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)

We examined the phosphorylation state of tau factor in hippocampal delayed neuronal death (DND) after transient forebrain ischemia. A transient phosphorylation increase at serine 199/202 but not serine 396 of tau factor after transient ischemia was clearly observed. Intraventricular injections of olomoucine and U-0126 (CDK5 and MAP kinase inhibitors, respectively) inhibited hyperphosphorylation. In contrast, wortmannin (PI3 kinase inhibitor) increased phosphorylation at serine 199/202 and corresponded with an increase in GSK3 phosphorylation. Our findings suggest that CDK5, MAP kinase, and GSK3 phosphorylate these sites after ischemia. We prepared recombinant normal human tau (N-Tau40) with TAT-HA protein and dephosphorylated-form human Tau-40 (D-tau40) in which 199/202 serines were changed to alanine by site-directed mutagenesis. Intraventricularly injected D-tau40 protected somewhat against DND while N-Tau40 did not. These data suggest that hyperphosphorylation at serine 199/202 of tau factor is induced by MAP kinase, CDK5, and GSK3, and contributes to ischemic neuronal injury.
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PMID:Hyperphosphorylation at serine 199/202 of tau factor in the gerbil hippocampus after transient forebrain ischemia. 1681 3

Protein kinases play important roles in regulating cellular signal transduction and other biochemical processes, and they are attractive targets for drug discovery programs in many disease areas. Most kinase inhibitors under development as drugs act by directly competing with ATP at the ATP-binding site of the kinase. There are more than 500 protein kinases, and the ATP-binding site is highly conserved among them. Therefore selectivity is an essential requirement for clinically effective drugs, and understanding the structural characteristics of ATP-binding sites is of crucial importance. The objective of the present study was to elucidate the structural characteristics of the adenosine-binding site of four major kinase groups, AGC (PKA, PKG, and PKC families), CaMK (calcium/calmodulin-dependent protein kinases), CMGC (CDK, MAPK, GSK3, and CLK families), and TK (tyrosine kinases). To do this, we classified the kinases into groups by using feed-forward multilayer perceptron (MLP) neural networks and structural, electronic, and hydrophobic descriptors of the amino acids at the adenosine-binding site. A total of 275 kinases were classified in two ways: (1) kinases belonging to a certain group were distinguished from those not belonging to that group, and (2) all of the kinases were classified into four groups. More than 85% of the kinases were correctly classified by both methods. Trained neural networks clarified which amino acids and which properties characterize the adenosine-binding site of each group, and the results were visualized by molecular graphics. Comparison of the modeled neural networks and the distributions of amino acids provided more detailed information on the structural characteristics of each group. Application of the present results to drug development is also discussed.
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PMID:Elucidation of characteristic structural features of ligand binding sites of protein kinases: a neural network approach. 1699 46

Insulin receptor signaling regulates female reproductive function acting in the central nervous system and ovary. Female mice that globally lack insulin receptor substrate (IRS) 2, which is a key mediator of insulin receptor action, are infertile with defects in hypothalamic and ovarian functions. To unravel the tissue-specific roles of IRS2, we examined reproductive function in female mice that lack Irs2 only in the neurons. Surprisingly, these animals had minimal defects in pituitary and ovarian hormone levels, ovarian anatomy and function, and breeding performance, which indicates that the central nervous system IRS2 is not an obligatory signaling component for the regulation of reproductive function. Therefore, we undertook a detailed analysis of ovarian function in a novel Irs2 global null mouse line. Comparative morphometric analysis showed reduced follicle size, increased numbers of atretic follicles, as well as impaired oocyte growth and antral cavity development in Irs2 null ovaries. Granulosa cell proliferation was also defective in the Irs2 null ovaries. Furthermore, the insulin- and eCG-stimulated phosphoinositide-3-OH kinase signaling events, which included phosphorylation of Akt/protein kinase B and glycogen synthase kinase 3-beta, were impaired, whereas mitogen-activated protein kinase signaling was preserved in Irs2 null ovaries. These abnormalities were associated with reduced expression of cyclin D2 and increased CDKN1B levels, which indicates dysregulation of key components of the cell cycle apparatus implicated in ovarian function. Our data suggest that ovarian rather than central nervous system IRS2 signaling is important in the regulation of female reproductive function.
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PMID:Role of central nervous system and ovarian insulin receptor substrate 2 signaling in female reproductive function in the mouse. 1732 94

Constitutive activation of MEK-ERK signaling is often found in melanomas. Here, we identify a mechanism that links ERK with JNK signaling in human melanoma. Constitutively active ERK increases c-Jun transcription and stability, which are mediated by CREB and GSK3, respectively. Subsequently, c-Jun increases transcription of target genes, including RACK1, an adaptor protein that enables PKC to phosphorylate and enhance JNK activity, enforcing a feed-forward mechanism of the JNK-Jun pathway. Activated c-Jun is also responsible for elevated cyclin D1 expression, which is frequently overexpressed in human melanoma. Our data reveal that, in human melanoma, the rewired ERK signaling pathway upregulates JNK and activates the c-Jun oncogene and its downstream targets, including RACK1 and cyclin D1.
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PMID:Rewired ERK-JNK signaling pathways in melanoma. 1748 34

B-chronic lymphocytic leukemia (B-CLL) cell is characterized by the accumulation of long-lived CD5+ B lymphocytes, whose survival in vivo is in part dependent on exogenous factors such as cytokines and/or extracellular matrix proteins. Homeostatic chemokines are critical mediators of lymphoid cell trafficking. However, how they function in cell signaling and survival remains ill-defined. In this study, we have investigated the role of the homeostatic chemokines, CXCL12, CCL21, CCL19 and CXCL13, in B-CLL cell survival. Using primary leukemic cells isolated from 26 patients, we observed that each chemokine enhances cell survival. Chemokines induced the phosphorylation of ERK1/2 and p90RSK, and of Akt and its effectors GSK3 and FOXO3a. Consistently, inhibitors against mitogen-activated protein kinase/extracellular signal-regulated kinase and phosphatidylinositol 3-kinase inhibited chemokine-induced survival. Moreover, using a constitutively active mutated form of FOXO3a or siRNAs against FOXO3a in transfection experiments performed in primary B-CLL cells, we directly demonstrated the critical role of FOXO3a in both spontaneous and chemokine-induced B-CLL cell survival. Overall, our data support the notion that homeostatic chemokines contribute to B-CLL resistance to cell death through inactivation of the transcription factor FOXO3a, which may represent a novel therapeutic target in this hematopoietic malignancy.
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PMID:Homeostatic chemokines increase survival of B-chronic lymphocytic leukemia cells through inactivation of transcription factor FOXO3a. 1749 28

Cell therapy with bone marrow-derived mesenchymal stem cells (MSCs) has been shown to have great promises in cardiac repair after myocardial infarction. However, poor viability of transplanted MSCs in the infracted heart has limited the therapeutic efficacy. Our previous studies have shown in vitro that rat MSCs undergo caspase-dependent apoptosis in response to hypoxia and serum deprivation (Hypoxia/SD). Recent findings have implicated statins, an established class of cholesterol-lowering drugs, enhance the survival of cells under various conditions. In this study, we investigated the effect of lovastatin on rat MSCs apoptosis induced by Hypoxia/SD, focusing in particular on regulation of mitochondrial apoptotic pathway and the survival signaling pathways. We demonstrated that lovastatin (0.01-1 microM) remarkably prevented MSCs from Hypoxia/SD-induced apoptosis through inhibition of the mitochondrial apoptotic pathway, leading to attenuation of caspase-3 activation. The loss of mitochondrial membrane potential and cytochrome-c release from mitochondria to cytosol were significantly inhibited by lovastatin. Furthermore, the antiapoptotic effect of lovastatin on mitochondrial apoptotic pathway was effectively abrogated by both PI3K inhibitor, LY294002 and ERK1/2 inhibitor, U0126. The phosphorylations of Akt/GSK3 beta and ERK1/2 stimulated by lovastatin were detected. The activation of ERK1/2 was inhibited by a PI3K inhibitor, LY294002, but U0126, a ERK1/2 inhibitor did not inhibit phosphorylation of Akt and GSK3 beta. These data demonstrate that lovastatin protects MSCs from Hypoxia/SD-induced apoptosis via PI3K/Akt and MEK/ERK1/2 pathways, suggesting that it may prove a useful therapeutic adjunct for transplanting MSCs into damaged heart after myocardial infarction.
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PMID:Lovastatin protects mesenchymal stem cells against hypoxia- and serum deprivation-induced apoptosis by activation of PI3K/Akt and ERK1/2. 1749 1

The cardiac glycoside ouabain initiates a cascade of signaling events through Na+,K+-ATPase, leading to an increase in cell growth and proliferation in different cell types. We explored the effects of ouabain on glucose metabolism in skeletal muscle and clarified the mechanisms of ouabain signal transduction. In rat soleus muscle 200 microM ouabain decreased basal glucose uptake without effect on insulin-stimulated glucose uptake. Ouabain increased glycogen synthesis additively to insulin and this effect was abolished in the presence of a MEK1/2 inhibitor (PD98059) or a c-Src inhibitor (PP2). Ouabain exposure reduced glucose oxidation, and this effect was reversed in the presence of PP2. Incubation with ouabain did not affect intramuscular ATP and its metabolites; however acetyl-CoA carboxylase phosphorylation was reduced, with no effect on AMPK phosphorylation. Insulin-stimulated Akt phosphorylation was not affected by ouabain. Ouabain reduced basal and insulin-stimulated phosphorylation of PKC alpha/beta and delta isoforms, whereas phosphorylation of PKCzeta was unchanged. Ouabain exposure increased interaction of 1- and 2-subunits of Na-pump with c-Src, as assessed by co-immunoprecipitation with c-Src. Phosphorylation of ERK1/2, GSK 3 / and p90rsk activity was increased in response to ouabain, and these effects were prevented in the presence of PD98059 and PP2. In conclusion, the cardiac glycoside ouabain stimulates glycogen synthesis additively to insulin in rat skeletal muscle. This effect is mediated by activation of c-Src-, ERK1/2- p90rsk- and GSK3-dependent signaling pathway.
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PMID:Metabolic and signaling events mediated by cardiotonic steroid ouabain in rat skeletal muscle. 1753 36

Originally identified as collapse-inducing and repellent proteins for neuronal processes, semaphorins are now implicated in a diverse array of cellular responses, contributing not only to embryonic development, but also to the maintenance of tissue integrity in the adult organism. In addition, semaphorins play a role in the pathological context. Some Semaphorins can act at a distance, facilitating the navigation of cells or axonal process, whilst others evoke responses in a contact-dependent fashion. The intracellular signaling mechanisms employed by the semaphorins are beginning to be determined, and much work in recent years implicates a host of intracellular kinases in mediating Semaphorin function. These include the tyrosine kinase Fyn and the serine/threonine kinases Cdk5, GSK3, MAPK, and LIMK, and the lipid kinase PI3K. What follows is a review of this work with respect to their functions in mediating specific semaphorin-induced responses.
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PMID:Intracellular kinases in semaphorin signaling. 1760 44

The specificities of 65 compounds reported to be relatively specific inhibitors of protein kinases have been profiled against a panel of 70-80 protein kinases. On the basis of this information, the effects of compounds that we have studied in cells and other data in the literature, we recommend the use of the following small-molecule inhibitors: SB 203580/SB202190 and BIRB 0796 to be used in parallel to assess the physiological roles of p38 MAPK (mitogen-activated protein kinase) isoforms, PI-103 and wortmannin to be used in parallel to inhibit phosphatidylinositol (phosphoinositide) 3-kinases, PP1 or PP2 to be used in parallel with Src-I1 (Src inhibitor-1) to inhibit Src family members; PD 184352 or PD 0325901 to inhibit MKK1 (MAPK kinase-1) or MKK1 plus MKK5, Akt-I-1/2 to inhibit the activation of PKB (protein kinase B/Akt), rapamycin to inhibit TORC1 [mTOR (mammalian target of rapamycin)-raptor (regulatory associated protein of mTOR) complex], CT 99021 to inhibit GSK3 (glycogen synthase kinase 3), BI-D1870 and SL0101 or FMK (fluoromethylketone) to be used in parallel to inhibit RSK (ribosomal S6 kinase), D4476 to inhibit CK1 (casein kinase 1), VX680 to inhibit Aurora kinases, and roscovitine as a pan-CDK (cyclin-dependent kinase) inhibitor. We have also identified harmine as a potent and specific inhibitor of DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A) in vitro. The results have further emphasized the need for considerable caution in using small-molecule inhibitors of protein kinases to assess the physiological roles of these enzymes. Despite being used widely, many of the compounds that we analysed were too non-specific for useful conclusions to be made, other than to exclude the involvement of particular protein kinases in cellular processes.
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PMID:The selectivity of protein kinase inhibitors: a further update. 1785 Feb 14

Inhibition of glycogen synthase kinase 3beta (GSK3beta) as a consequence of its phosphorylation by protein kinase B/Akt (PKB/Akt) has been implicated in cardiac myocyte hypertrophy in response to endothelin-1 or phenylephrine. We examined the regulation of GSK3alpha (which we show to constitute a significant proportion of the myocyte GSK3 pool) and GSK3beta in cardiac myocytes. Although endothelin increases phosphorylation of GSK3 and decreases its activity, the response is less than that induced by insulin (which does not promote cardiac myocyte hypertrophy). GSK3 phosphorylation induced by endothelin requires signalling through the extracellular signal-regulated kinase 1/2 (ERK1/2) cascade and not the PKB/Akt pathway, whereas the reverse is true for insulin. Cardiac myocyte hypertrophy involves changes in morphology, and in gene and protein expression. The potent GSK3 inhibitor 1-azakenpaullone increases myocyte area as a consequence of increased cell length whereas phenylephrine increases both length and width. Azakenpaullone or insulin promotes AP1 transcription factor binding to an AP1 consensus oligonucleotide, but this was significantly less than that induced by endothelin and derived principally from increased binding of JunB protein, the expression of which was increased. Azakenpaullone promotes significant changes in gene expression (assessed by Affymetrix microarrays), but the overall response is less than with endothelin and there is little overlap between the genes identified. Thus, although GSK3 may contribute to cardiac myocyte hypertrophy in some respects (and presumably plays an important role in myocyte metabolism), it does not appear to contribute as significantly to the response induced by endothelin as has been maintained.
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PMID:Glycogen synthase kinases 3alpha and 3beta in cardiac myocytes: regulation and consequences of their inhibition. 1799 64


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