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)

Protease-activated receptor-2 (PAR-2) may have proinflammatory effects in some tissues and protective effects in other tissues. The role of PAR-2 in in vivo myocardial ischemia-reperfusion has not yet been determined. This study tested the hypothesis that PAR-2 activation with the PAR-2 agonist peptide SLIGRL (PAR-2 AP) reduces myocardial infarct size when given at reperfusion in vivo, and this cardioprotection involves the ERK1/2 pathway. Anesthetized rats were randomly assigned to the following groups with 30 min of regional ischemia and 3 h reperfusion: 1) control with saline; 2) vehicle (DMSO); 3) PAR-2 AP, 1 mg/kg given intravenously 5 min before reperfusion; 4) scrambled peptide (SP), 1 mg/kg; 5) the ERK1/2 inhibitor PD-98059 (PD), 0.3 mg/kg given 10 min before reperfusion; 6) the phosphatidylinositol 3-kinase inhibitor LY-294002 (LY), 0.3 mg/kg given 10 min before reperfusion; 7) PD + PAR-2 AP, 0.3 mg/kg PD given 5 min before PAR-2 AP; 8) LY + PAR-2 AP, 0.3 mg/kg LY given 5 min before PAR-2 AP; 9) chelerythrine (Chel) alone, 5 mg/kg given 10 min before reperfusion; and 10) Chel + PAR-2 AP, Chel was given 5 min before PAR-2 AP (10 min before reperfusion). Activation of ERK1/2, ERK5, Akt, and the downstream targets of ERK1/2 [P90 RSK and bcl-xl/bcl-2-associated death promoter (BAD)] was determined by Western blot analysis in separate experiments. PAR-2 AP significantly reduced infarct size compared with control (36 +/- 2% vs. 53 +/- 1%, P < 0.05), and SP had no effect on infarct size (53 +/- 3%). PAR-2 AP significantly increased phosphorylation of ERK1/2, p90RSK, and BAD but not Akt or ERK5. Accordingly, the infarct-size sparing effect of PAR-2 AP was abolished by PD (PAR-2 AP, 36 +/- 2% vs. PD + PAR-2 AP, 50 +/- 1%; P < 0.05) and by Chel (Chel + PAR-2 AP, 58 +/- 2%) but not by LY (PAR-2 AP, 36 +/- 2% vs. LY + PAR-2 AP, 38 +/- 3%; P > 0.05). Therefore, PAR-2 activation is cardioprotective in the in vivo rat heart ischemia-reperfusion model, and this protection involves the ERK1/2 pathway and PKC.
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PMID:PAR-2 activation at the time of reperfusion salvages myocardium via an ERK1/2 pathway in in vivo rat hearts. 1772 Jul 72

Mos and the mitogen-activated protein kinase (MAPK) cascade have been established as crucial regulators of second meiotic metaphase arrest, the so-called CSF arrest, in mammalian oocytes. They are also thought to play a role in regulating mitotic metaphase arrest of early mammalian embryos. In the present study, we examined whether mitotic arrest is induced in early mouse embryos by activation of extracellular signal-regulated kinases (ERKs), which are major MAPKs in mouse eggs, and their substrate, p90Ribosomal S6 kinase (RSK), as reported in Xenopus embryos. Wild-type Mos (wt-Mos), degradation-resistant Mos mutant (P2G-Mos) or constitutive active mutant of MAPK/ERK kinase, MEK (SDSE-MEK), was expressed in early mouse embryos by injecting the respective expression vectors into the pronucleus of fertilized eggs, and the developmental rates were then examined up to 72 h after insemination. Expression of P2G-Mos and SDSE-MEK succeeded in activating ERKs and RSK in developing mouse embryos, while wt-Mos failed to activate them in spite of expression of mos mRNA, indicating that the wt-Mos protein is unstable in early mouse embryos. Although the activated levels of ERKs and RSK in the vector-injected embryos were comparable to those of meiotically arrested mouse oocytes, their developmental rates were identical to those of the control embryos. These results suggest that activation of MAPK and RSK does not induce mitotic arrest in early mouse embryos. The present study indicates that there are large physiological differences between early mouse embryos and mouse oocytes and that CSF arrest of mouse eggs in mitosis should be discussed separately from that in meiosis.
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PMID:Mos and the mitogen-activated protein kinase do not show cytostatic factor activity in early mouse embryos. 1782 76

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

5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) is a commonly used pharmacological agent to study physiological effects which are similar to those of exercise. However, signal transduction pathways by which AICAR elicits downstream effects in liver are poorly understood. We report here that AICAR not only activated AMPK but also phosphorylated/deactivated glycogen synthase kinase-3 alpha/beta (GSK-3alpha/beta) and dephophorylated/activated glycogen synthase (GS) in a time-dependent manner in human hepatoma HepG2 cells. The signal connection between AICAR and GSK-3 is indirect and involves activation of Raf-1/MEK/p42/44(MAPK)/p90(RSK) signaling cascade as pharmacologic inhibition of MEK significantly reduced phosphorylation/deactivation of GSK-3 and consequent dephosphorylation/activation of GS. Moreover, silencing the expression of p90(RSK), a substrate of p42/44(MAPK), attenuated AICAR-dependent GSK-3 phosphorylation, implicating this kinase as a key mediator of AICAR signaling to GSK-3. Furthermore, consistent with the involvement of Raf-1 kinase cascade, AICAR-induced low-density lipoprotein (LDL) receptor expression in a p42/44(MAPK)-dependent manner. Finally, AICAR requires AMPK-alpha2-dependent and -independent pathways to activate Raf-1 kinase cascade as suppression of AMPKalpha2 activity, and not of AMPKalpha1, partially blocked AICAR-dependent p42/44(MAPK) activation and GSK-3 phosphorylation/deactivation. Collectively, these results highlight Raf-1 signaling cascade as the critical mediator of AICAR action on glucose and lipid metabolism in HepG2 cells.
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PMID:AICAR positively regulate glycogen synthase activity and LDL receptor expression through Raf-1/MEK/p42/44MAPK/p90RSK/GSK-3 signaling cascade. 1794 90

Polycystic kidney disease (ADPKD) results from failure of the kidney to properly maintain three-dimensional structure after loss of either polycystin-1 or -2. Mice with kidney selective inactivation of Pkd1 during embryogenesis develop profound renal cystic disease and die from renal failure within 3 weeks of birth. In this model, cysts form exclusively from cells in which Cre recombinase is active, but the apparent pace of cyst expansion varies by segment and cell type. Intercalated cells do not participate in cyst expansion despite the presence of cilia up to at least postnatal day 21. Cystic segments show a persistent increase in proliferation as determined by bromodeoxyuridine (BrdU) incorporation; however, the absolute proliferative index is dependent on the underlying proliferative potential of kidney tubule cells. Components of the extracellular regulated kinase (MAPK/ERK) pathway from Ras through MEK1/2 and ERK1/2 to the effector P90(RSK) are activated in both perinatal Pkd1 and adult Pkd2 ortholgous gene disease models. The pattern of MAPK/ERK activation is focal and does not correlate with the pattern of active proliferation identified by BrdU uptake. The possibility of a causal relationship between ERK1/2 activation and cyst cell proliferation was assessed in vivo in the acute perinatal Pkd1 model of ADPKD using MEK1/2 inhibitor U0126. U0126 treatment had no effect on progression of cyst formation in this model at doses sufficient to reduce phospho-ERK1/2 in cystic kidneys. Cysts in ADPKD exhibit both increased proliferation and activation of MAPK/ERK, but cyst growth is not prevented by inhibition of ERK1/2 activation.
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PMID:Cyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1. 1826 4

The differential usage of signaling pathways by chemokines and cytokines in eosinophils is largely unresolved. In this study, we investigate signaling similarities and differences between CCL11 (eotaxin) and IL-5 in a phosphosite screen of human eosinophils. We confirm many previously known pathways of cytokine and chemokine signaling and elucidate novel phosphoregulation in eosinophils. The signaling molecules that were stimulated by both agents were members of the ERK1/2 and p38 MAPK pathways and their downstream effectors such as RSK and MSK1/2. Both agents inhibited S6 kinase, protein kinase Cepsilon, and glycogen synthase kinase 3 alpha and beta. The molecules that were differentially regulated include STATs and protein kinase R (PKR). One of the chief findings in this investigation was that PKR and eukaryotic initiation factor 2alpha are phosphorylated under basal conditions in eosinophils and neutrophils. This basal phosphorylation was linked to autocrine secretion of TGF-beta in eosinophils. TGF-beta directly activates PKR in eosinophils. Basal phosphorylation of PKR was inhibited by incubation of eosinophils with a neutralizing anti-TGF-beta Ab suggesting its physiological importance. We show that inhibition of PKR activity prolongs eosinophil survival. The eosinophil survival factor IL-5 strongly suppresses phosphorylation of PKR. The biological relevance of IL-5 inhibition of phospho-PKR was established by the observation that ex vivo bone marrow-derived eosinophils from OVA-immunized mice had no PKR phosphorylation in contrast to the high level of phosphorylation in sham-immunized mice. Together, our findings suggest that survival of eosinophils is in part controlled by basal activation of PKR through autocrine TGF-beta and that this could be modulated by a Th2 microenvironment in vivo.
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PMID:A phosphosite screen identifies autocrine TGF-beta-driven activation of protein kinase R as a survival-limiting factor for eosinophils. 1832 38

Valproate, an anticonvulsant and mood stabilizer, up-regulates Bcl-2, a neurotrophic/neuroprotective protein. In this study, we investigated the molecular mechanism through which Bcl-2 is up-regulated by valproate using cultured human neuron-like cells. Valproate, within therapeutically relevant ranges, induced time- and concentration-dependent up-regulations of both Bcl-2 messenger RNA and protein implicating an underlying gene transcriptional-mediated mechanism. Bcl-2 up-regulations were associated with ERK1/2 and PI3K pathway activations and elevated levels of activated phospho-RSK and phospho-CREB, convergent targets of the ERK1/2 and PI3K pathways. Valproate increased transcriptional activity of a human bcl-2 promoter-reporter gene construct. This effect was attenuated, but not blocked, by mutation of a CREB DNA binding site, a CRE site in the human bcl-2 promoter sequence. ERK and/or PI3K pathway inhibitors and RSK1 small hairpin RNA knockdown reduced, but did not abolish, baseline and valproate-induced promoter activities and lowered Bcl-2 protein levels. These data collectively suggest that valproate induces Bcl-2 regulation partially through activations of the ERK and PI3K cascades and their convergent kinase, RSK, although other unknown mechanism(s) are likely involved. Given the known roles of Bcl-2 in the central nervous system, the current findings offer a partial yet complex molecular mechanistic explanation for the known neurobiological effects of valproate including neurite growth, neuronal survival, and neurogenesis.
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PMID:Evidence for involvement of ERK, PI3K, and RSK in induction of Bcl-2 by valproate. 1867 83

PKC signaling is critical for follicular development and the induction of ovulatory genes including Pgr, Prkg2, and Cyp11a1 (SCC). We investigated PKC signaling mechanisms in the JC-410 porcine granulosa cell line stably expressing an SCC-luciferase reporter gene containing 2kb of the porcine SCC promoter. Addition of phorbol 12-myristate 13-acetate (PMA), which activates protein kinase C, induced the promoter approximately 6-fold over the basal levels in 4h. This effect was predominantly mediated by the PKC beta and delta isoforms. PMA-mediated induction of the SCC promoter was sensitive to inhibition of ERK1/2 or JNK. Inhibition of p38 MAP kinase or Src tyrosine kinase did not alter the PMA-mediated inducibility of the promoter. SCC promoter induction in response to PMA treatment required basal EGF-receptor activity, but did not involve ectodomain shedding. Western blot analyses using phospho-specific antibodies showed that PMA treatment of JC-410 cells induced phosphorylation of MEK1/2, ERK1/2, and its downstream target p90 RSK at 15min. We also documented the rapid phosphorylation of JNK1/2 in response to PMA treatment. Phosphorylation of ERK and JNK was robust and sustained in contrast to activation of PKA and EGF-receptor signaling in these cells. Pretreatment of JC-410 granulosa cells with IGF-1 had a synergistic effect on PMA-mediated induction of the SCC promoter. We demonstrated the importance of PMA activation of ERK signaling and the synergism with IGF-1 by showing similar responses for Prkg2 expression in primary granulosa cells. In conclusion, our studies demonstrated PMA activation of ERK and JNK signaling which is relevant in the regulation of gene expression during follicular development, ovulation, and luteinization.
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PMID:Identification of ERK and JNK as signaling mediators on protein kinase C activation in cultured granulosa cells. 1869 3

A major question in the process of dendrite development and complexity is not whether neuronal activity plays a role, but how it contributes to specific components of the mature dendrite pattern. Neurons interpret activity into the influx of calcium ions leading to activation of signaling pathways. The dynamics of calcium-activated signaling pathways after neuronal activity and the contribution to formation of dendrite complexity remain unclear. Here, we show that one calcium activated signaling pathway, extracellular signal-regulated kinase (ERK), showed differential activity in cortical neurons. In response to depolarizing stimuli, ERK was active for less than an hour in most neurons, whereas in others ERK remained active for several hours. Further, neurons in which ERK activity was sustained, displayed greater dendrite complexity than neurons that did not display sustained ERK activity. Interestingly, this difference in dendrite complexity was detected in some, but not all, morphological parameters. Pharmacological inhibition of sustained ERK activity inhibited calcium-activated dendrite complexity. Increasing the duration and degree of ERK phosphorylation, and thus activity, with dominant negative MAP kinase phosphatase-1 accentuated dendrite complexity. Neurons in which ERK activity was sustained activated downstream nuclear targets including RSK, MSK, cAMP response element binding protein (CREB), CRE-mediated gene transcription, and stabilized c-Fos. Further, the increase in dendrite complexity mediated by sustained ERK activity was inhibited by expression of a dominant negative CREB. These data indicate that ERK-mediated activity induced dendrite complexity via sustained signaling and CREB-mediated signaling.
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PMID:ERK mediates activity dependent neuronal complexity via sustained activity and CREB-mediated signaling. 1883 11

Na(+)/H(+) exchanger (NHE-1) inhibition was demonstrated to induce the regression of cardiac hypertrophy (CH) in several experimental models and to inhibit mitochondrial death pathway in "in-vitro" experiments. Since recent reports show that NHE-1 inhibition delays the transition from CH to failure, and apoptosis plays a key role in this process, we investigated the effect of chronic treatment with the NHE-1 blocker cariporide on CH and apoptosis in the SHR. One month of cariporide treatment (30 mg x kg(-1) x day(-1)) induced the regression of CH (cardiomyocyte cross-sectional area: 468 +/- 20 vs. 285 +/- 9 microm(2) in untreated and cariporide-treated spontaneously hypertensive rats; P < 0.05). Apoptosis was assessed by TUNEL staining, the expression of Bcl-2, Bax, and activation of caspase-3 and PARP-1 by immunoblot. Cariporide treatment decreased the TUNEL-positive cells, the Bax-to-Bcl-2 ratio (3.16 +/- 0.32 vs. 1.70 +/- 0.17, untreated and cariporide-treated, respectively; P < 0.05); caspase-3 and PARP-1 activation (465 +/- 62 vs. 260 +/- 22 and 2,239 +/- 62 vs. 1,683 +/- 85 AU, untreated and cariporide-treated, respectively; P < 0.05). Angiotensin II, a growth factor and apoptotic stimulus, was used to induce O(2)(-) production that activated the ERK1/2-p90(RSK) pathway, increasing NHE-1 phosphorylation. These effects were prevented by losartan, N-(2-mercaptopropionyl)-glycine, and cariporide. In conclusion, we present data demonstrating that chronic NHE-1 inhibition with cariporide decreases both hypertrophy and apoptosis susceptibility in the spontaneously hypertensive rat heart. The antiapoptotic effect would be the consequence of two different actions of cariporide: the prevention of cytosolic Na(+) and Ca(2+) overload due to the inhibition of the sarcolemmal NHE-1 and a direct mitochondrial effect preventing mitochondrial permeability transition pore opening.
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PMID:Chronic NHE-1 blockade induces an antiapoptotic effect in the hypertrophied heart. 1917 46


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