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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During the course of screening for the agents that activate transforming growth factor-beta (TGF-beta) signaling cascade, onnamide A and theopederin B, heterocyclic compounds related to mycalamides from a marine sponge, were found to induce plasminogen activator inhibitor-1 (PAI-1) promoter-derived gene expression in Mv1Lu cells. The maximum induction of the PAI-1 promoter by onnamide A and theopederin B was observed at the concentrations of 50 nM and 2 nM, respectively. These compounds strongly inhibited protein synthesis at the 50% inhibitory concentrations of 30 nM for onnamide A and 1.9 nM for theopederin B, and induced activation of p38 mitogen-activated protein kinase and c-Jun NH2-terminal protein kinase (JNK). Anisomycin, a well-known inducer of ribotoxic stress that inhibits protein synthesis and activates both p38 kinase and JNK, also activated PAI-1 gene expression. Furthermore, PAI-1 expression by onnamide A, theopederin B, and anisomycin was inhibited by SB202190 and SP600125, specific inhibitors of stress-activated protein kinases. Onnamide A and theopederin B were cytotoxic to a variety of cell lines and strongly induced apoptosis in HeLa cells within 24 h, which was accompanied by the sustained activation of p38 kinase and JNK. These results suggest that onnamide A and theopedirin B trigger a ribotoxic stress-like response, thereby inducing p38 kinase and JNK activation, the kinase-dependent PAI-1 gene expression, and apoptosis.
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PMID:Inhibition of protein synthesis and activation of stress-activated protein kinases by onnamide A and theopederin B, antitumor marine natural products. 1595 59

The fusion of Abl with either Bcr or Tel in human leukaemia leads to the constitutive activation of Abl tyrosine kinase, which in turn induces growth-factor-independent proliferation and cell survival. However, the mechanism by which Bcr-Abl induces cellular transformation has not yet been well characterized. Here, we show that Bcr-Abl-expressing cells are resistant to growth inhibition and apoptosis mediated by transforming growth factor-beta (TGF-beta). Interestingly, we observed that the suppressive effects of Bcr-Abl on TGF-beta responses were not mediated by an impairment of Smad signalling, which is believed to act as the principal mediator of TGF-beta responses. In contrast, we found that Bcr-Abl can target the protein kinase AKT and the transcription factor Fox O3 to interfere with growth inhibition and apoptosis in response to TGF-beta. Our results show a novel mechanism of cellular transformation by the oncogenic fusion protein Bcr-Abl through suppression of the cytostatic actions of TGF-beta.
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PMID:Bcr-Abl activates the AKT/Fox O3 signalling pathway to restrict transforming growth factor-beta-mediated cytostatic signals. 1611 47

The transforming growth factor-beta (TGF-beta) superfamily of growth factors is responsible for a variety of physiologic actions, including cell cycle regulation. Activin is a member of the TGF-beta superfamily that inhibits the proliferation of breast cancer cells. Activin functions by interacting with its type I and type II receptors to induce phosphorylation of intracellular signaling molecules known as Smads. Smads regulate transcription of many genes in a cell- and tissue-specific manner. In this study, the role of activin A in growth regulation of breast cancer cells was investigated. Activin stimulated the Smad-responsive promoter, p3TP, 2-fold over control in T47D breast cancer cells. Activin inhibited cellular proliferation of T47D breast cancer cells after 72 hours, an effect that could be abrogated by incubation with the activin type I receptor inhibitor, SB431542. Activin arrested T47D cells in the G0-G1 cell cycle phase. Smad2 and Smad3 were phosphorylated in response to activin and accumulated in the nucleus of treated T47D cells. Infection of T47D cells with adenoviral Smad3 resulted in cell cycle arrest and activation of p3TP-luciferase, whereas a adenoviral dominant-negative Smad3 blocked activin-mediated cell cycle arrest and gene transcription. Activin maintained expression of p21 and p27 cyclin-dependent kinase inhibitors involved in cell cycle control, enhanced expression of p15, reduced cyclin A expression, and reduced phosphorylation of the retinoblastoma (Rb) protein. Smad3 overexpression recapitulated activin-induced p15 expression and repression of cyclin A and Rb phosphorylation. These data indicate that activin A inhibits breast cancer cellular proliferation and activates Smads responsible for initiating cell cycle arrest.
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PMID:Activin A mediates growth inhibition and cell cycle arrest through Smads in human breast cancer cells. 1614 Sep 69

AMP-activated protein kinase (AMPK) promotes glucose transport, maintains ATP stores, and prevents injury and apoptosis during ischemia. AMPK has several direct molecular targets in the heart but also may interact with other stress-signaling pathways. This study examined the role of AMPK in the activation of the p38 mitogen-activated protein kinase (MAPK). In isolated heart muscles, the AMPK activator 5-aminoimidazole-4-carboxy-amide-1-beta-D-ribofuranoside (AICAR) increased p38 MAPK activation. In AMPK-deficient mouse hearts, expressing a kinase-dead (KD) alpha2 catalytic subunit, p38 MAPK activation was markedly reduced during low-flow ischemia (2.3- versus 7-fold in wild-type hearts, P<0.01) and was similarly reduced during severe no-flow ischemia in KD hearts (P<0.01 versus ischemic wild type). Knockout of the p38 MAPK upstream kinase, MAPK kinase 3 (MKK3), did not affect ischemic activation of either AMPK or p38 MAPK in transgenic mkk3(-/-) mouse hearts. Ischemia increased p38 MAPK recruitment to transforming growth factor-beta-activated protein kinase 1-binding protein 1 (TAB1), a scaffold protein that promotes p38 MAPK autophosphorylation. Moreover, TAB1 was associated with the alpha2 catalytic subunit of AMPK. p38 MAPK recruitment to TAB1/AMPK complexes required AMPK activation and was reduced in ischemic AMPK-deficient transgenic mouse hearts. The potential role of p38 MAPK in mediating the downstream action of AMPK to promote glucose transport was also assessed. The p38 MAPK inhibitor SB203580 partially inhibited both AICAR- and hypoxia-stimulated glucose uptake and GLUT4 translocation. Activation of p38 MAPK by anisomycin also increased glucose transport in heart muscles. Thus, AMPK has an important role in promoting p38 MAPK activation in the ischemic heart by inducing p38 MAPK autophosphorylation through interaction with the scaffold protein TAB1.
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PMID:AMP-activated protein kinase activates p38 mitogen-activated protein kinase by increasing recruitment of p38 MAPK to TAB1 in the ischemic heart. 1617 88

The p38 mitogen-activated protein kinase (MAPK) pathway is activated by IFNs and other cytokines to mediate signals for important cellular functions, including transcriptional regulation and apoptosis. We examined the role of the p38 pathway in the generation of the effects of myelosuppressive cytokines on human hematopoiesis. Pharmacologic inhibition of p38 using BIX-01208 resulted in reversal of IFN-, tumor necrosis factor-alpha (TNF-alpha)-, and transforming growth factor-beta (TGF-beta)-mediated suppression of human erythroid (blast-forming unit-erythroid) and myeloid (granulocyte-macrophage colony-forming unit) colony formation, consistent with a key role for p38 in the generation of myelosuppressive signals by different cytokines. Similarly, the myelosuppressive effects of TNF-alpha and TGF-beta were reversed by small interfering RNAs targeting p38alpha expression, further establishing the requirement of this kinase in the induction of myelosuppressive responses. As TNF overproduction has been implicated in the pathophysiology of bone marrow failure states, we determined whether pharmacologic inhibition of p38 reverses the hematopoietic defects seen in bone marrows from patients with myelodysplastic syndromes (MDS) and the anemia of chronic disease. Addition of pharmacologic inhibitors of p38 on such bone marrows resulted in increased numbers of erythroid and myeloid progenitors. Similarly, inhibition of the activity of the downstream effectors of p38, MAPK activated protein kinase-2, and mitogen and stress activated kinase 1 partially restored the hematopoietic defect seen in these bone marrows. Taken altogether, our data implicate the p38 MAPK in the pathophysiology of myelodysplasias and suggest that p38 pharmacologic inhibitors may have therapeutic applications in the treatment of MDS.
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PMID:Role of the p38 mitogen-activated protein kinase pathway in cytokine-mediated hematopoietic suppression in myelodysplastic syndromes. 1620 77

Tranilast, an antiallergic medication, is a very promising inhibitor of restenosis after balloon angioplasty. Tranilast can prevent the proliferation and migration of smooth muscle cells by activating the gene expression of p21, a strong cyclin/cyclin-dependent kinase (CDK) inhibitor, and by arresting cell growth at the G0/G1 phase. The signaling pathway of Tranilast in regulating p21 is to our best interest and is elucidated in the present study. The major emphasis was weighted on exploring the regulatory effects of Tranilast on promoter activity of p21. By serial deletion analysis, the sequence between -74 and -83 bp of the p21 promoter, previously identified as the transforming growth factor-beta (TGF-beta)-response element, was found sufficient, where as most of the promoter region 5' to -111 bp was found unnecessary for the transcriptional activation of p21 by both TGF-beta1 and Tranilast. Tranilast was also found to induce phosphorylation of Smad2 (a cytoplasmic signaling molecule essential for mediating TGF-beta signal transduction). Transfection of DeltakTbetaRII, a truncated form of TGF-beta type II receptor known to exert a dominant-negative effect on TGF-beta signaling, was found to suppress the signaling of both Tranilast and TGF-beta1 to a similar extent. These results suggested that induction of p21 by Tranilast might be closely related to TGF-beta signal transduction pathway.
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PMID:Transcriptional activation of p21 by Tranilast is mediated via transforming growth factor beta signal pathway. 1628 27

1.--The immunomodulating agent FTY720 is a substrate for the sphingosine kinase and the phosphorylated form is able to bind to sphingosine 1-phosphate (S1P) receptors. In this study, we show that exposure of renal mesangial cells to phospho-FTY720 leads to a rapid and transient activation of several protein kinase cascades, including the mitogen- and stress-activated protein kinases. The nonphosphorylated FTY720 also increased MAPK phosphorylation, but with a reduced potency and a more delayed time course. In addition, phospho-FTY720 and FTY720 are able to increase phosphorylation of Smad proteins which are classical members of the transforming growth factor-beta (TGF-beta) signalling device, thus suggesting a crosstalk between FTY720 and TGF-beta signalling. 2.--Pretreatment with the S1P(3) receptor antagonist suramin inhibits FTY720 and phospho-FTY720-induced Smad phosphorylation, whereas pertussis toxin pretreatment, which blocks G(i/0) proteins, has no effect on Smad phosphorylation. 3.--Since TGF-beta is a potent profibrotic cytokine in mesangial cells and upregulates the connective tissue growth factor (CTGF) and collagen as important hallmarks in the fibrotic sequelae, we investigated whether FTY720 and phospho-FTY720 are able to mimic these effects of TGF-beta. Indeed, FTY720 and phospho-FTY720 markedly upregulate CTGF and collagen type IV protein expressions. In addition, the tissue inhibitor of metalloproteinase-1 is transcriptionally activated by FTY720, whereas cytokine-induced matrix metalloproteinase-9 is down-regulated by FTY720. 4.--Depletion of the TGF-beta receptor type II by the siRNA transfection technique blocks not only Smad phosphorylation but also CTGF upregulation. Similarly, Smad-4 depletion by siRNA transfection also abrogates CTGF upregulation induced by FTY720 and phospho-FTY720. 5.--In summary, our data show that FTY720 and phospho-FTY720 not only activate the Smad signalling cascade in mesangial cells, but also upregulate the expression of CTGF and collagen. These findings suggest that FTY720 may have additional effects besides the established immunomodulatory action and, importantly, a profibrotic activity has to be considered in future experimental approaches.
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PMID:The immunomodulator FTY720 and its phosphorylated derivative activate the Smad signalling cascade and upregulate connective tissue growth factor and collagen type IV expression in renal mesangial cells. 1629 53

In this paper, we investigated the inhibitory mechanism of the production of nitric oxide (NO) by polyanions and liposomes composed of phosphatidylserine (PS-liposomes) focusing on cytokine production and mitogen activated protein kinase (MAP kinase) activation. NO production by macrophages was inhibited by treatment with oxidized lipoprotein (OxLDL), maleylated bovine serum albumin (mBSA), and heparin. No inhibitory effect was exhibited by poly-cytidilic acid (PolyC). To clarify the mechanism of the inhibitory effect of polyanions on NO production, we evaluated the productions of transforming growth factor-beta (TGF-beta) and interleukin (IL)-10 which are known to be anti-inflammatory cytokines. TGF-beta was produced when macrophages were treated with OxLDL as was the case with PS-liposomes. No increase in TGF-beta production was observed for mBSA, heparin, and PolyC. On the other hand, significant production of IL-10 was observed using mBSA. Extracellular signal-regulated kinase (ERK), a member of the MAP kinase superfamily, was activated when macrophages were treated with OxLDL as well as PS-liposomes. In the case of mBSA, the activation of ERK and c-Jun N-terminal kinase (JNK) was observed. No activation of p38 MAP kinase was observed using any of the polyanions. Although heparin had an inhibitory effect on NO production by macrophages, no activation of MAP kinase or production of TGF-beta and IL-10 was observed. The inhibitory effect of these ligands on NO production may be regulated via different signaling pathways.
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PMID:Comparison of inhibitory effects of polyanions on nitric oxide production by macrophages stimulated with LPS. 1650 53

Previous studies have revealed that transforming growth factor-beta-activated protein kinase 1 (TAB1) interacts with p38alpha and induces p38alpha autophosphorylation. Here, we examine the sequence requirements in TAB1 and p38alpha that drive their interaction. Deletion and point mutations in TAB1 reveal that a proline residue in the C terminus of TAB1 (Pro412) is necessary for its interaction with p38alpha. Furthermore, a cryptic D-domain-like docking site was identified adjacent to the N terminus of Pro412, putting Pro412 in the phi(B)+3 position of the docking site. Through mutational analysis, we found that the previously identified hydrophobic docking groove in p38alpha is involved in this interaction, whereas the CD domain and ED domain are not. Furthermore, chimeric analysis with p38beta (which does not bind to TAB1) revealed a previously unidentified locus of p38alpha comprising Thr218 and Ile275 that is essential for specific binding of p38alpha to TAB1. Converting either of these residues to the corresponding amino acid of p38beta abolishes p38alpha interaction with TAB1. These p38alpha mutants still can be fully activated by p38alpha upstream activating kinase mitogen-activated protein kinase kinase 6, but their basal activity and activation in response to some extracellular stimuli are reduced. Adjacent to Thr218 and Ile275 is a site where large conformational changes occur in the presence of docking-site peptides derived from p38alpha substrates and activators. This suggests that TAB1-induced autophosphorylation of p38alpha results from conformational changes that are similar but unique to those seen in p38alpha interactions with its substrates and activating kinases.
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PMID:Determinants that control the specific interactions between TAB1 and p38alpha. 1664 77

The Snf1/AMP-activated protein kinase (AMPK) family is important for metabolic regulation and is highly conserved from yeast to mammals. The upstream kinases are also functionally conserved, and the AMPK kinases LKB1 and Ca2+/calmodulin-dependent protein kinase kinase activate Snf1 in mutant yeast cells lacking the native Snf1-activating kinases, Sak1, Tos3, and Elm1. Here, we exploited the yeast genetic system to identify members of the mammalian AMPK kinase family by their function as Snf1-activating kinases. A mouse embryo cDNA library in a yeast expression vector was used to transform sak1Delta tos3Delta elm1Delta yeast cells. Selection for a Snf+ growth phenotype yielded cDNA plasmids expressing LKB1, Ca2+/calmodulin-dependent protein kinase kinase, and transforming growth factor-beta-activated kinase (TAK1), a member of the mitogen-activated protein kinase kinase kinase family. We present genetic and biochemical evidence that TAK1 activates Snf1 protein kinase in vivo and in vitro. We further show that recombinant TAK1, fused to the activation domain of its binding partner TAB1, phosphorylates Thr-172 in the activation loop of the AMPK catalytic domain. Finally, expression of TAK1 and TAB1 in HeLa cells or treatment of cells with cytokines stimulated phosphorylation of Thr-172 of AMPK. These findings indicate that TAK1 is a functional member of the Snf1/AMPK kinase family and support TAK1 as a candidate for an authentic AMPK kinase in mammalian cells.
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PMID:Mammalian TAK1 activates Snf1 protein kinase in yeast and phosphorylates AMP-activated protein kinase in vitro. 1683 26


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