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)

BMP receptors determine the intensity of BMP signals via Smad1 C-terminal phosphorylations. Here we show that a finely controlled cell biological pathway terminates this activity. The duration of the activated pSmad1(Cter) signal was regulated by sequential Smad1 linker region phosphorylations at conserved MAPK and GSK3 sites required for its polyubiquitinylation and transport to the centrosome. Proteasomal degradation of activated Smad1 and total polyubiquitinated proteins took place in the centrosome. Inhibitors of the Erk, p38, and JNK MAPKs, as well as GSK3 inhibitors, prolonged the duration of a pulse of BMP7. Wnt signaling decreased pSmad1(GSK3) antigen levels and redistributed it from the centrosome to cytoplasmic LRP6 signalosomes. In Xenopus embryos, it was found that Wnts induce epidermis and that this required an active BMP-Smad pathway. Epistatic experiments suggested that the dorsoventral (BMP) and anteroposterior (Wnt/GSK3) patterning gradients are integrated at the level of Smad1 phosphorylations during embryonic pattern formation.
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PMID:Integrating patterning signals: Wnt/GSK3 regulates the duration of the BMP/Smad1 signal. 1804 39

Abnormal hyperphosphorylation of tau is believed to constitute a critical biochemical event in the process of neurofibrillary degeneration of Alzheimer's disease. We have developed a cellular model where apparently authentic PHF-like tau hyperphosphorylation is induced by okadaic acid. To gain deeper insight into the complex mechanisms of this pathological process we tested a variety of kinase inhibitors in this model. We found that K252a is differentiated from staurosporine by its inhibition of ERK2: both compounds are structurally related microbial metabolites generally believed to have only moderate kinase selectivity. However, since ERK2 inhibitors are exceedingly rare, we used this differential inhibitory property of K252a to demonstrate the involvement of ERK2 in PHF-type tau hyperphosphorylation. K252a was uniquely able to completely suppress the okadaic acid-induced tau hyperphosphorylation in SH-SY5Y cells and rat brain slices by way of including ERK2 in its inhibitory spectrum, and to conserve the normal binding of tau to tubulin. GSK3 inhibitors partially affected the normal state of tau phosphorylation in SH-SY5Y cells, but had no impact on okadaic acid-induced tau hyperhosphorylation. As K252a is the first molecule identified capable of preventing the spectrum of PHF-like tau hyperphosphorylation markers, it may represent a conceptual starting point for therapeutic development of suitable spectrum kinase inhibitors.
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PMID:Inhibition of PHF-like tau hyperphosphorylation in SH-SY5Y cells and rat brain slices by K252a. 1843 Sep 96

Thiadiazolidinones (TDZDs) are small molecules that inhibit glycogen synthase kinase 3-beta (GSK3-beta) activity in a non competitive manner to ATP. NP00111, a new TDZD, besides causing inhibition of GSK-3beta, has also shown to be an agonist of PPARgamma . Since phosphorylation and consequent inhibition of GSK-3beta by PI-3K/Akt and agonism of PPARgamma have shown to afford neuroprotection in several in vitro and in vivo models, we have studied the potential neuroprotective effect of NP00111 in an "in vitro" model of ischemia-reperfusion. NP00111, at the concentration of 10 microM, significantly protected adult rat hippocampal slices subjected to oxygen and glucose deprivation (OGD) for 1 h followed by 3 h re-oxygenation, measured as lactic dehydrogenase (LDH) released to the extracellular media. The protective effects of NP00111 were more pronounced during the re-oxygenation period in comparison to the OGD period. Other GSK-3beta inhibitors like lithium or AR-A014418 did not afford protection in this model. However, the PPARgamma agonist rosiglitazone was protective at 3 microM. Protection afforded by NP00111 and rosiglitazone were prevented by the PPARgamma antagonist GW9662, suggesting that both NP00111 and rosiglitazone were preventing cell death caused by oxygen-glucose deprivation via activation of PPARgamma. NP00111 increased by two fold phosphorylation of ERK1/2 and its protective effects were lost when the hippocampal slices were co-incubated with the mitogen-activated protein kinase (MAPK) inhibitor PD98059. In conclusion, the novel TDZD NP00111 was protective against OGD in rat hippocampal slices by a mechanism related to phosphorylation of ERK1/2 via activation of PPARgamma.
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PMID:Neuroprotective effect of the new thiadiazolidinone NP00111 against oxygen-glucose deprivation in rat hippocampal slices: implication of ERK1/2 and PPARgamma receptors. 1847 12

In order to evaluate the role of insulin in chicken, an insulin immuno-neutralization was performed. Fed chickens received 1 or 3 i.v. injections of anti-insulin serum (2-h intervals), while fed or fasted controls received normal serum. Measurements included insulin signaling cascade (at 1 h in liver and muscle), metabolic or endocrine plasma parameters (at 1 and 5 h), and qRT-PCR analysis (at 5 h) of 23 genes involved in endocrine regulation, metabolisms, and transcription. Most plasma parameters and food intake were altered by insulin privation as early as 1 h and largely at 5 h. The initial steps of insulin signaling pathways including insulin receptor (IR), IR substrate-1 (IRS-1), and Src homology collagen and downstream elements: phosphatidylinositol 3-kinase (PI3K), Akt, GSK3, ERK2, and S6 ribosomal protein) were accordingly turned off in the liver. In the muscle, IR, IRS-1 tyrosine phosphorylation, and PI3K activity remained unchanged, whereas several subsequent steps were altered by insulin privation. In both tissues, AMPK was not altered. In the liver, insulin privation decreased Egr1, PPAR gamma, SREBP1, THRSP alpha (spot 14), D2-deiodinase, glucokinase (GK), and fatty acid synthase (whereas D3-deiodinase and IGF-binding protein 1 transcripts were up-regulated. Liver SREBP1 and GK and plasma IGFBP1 proteins were accordingly down- and up-regulated. In the muscle, PPAR beta delta and atrogin-1 mRNA increased and Egr1 mRNA decreased. Changes in messengers were partly mimicked by fasting. Thus, insulin signaling in muscle is peculiar in chicken and is strictly dependent on insulin in fed status. The 'diabetic' status induced by insulin immuno-neutralization is accompanied by impairments of glucagon secretion, thyroid axis, and expression of several genes involved in regulatory pathways or metabolisms, evidencing pleiotropic effects of insulin in fed chicken.
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PMID:Insulin immuno-neutralization in chicken: effects on insulin signaling and gene expression in liver and muscle. 1849 18

Glargine and detemir are long-acting human insulin analogues with a smooth peakless profile of action. Although their binding affinities to the insulin receptor have been studied, little is known about the subsequent signalling properties activated after the binding. We directly compared intracellular signalling properties of them in various cultured cells. Regarding the metabolic signalling, glargine and insulin-induced comparable dose-dependent phosphorylation of insulin receptor, IRS-1, Akt, and GSK3, whereas detemir-induced kinetics were markedly lower in 3T3-L1 adipocytes and L6 myocytes. A similar pattern of phosphorylation induction was observed in primary hepatocytes and vascular smooth muscle cells (VSMCs). Because of the binding of detemir to albumin with high affinity, the phosphorylation kinetics and glucose uptake of detemir, but not glargine, decreased with increasing concentrations of BSA. Concerning the mitogenic properties, glargine and insulin-induced comparable dose-dependent phosphorylation of MAP kinase (MAPK) and 5-bromo-2'-deoxyuridine (BrdU) incorporation. Detemir-induced phosphorylation of MAPK was apparently reduced, whereas it stimulated BrdU incorporation with relatively similar dose-dependent manner in VSMCs. These results indicate that glargine has comparable properties to human insulin in metabolic and mitogenic signalling and action. In contrast, detemir-induced metabolic signaling is less potent in all cell types studied, and is reduced further by increasing concentrations of albumin.
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PMID:Characteristics of signalling properties mediated by long-acting insulin analogue glargine and detemir in target cells of insulin. 1858 15

The intensity of the BMP signal is determined by cell surface receptors that phosphorylate Smad1/5/8 at the C-terminus. In addition to this BMP-activated phosphorylation, recent studies have shown that sequential phosphorylations by MAPK and GSK3 kinases can negatively regulate the activity of the pSmad1Cter signal. These phosphorylations in the linker region cause Smad1 to be transported to the centrosomal region, polyubiquitinylated and degraded by the proteasomal machinery. In Xenopus embryos, Wnt signals, which regulate GSK3, induce ectoderm to adopt an epidermal fate, and this Wnt effect requires an active BMP-Smad1/5/8 signaling pathway. These findings have profound implications for understanding how dorsal-ventral and anterior-posterior patterning are seamlessly integrated in the early embryonic morphogenetic field.
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PMID:Integrating positional information at the level of Smad1/5/8. 1859 Aug 18

Conventional regimens have limited impact against non-small cell lung cancer (NSCLC). Current research is focusing on multiple pathways as potential targets, and this study investigated molecular mechanisms underlying the combination of the PKC beta inhibitor enzastaurin with the multitargeted antifolate pemetrexed in the NSCLC cells SW1573 and A549. Pharmacologic interaction was studied using the combination-index method, while cell cycle, apoptosis induction, VEGF secretion and ERK1/2 and Akt phosphorylation were studied by flow cytometry and ELISAs. Reverse transcription-PCR, western blot and activity assays were performed to assess whether enzastaurin influenced thymidylate synthase (TS) and the expression of multiple targets involved in cancer signaling and cell cycle distribution. Enzastaurin-pemetrexed combination was highly synergistic and significantly increased apoptosis. Enzastaurin reduced both phosphoCdc25C, resulting in G2/M checkpoint abrogation and apoptosis induction in pemetrexed-damaged cells, and GSK3 beta and Akt phosphorylation, which was additionally reduced by drug combination (-58% in A549). Enzastaurin also significantly reduced pemetrexed-induced upregulation of TS expression, possibly through E2F-1 reduction, whereas the combination decreased TS in situ activity (>50% in both cell lines) and VEGF secretion. The effects of enzastaurin on signaling pathways involved in cell cycle control, apoptosis and angiogenesis, as well as on the expression of genes involved in pemetrexed activity provide a strong experimental basis to their evaluation as pharmacodynamic markers in clinical trials of enzastaurin-pemetrexed combination in NSCLC patients.
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PMID:Molecular pathways involved in the synergistic interaction of the PKC beta inhibitor enzastaurin with the antifolate pemetrexed in non-small cell lung cancer cells. 1872 66

In this perspective, I discuss the complex interplay between GC signaling and the kinome that ultimately determines the cell fate after GC treatment. Apoptosis ensues when the cell express sufficient levels of GR and Bim together with a kinome favoring GSK3 activation. Protein kinases that prevent Bim up-regulation and/or inhibit GSK3, confer GC-resistance on the cell. GC-resistance may be overcome in T and B lymphoid malignancies by inhibiting the JNK, Src, PI3K, Akt or mTOR survival pathways. Both staurosporine and rapamycin have recently been proved efficient to sensitize resistant T and B malignant cells to GC-induced apoptosis. This is a proof-of-principle that it is possible to improve GC therapy by altering the cell's kinome.
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PMID:[The kinome and glucocorticoid-induced apoptosis]. 1900 Apr 40

We investigated the role of SB202190, a selective p38 mitogen-activated protein kinase (MAPK) inhibitor in cerebellar granule neurons (CGC) in response to serum potassium deprivation (S/K deprivation), an apoptotic stimulus. CGC apoptosis after S/K deprivation was shown to be mediated through cell cycle re-entry and the induction of transcription factor E2F-1. We found that SB 202190 (10muM) inhibits retinoblastoma protein (pRb) phosphorylation, in response to S/K deprivation. Moreover, the expression of cyclin E and E2F-1 were also significantly decreased. Interestingly, SB202190 did not affect or modulate the increase in the protein expression levels of cyclin D1. Similarly, p-Akt and p-GSK3 protein levels, measured after 12h S/K deprivation, did not appear to be regulated by SB 202190 (10muM). These data indicate that the neuroprotective effects of the p38 inhibitor were not mediated via Akt activation. In conclusion, these results suggest that p38MAPK converged with the cell cycle in S/K deprivation-induced apoptosis through pRb phosphorylation.
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PMID:The p38(MAPK) signaling pathway regulates neuronal apoptosis through the phosphorylation of the retinoblastoma protein. 1900 33

Dendritic cells (DCs) are the most potent antigen-presenting cells for naive T cells. In this study, scavenger receptor class A type I and type II (SR-A) were shown to be expressed by peripheral blood DCs (PBDCs) and monocyte-derived DCs (MDDCs). In addition, the binding of anti-SR-A antibody to these cells was lower in the presence of fucoidan, an SR-A agonist. Treatment of these DCs with fucoidan or anti-SR-A antibody markedly increased the surface expression of costimulatory molecules CD83 and major histocompatibility complex class II on the CD11c(high)CD123(low) myeloid subset of PBDCs. Furthermore, fucoidan-treated PBDCs produced tumor necrosis factor-alpha (TNF-alpha) but not IL-12p70. In addition, fucoidan-induced maturation was eliminated by pretreatment with TNF-alpha-neutralizing antibody. Finally, interferon-gamma secretion and T-cell proliferation were enhanced by coculture of T cells with fucoidan-matured PBDCs. Specific inhibitors of p38 MAPK and glycogen synthase kinase 3 suppressed TNF-alpha production and maturation of fucoidan-treated PBDCs. Moreover, MDDCs lacking SR-A failed to up-regulate CD83 expression, TNF-alpha production, and phosphorylation of p38 MAPK and glycogen synthase kinase 3-beta in the presence of fucoidan. Taken together, these results suggest that ligation of SR-A leads to induction of TNF-alpha, which subsequently induces PBDC maturation, thereby leading to enhanced T-cell stimulatory capacity.
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PMID:Ligand of scavenger receptor class A indirectly induces maturation of human blood dendritic cells via production of tumor necrosis factor-alpha. 1935 58


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