathway by addition of the PI3K inhibitor 2-[4-morpholinyl]-8-phenyl-4H-1-benzopyran-4-one (LY294002) or the mTOR inhibitor rapamycin, although reducing several parameters of transformation, also failed to block transformation. However, simultaneous inhibition of signaling by the Ras-MAPK pathway and the PI3K-mTOR pathway essentially blocked transformation. These data indicate that transformation of CEF by v-Src is mediated by two parallel pathways, the Ras-MAPK pathway and the PI-3K-mTOR pathway, which both contribute to transformation. The possibility that simultaneous activation of other pathways is also required is not excluded.
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PMID:Transformation by v-Src: Ras-MAPK and PI3K-mTOR mediate parallel pathways. 1035 90

We investigated a possible role of reactive oxygen species (ROS) in p70(S6k) activation, which plays an important role in the progression of cells from G(0)/G(1) to S phase of the cell cycle by translational up-regulation of a family of mRNA transcripts that encode for components of the protein synthetic machinery. Treatment of mouse epidermal cell JB6 with H(2)O(2) generated extracellularly by glucose/glucose oxidase led to the activation of p70(S6k) and p90(Rsk) and to phosphorylation of p42(MAPK)/p44(MAPK). The activation of p70(S6k) and p90(Rsk) was dose-dependent and transient, maximal activities being in extracts treated for 15 and 30 min, respectively. Further characterization of ROS-induced activation of p70(S6k) using specific inhibitors for p70(S6k) signaling pathway, rapamycin, and wortmannin revealed that ROS acted upstream of the rapamycin-sensitive component FRAP/RAFT and wortmannin-sensitive component phosphatidylinositol 3-kinase, because both inhibitors caused the inhibition of ROS-induced p70(S6k) activity. In addition, Ca(2+) chelation also inhibited ROS-induced activation of p70(S6k), indicating that Ca(2+) is a mediator of p70(S6k) activation by ROS. However, down-regulation of 12-O-tetradecanoylphorbol-13-acetate (TPA)-responsive protein kinase C (PKC) by chronic pretreatment with TPA or a specific PKC inhibitor Ro-31-8220 did not block the activation of p70(S6k) by ROS, indicating that the activation of TPA-responsive PKC was not required for stimulation of p70(S6k) activity by H(2)O(2) in JB6 cells. Exposure of JB6 cells to platelet-derived growth factor or epidermal growth factor led to a rapid increase in H(2)O(2), phosphorylation, and activation of p70(S6k), which were antagonized by the pretreatment of catalase. Taken together, the results suggest that ROS act as a messenger in growth factor-induced p70(S6k) signaling pathway.
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PMID:Hydrogen peroxide activates p70(S6k) signaling pathway. 1055 13

In order to study the role of phosphatidylinositol-3-kinase (PI3K), PKB, FRAP, S6 kinase, and MAP kinase in insulin-stimulated glycogen synthesis, we used a specific inhibitor of PI3K, LY294002, the immunosuppressant inhibitor of FRAP, rapamycin, and the inhibitor of MAPK kinase (MEK)/MAPK, PD98059, in rat HTC hepatoma cells overexpressing human insulin receptors. The PI3K inhibitor LY294002 completely blocks insulin-stimulated glycogen synthesis by inhibiting glycogen synthase, PKB (Akt-1), and FRAP (RAFT) autophosphorylation, as well as p70 S6 kinase activation, whereas insulin receptor substrates tyrosine phosphorylation and MEK activity were not affected. However, rapamycin only partially blocks insulin-stimulated glycogen synthesis by partial inhibition of glycogen synthase, whereas it completely blocks S6 kinase activation and FRAP autophosphorylation, but does not affect either PKB autophosphorylation, MEK activity, or insulin receptor tyrosine phosphorylation. Insulin-stimulated glycogen synthesis and glycogen synthase were not affected by the MEK/MAPK inhibitor PD98059. These data suggest that the PI3K, and not the MAPK pathway plays an important role in the insulin-stimulated glycogen synthesis in the hepatocyte, partly mediated by FRAP and S6 kinase activation. However, the inhibition of FRAP and S6 kinase activation is not sufficient to block insulin-stimulated glycogen synthesis, suggesting an important role of a branching pathway upstream of S6 kinase and downstream of PI3K, which is probably mediated by PKB in the signaling of the insulin receptor in hepatoma HTC cells.
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PMID:Stimulation of glycogen synthesis by insulin requires S6 kinase and phosphatidylinositol-3-kinase in HTC-IR cells. 1062 81

Since autocrine regulation of HGF-Met is implicated in many forms of human cancer, we investigated whether the predisposition to develop ovarian cancer in women with hereditary ovarian cancer syndromes involves changes in the expression of HGF-Met by the tissue of origin of epithelial ovarian cancers, the ovarian surface epithelium (OSE). We compared cultures of normal OSE from women with (FH-OSE) (n=20) and with no (NFH-OSE) (n=48) family histories of ovarian cancer, SV40 Tag immortalized OSE lines (IOSE, n=5) and ovarian cancer cell lines (n=3). Cultures derived from 21/22 women with NFH-OSE and 13/13 women with FH-OSE expressed Met mRNA initially. After two to three passages, Met was downregulated in 37% of NFH-OSE cultures but persisted in 100% of FH-OSE cultures and ovarian cancer lines, like other epithelial differentiation markers that are stabilized in FH-OSE and neoplasia. HGF and Met mRNA were concomitantly expressed by NFH-OSE from only three of 32 women but in FH-OSE from eight of 13 women, and also in five of five IOSE and two of three ovarian cancer lines. Conditioned media from FH-OSE, but not NFH-OSE, contained immunoreactive HGF and induced cohort migration which was inhibited by neutralizing HGF antibody. Several signaling molecules of the PI3K pathway, including Akt2 and p70 S6K, were constitutively activated in FH-OSE from six of six women but in NFH-OSE from only four of eight women. Exogenous HGF was mitogenic in OSE, and that effect was regulated through the MAP kinase (ERK1/ERK2) and FRAP/p70 S6K pathways. The proliferative response to HGF was greater in NFH-OSE than in FH-OSE cultures. The results show that FH-OSE cultures differ from NFH-OSE by increased stability of Met expression and by HGF secretion. Constitutive phosphorylation of kinases and a diminished growth response to HGF suggest the presence of autocrine regulation in FH-OSE. In analogy with other cell types where an autocrine HGF-Met loop has been implicated in tumorigenic transformation, this change in FH-OSE may play a role in the enhanced susceptibility to ovarian carcinogenesis in women with hereditary ovarian cancer syndromes.
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PMID:Coexpression of hepatocyte growth factor-Met: an early step in ovarian carcinogenesis? 1131 76

Alterations in gene expression represent key events in carcinogenesis. We have studied HPV-induced cervical carcinogenesis, using an HPV-33-positive cell line (UT-DEC-1) established from a low-grade vaginal dysplasia (VAIN-I). Early-passage cells contained HPV-33 in episomal form, but these were superseded at later passages by cells carrying only integrated virus. To gain insight into the biologic significance of HPV integration, we compared the level of gene expression in normal vaginal keratinocytes, early-passage and late-passage UT-DEC-1 cells, using cDNA microarrays. Total RNA was isolated from cells by CsCl-gradient centrifugation, reverse-transcribed with MMLV reverse transcriptase and labeled with alpha-(32)P ATP. A cDNA microarray expression profile analysis was performed with Clontech's Human Cancer 1.2 cDNA expression array kit. The 16 upregulated genes (cut-off 2-fold), identified by comparing both cell types to control keratinocytes, appeared to support cell-cycle progression or to be functional in mitosis. These included, e.g., MCM4 DNA replication licensing factor, cdc2p34 and chromatin assembly factor 1 p48 subunit. Downregulated genes (44 altogether) interfered with apoptosis and cell adhesion, including the apoptosis-inducing genes FRAP, Bik and caspase-9 precursor. The most significant differences between the late and early passages (29 and 46 constantly up- and downregulated genes without any fluctuation) were overexpression of the transcription factors E2F5 with its dimerization partner DP1, NF-kappa B and serine/threonine kinases and underexpression of enzymes of the MAPK pathway. Acquisition of a selective growth advantage after viral integration might be explained by a major shift from a MAPK pathway to cell-cycle dysregulation (G(2)/M).
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PMID:Transcriptional profiling of a human papillomavirus 33-positive squamous epithelial cell line which acquired a selective growth advantage after viral integration. 1211 47

Scaffold proteins play a major role in regulating MAP kinase pathways. In yeast, the Mpk1p-MAP kinase pathway functions to maintain the integrity of the cytoskeleton and the cell wall. In this module, the MEKK Bck1p functions upstream of the MEKs Mkk1p and Mkk2p, which in turn activate the MAP kinase Mpk1p. Mpk1p regulates several nuclear targets, including the transcription factors Rlm1p and SBF, and the two HMG1-like proteins NHP6A and NHP6B. Here we show that Mpk1p constitutively shuttles between the nucleus and the cytoplasm, and both Mpk1p and Mkk1p localize to sites of polarized growth in a Spa2p-dependent manner. Spa2p belongs to a group of proteins that includes Bni1p, Bud6p, and Pea2p, which are involved in the dynamic organization of the actin cytoskeleton during polarized growth. FRAP analysis shows that Spa2p-GFP is stably anchored at bud tips, whereas Mpk1p binds transiently. Spa2p interacts with Mkk1p and Mpk1p, and membrane bound Spa2p is sufficient to recruit Mkk1p and Mpk1p but not other MAP kinases to the cell cortex. Taken together, these results suggest that Spa2p functions as a scaffold-like protein for the cell wall integrity pathway during polarized growth.
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PMID:Spa2p functions as a scaffold-like protein to recruit the Mpk1p MAP kinase module to sites of polarized growth. 1236 75

In differentiated 3T3-L1 adipocytes, insulin stimulated the expression of the mRNA for the genes encoding Fra-1 (>100-fold), which is a component of the AP-1 transcriptional complex, beta-actin (6.0-fold) and hexokinase II (2.4-fold). We have examined the signalling pathways involved in these effects of insulin. Rapamycin, which binds to FRAP/mTOR and completely suppressed the activation of p70S6 kinase by insulin, almost completely blocked the induction of the hexokinase II gene, and caused an approximately 50% inhibition of the induction of the Fra-1 gene. PD98059, which completely blocks MAP kinase activation by insulin, inhibited insulin-induced Fra-1 and beta-actin gene expression by approximately 70% and 40%, respectively. These findings suggest that a FRAP/mTOR-dependent pathway is responsible for the induction of hexokinase II expression, and that MAP kinase is required, at least in part, for the stimulation of beta-actin gene expression. However, the induction of Fra-1 gene expression by insulin requires both the FRAP/mTOR and MAP kinase pathways.
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PMID:Multiple signalling pathways mediate insulin-stimulated gene expression in 3T3-L1 adipocytes. 1239 86


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