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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism by which 12-O-tetradecanoylphorbol-13-acetate (TPA) triggers cell-cycle progression at G1 phase in mouse embryonic fibroblast C3H 10T1/2 cells was examined. TPA treatment resulted in a temporary induction of cyclin D1 peaking at 9 h post stimulation. PD98059 (10 microM), the specific inhibitor of MAPK kinase, completely blocked TPA-stimulated cyclin D1 induction and DNA synthesis, confirming that MAPK activation plays an essential role in TPA-stimulated cell-cycle progression. Although both PKCalpha and PKCepsilon are expressed in C3H 10T1/2 cells, inhibitor studies suggest that PKCepsilon activation is required for the activation of MEK/MAPK signal transduction cascade. p70s6K, an important kinase involved in the regulation of protein synthesis and cell-cycle progression, has been reported to be activated through a PKC-dependent pathway (TPA-activatable) in addition to a PI3K-dependent pathway. Here, we demonstrate for the first time that TPA-stimulated MAPK activation is essential for the phosphorylation of several key residues involved in the activation of p70s6K, namely, thr389, thr421, and ser424. Vanadate, the tyrosine phosphatase inhibitor, triggered a sustained elevation of the level of active MAPK. However, corresponding to a rapid loss of cyclin D1 protein, vanadate treatment resulted in a significant shut out of 3H-thymidine incorporation into DNA regardless of TPA cotreatment. Vanadate treatment also led to the increase of active MEK, increased phosphorylation of p70s6K at thr389, thr421, and ser424 yet without activation of PKB. These data suggest that vanadate can selectively perturb the activation of signaling components which raises the interesting issue as to how vanadate downregulates the cyclin D1 level.
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PMID:Modulation of cyclin D1 and its signaling components by the phorbol ester TPA and the tyrosine phosphatase inhibitor vanadate. 1116 72

Members of the AF4/FMR2 family of nuclear proteins are involved in human diseases such as acute lymphoblastic leukemia and mental retardation. Here we report the identification and characterization of the Drosophila lilliputian (lilli) gene, which encodes a nuclear protein related to mammalian AF4 and FMR2. Mutations in lilli suppress excessive neuronal differentiation in response to a constitutively active form of Raf in the eye. In the wild type, Lilli has a partially redundant function in the Ras/MAPK pathway in differentiation but it is essential for normal growth. Loss of Lilli function causes an autonomous reduction in cell size and partially suppresses the increased growth associated with loss of PTEN function. These results suggest that Lilli acts in parallel with the Ras/MAPK and the PI3K/PKB pathways in the control of cell identity and cellular growth.
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PMID:Lilliputian: an AF4/FMR2-related protein that controls cell identity and cell growth. 1117 3

In G0/G1 cell cycle arrested mouse Y1 adrenocortical tumor cells ACTH39, a weak mitogen and strong anti-mitogenic agent, blocks FGF2 mitogenic activity at G1 phase, keeping untouched ERK-MAPK activation and c-Fos protein induction. Here we report two anti-mitogenic mechanisms initiated in ACTH receptors and mediated by cAMP/PKA: a) post-transcriptional down regulation of c-Myc protein; b) dephosphorylation of AKT/PKB. In Y-1 cells the activity of the Mad/Max/Myc network of transcription factors seems to be regulated by c-Myc levels. FGF2 induces c-myc gene and stabilizes c-Myc protein by a process dependent on ERK-MAPK (PD98059 sensitive), but not on PI3K (Wortmannin resistant). ACTH39, on the other hand, causes rapid decrease in c-Myc levels induced by FGF2 in wild type Y1 cells, but not in PKA-deficient Y1 clones. The ACTH inhibition of DNA synthesis stimulated by FGF2 is reversed by transient transfection and induction of the MycER chimera (fusion of c-Myc and estrogen-receptor), suggesting that c-Myc down regulation is an efficient anti-mitogenic mechanism activated by ACTH. Y1 cells display high constitutive levels of AKT/PKB, that is dependent on elevated Ras x GTP. FGF2 up regulates Ras x GTP, PI3K and AKT/PKB. ACTH antagonizes this mitogenic effect of FGF2, promoting rapid dephosphorylation of AKT/PKB.
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PMID:Signal transduction in G0/G1-arrested mouse Y1 adrenocortical cells stimulated by ACTH and FGF2. 1119 59

Grb10 is a member of a family of adapter proteins that binds to tyrosine-phosphorylated receptors including the insulin receptor kinase (IRK). In this study recombinant adenovirus was used to over-express hGrb10zeta, a new Grb10 isoform, in primary rat hepatocytes and the consequences for insulin signaling were evaluated. Over-expression of hGrb10zeta resulted in 50% inhibition of insulin-stimulated IRK autophosphorylation and activation. Analysis of downstream events showed that hGrb10zeta over-expression specifically inhibits insulin-stimulated glycogen synthase (GS) activity and glycogen synthesis without affecting insulin-induced IRS1/2 phosphorylation, PI3-kinase activation, insulin like growth factor binding protein-1 (IGFBP-1) mRNA expression, and ERK1/2 MAP kinase activity. The classical pathway from PI3-kinase through Akt-PKB/GSK-3 leading to GS activation by insulin was also not affected by hGrb10zeta over-expression. These results indicate that hGrb10zeta inhibits a novel and presently unidentified insulin signaling pathway leading to GS activation in liver.
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PMID:Specific inhibition by hGRB10zeta of insulin-induced glycogen synthase activation: evidence for a novel signaling pathway. 1122 74

Stimulation of osteoblast survival signals may be an important mechanism of regulating bone anabolism. Protein kinase B (PKB/Akt), a serine-threonine protein kinase, is a critical regulator of normal cell growth, cell cycle progression, and cell survival. In this study we have investigated the signaling pathways activated by growth factors PDGF-BB, EGF, and FGF-2 and determined whether PDGF-BB, EGF, and FGF-2 activated Akt in human or mouse osteoblastic cells. The results demonstrated that both ERK1 and ERK2 were activated by FGF-2 and PDGF-BB. Activation of ERK1 and ERK2 by PDGF-BB and FGF-2 was inhibited by PD 098059 (100 microM), a specific inhibitor of MEK. Wortmannin (500 nM), a specific inhibitor of phosphatidylinositol 3-kinase ( PI 3-K), inhibited the activation of ERK1 and ERK2 by PDGF-BB but not by FGF-2 suggesting that PI 3-K mediated the activation of ERK MAPK pathway by PDGF-BB but not by FGF-2. Rapamycin, an inhibitor of p70 S6 protein kinase and a downstream target of ERK1/2 and PI 3-K, did not affect the activation of ERK1 and ERK2 by the growth factors. Furthermore, our results demonstrated that Akt, a downstream target of PI 3-K, was activated by PDGF-BB but not by FGF-2. Akt activation by PDGF-BB was inhibited by PI 3-kinase inhibitor LY294002. Rapamycin had no effect on Akt activation. Epidermal growth factor (EGF) also activated Akt in osteoblastic cells which was inhibited by LY294002 but not by rapamycin. Taken together, our data for the first time revealed that the activation of ERK1/2 by PDGF-BB is mediated by PI 3-K, and secondly, Akt is activated by PDGF-BB and EGF but not by FGF-2 in human and mouse osteoblastic cells. These results are of critical importance in understanding the role of these growth factors in apoptosis and cell survival. PDGF-BB and EGF but not FGF-2 may stimulate osteoblast cell survival.
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PMID:The cell survival signal Akt is differentially activated by PDGF-BB, EGF, and FGF-2 in osteoblastic cells. 1124 70

The serine/threonine kinase Akt/PKB is a potent regulator of cell survival and has oncogenic transformation potential. Previously, it has been shown that Akt can activate the transcription factor NF-kappaB and that this functions to block apoptosis induced by certain stimuli. The mechanism whereby Akt activates NF-kappaB has been controversial, with evidence supporting induction of nuclear translocation of NF-kappaB via activation of IkappaB kinase activity and/or the stimulation of the transcription function of NF-kappaB. Here we demonstrate that Akt targets the transactivation function of NF-kappaB by stimulating the transactivation domain of RelA/p65 in a manner that is dependent on IkappaB kinase beta activity and on the mitogen-activated protein kinase p38 (p38). Activation of RelA/p65 transactivation function requires serines 529 and 536, sites shown previously to be inducibly phosphorylated. Consistent with the requirement of p38 in the activation of NF-kappaB transcriptional function, expression of activated Akt induces p38 activity. Furthermore, the ability of IL-1beta to activate NF-kappaB is known to involve Akt, and we show here that IL-1beta induces p38 activity in manner dependent on Akt and IkappaB kinase activation. Interestingly, activated Akt and the transcriptional co-activators CBP/p300 synergize in the activation of the RelA/p65 transactivation domain, and this synergy is blocked by p38 inhibitors. These studies demonstrate that Akt, functioning through IkappaB kinase and p38, induces the transcription function of NF-kappaB by stimulating the RelA/p65 transactivation subunit of NF-kappaB.
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PMID:Akt stimulates the transactivation potential of the RelA/p65 Subunit of NF-kappa B through utilization of the Ikappa B kinase and activation of the mitogen-activated protein kinase p38. 1125 36

The modulation of GnT-V activity by signaling molecules in PI-3-K/PKB pathway in human hepatocarcinoma cell line 7721 was studied. GnT-V activity was determined after the transfection of sense or antisense cDNA of PKB into the cells, as well as the addition of activators, specific inhibitors, and the antibodies to the enzyme assay system or culture medium. It was found that the basal activity of GnT-V was up regulated by the sense and down regulated by the antisense cDNA of PKB transfected into 7721 cells. GnT-V was activated by PIP2, PIP3 or GTPgamma[S] added to the assay system, and the activation of PIP2 or GTPgamma[S] was abolished by LY2940002, a specific inhibitor of PI-3-K, but the activation of PIP3 was not attenuated by LY2940002. In addition, GnT-V activity in cultured parental or H-ras transfected cells was inhibited by the antibody against PKB or PI-3-K. These findings demonstrated the involvement of PI-3-K/PKB signaling pathway in the regulation of GnT-V. Moreover, ET18-OCH3, an inhibitor of Raf translocation and PI-PLC enzyme, which produces the activator of PKC, as well as the antibodies against Raf-1 or MEK also inhibited GnT-V activity in the parental and H-ras transfected cells. The inhibitory rates, however, were less in the transfected cells than those in the parental cells. These results reveal that in parental and H-ras transfected 7721 cells, the basal activity of GnT-V is also regulated by the Ras/Raf-1/MEK/MAPK cascade in addition to PI-3-K/PKB signaling pathway. The significance of these two pathways in the regulation of GnT-V and their relations to the activation of PKC previously reported by our laboratory (Ju TZ et al., 1995 Glyconjugate J 12, 767-772) was discussed.
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PMID:Modulation of the basal activity of phosphatidylinositol-3-kinase/protein kinase B signaling pathway in human hepatocarcinoma cells. 1126 40

Cyclooxygenase (COX) 2 expression is regulated via the Ras signaling pathway, and induction of mutated Ras rapidly increases COX-2 levels in intestinal epithelial cells. Protein kinase B (Akt/PKB) is an important effector of Ras signaling and a critical component of Ras-mediated transformation. Here we investigate the role of Akt/PKB in K-Ras-mediated induction of COX-2. Rat intestinal epithelial cells (IEC-6) were transfected with an inducible K-RasVal12 cDNA (IEC-iK-Ras cells). Addition of 5 mM isopropyl-1-thio-beta-D-galactopyranoside induced the expression of K-RasVal12, followed by increased activity of extracellular signal-regulated kinase and Akt/PKB. COX-2 levels were dramatically increased after induction of K-RasVal12. Inhibition of MAPK/ERK kinase activity by PD 98059 completely blocked the K-Ras-mediated induction of COX-2, whereas inhibition of PI3K/Akt/PKB activity with LY 294002 or by expressing a dominant negative Akt (Akt-K179M) partially blocked the induction of COX-2 by K-Ras. Transient transfection of cells with phosphatidylinositol 3-kinase and Akt expression vectors revealed that PI3/Akt/PKB activity predominantly regulates the stability of COX-2 mRNA. Thus, Akt/PKB activity is involved in K-Ras-induced expression of COX-2 and stabilization of COX-2 mRNA largely depends on the activation of Akt/PKB.
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PMID:K-Ras-mediated increase in cyclooxygenase 2 mRNA stability involves activation of the protein kinase B1. 1128 46

The lipid phosphatase SHIP2 (SH2 domain containing inositol 5-phosphatase 2) has recently been shown to be a potent negative regulator of insulin signaling and insulin sensitivity in vivo. We show here that SHIP2 is expressed in Chinese hamster ovary cells overexpressing the insulin receptor (CHO-IR cells) and tyrosine phosphorylated upon insulin stimulation. We show that SHIP2, which is recruited in anti-phosphotyrosine immunoprecipitates in insulin-stimulated cells, accounts for the insulin sensitivity or apparent increase in activity reported by Guilherme et al. (J. Biol. Chem. 271, 29533-29536, 1996). Overexpression of SHIP2 led to a decrease of the insulin-dependent PIP3 production as well as Akt/PKB activation and MAPK stimulation.
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PMID:The SH2 domain containing inositol 5-phosphatase SHIP2 controls phosphatidylinositol 3,4,5-trisphosphate levels in CHO-IR cells stimulated by insulin. 1140 40

Stimulation of Gq-coupled acetylcholine muscarinic receptors leads to proliferation of astroglial cells, but the signal transduction pathway(s) that mediate this mitogenic response have not been fully elucidated. In this study, we report on the ability of carbachol to stimulate the phosphorylation of Akt/PKB, an important target of phosphatidylinositol 3 kinase (PI3 kinase) in 1321N1 human astrocytoma cells. Carbachol induced a dose-dependent phosphorylation of Ser473 on Akt, peaking after 15 min. This effect was mediated by activation of the M3 subtype of muscarinic receptors and was inhibited by two PI3 kinase inhibitors. Inhibitors of protein kinase C, mitogen-activated protein kinase and p70S6 kinase, had no effect on carbachol-induced Akt phosphorylation. Carbachol-induced DNA synthesis was strongly inhibited by two PI3 kinase inhibitors, wortmannin and LY294002, suggesting that PI3 kinase activation plays an important role in carbachol-induced proliferation 1321N1 astrocytoma cells.
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PMID:Activation of phosphatidylinositol 3 kinase by muscarinic receptors in astrocytoma cells. 1140 31


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