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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stimulation of N-methyl-D-aspartate (NMDA) receptors is believed to underlie long-term memory formation, and excessive NMDA receptor activation has been linked to several neuropathological conditions. Phosphorylation and activation of p42/44 mitogen-activated protein kinase (ERK) is believed to mediate many of these effects, but the downstream targets of ERK in response to NMDA activation have not been determined. In primary cultures of rat cortical neurons, we found that NMDA was able to elevate phosphorylation of mitogen- and stress-activated kinase 1 (MSK1) as well as ERK. Likewise, brain-derived neurotrophic factor (BDNF) treatment increased phosphorylation of MSK1 and ERKs. The NMDA-induced MSK1 phosphorylation was sensitive to the MEK inhibitor 2'-amino-3'-methoxyflavone (PD98059) and the p38 inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580). MSK1 activation by NMDA was transient, although ERK remained phosphorylated within the neuronal cytoplasm for several hours. Although BDNF increased ribosomal S6 kinase (RSK) phosphorylation, NMDA had no discernable effect on the phosphorylation of RSKs. Thus, phosphorylation and activation of MSK1 but not RSK could be an important step in the pathway linking NMDA-induced ERK phosphorylation to the activation of transcription factors required for the formation of long-term memory.
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PMID:N-methyl-D-aspartate and brain-derived neurotrophic factor induce distinct profiles of extracellular signal-regulated kinase, mitogen- and stress-activated kinase, and ribosomal s6 kinase phosphorylation in cortical neurons. 1562 80

Stem cell factor (SCF) and its receptor, KIT, are essential to the migration and differentiation of melanocytes during embryogenesis. We previously demonstrated that apoptosis is induced by blocking survival function of the SCF/KIT interaction in a mouse neural crest cell (NCC) primary culture. Using the NCCmelb4 cell line, we investigated the occurrence of apoptosis in the cultured cells when KIT receptors were blocked by the monoclonal anti-KIT antibody (ACK2). Apoptosis following treatment with ACK2 was detected by DNA fragmentation assay, in situ apoptosis detection, and electron microscopy. We noted a decrease in extracellular signal-related kinase (ERK) and ribosomal S6 kinase (RSK) protein expression following ACK2 incubation. Western blot analysis and real-time quantitative RT-PCR revealed an apparent time-dependent reduction in Bcl-2 protein levels with respect to ACK2 within the NCCmelb4 cells. In terms of Bax expression, a difference was not found. Fas and caspase8 proteins increased time-dependently in proportion to ACK2 incubation. We noted apoptotic cell death upon addition of ACK2, with evidence of possible involvement of Bcl-2 and Fas in the induction of apoptosis. In contrast, no significant correlation between Fas ligand (Fas-L) expression and ACK2 was found. Fas activation appears to occur independent of Fas-L during ACK2-induced cell death. Therefore, we propose that Fas-L expression in NCCmelb4 cells does not play a major role in facilitating apoptosis. Furthermore, we hypothesize that these molecules combined with SCF/KIT play an important role in regulating the induction of vertebrate NCC apoptosis during embryogenesis.
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PMID:Bcl-2 reduced and fas activated by the inhibition of stem cell factor/KIT signaling in murine melanocyte precursors. 1565 78

The extracellular signal regulated kinase (ERK1 and ERK2) signal transduction pathways play a critical role in cell proliferation. Hyperactivation of the ERK proteins either through increased expression of membrane-bound growth factor receptors or genetic mutations of upstream proteins is thought to be involved in the pathogenesis of many human cancers. Thus, targeted inhibition of ERK signaling is viewed as a potential approach to prevent cancer cell proliferation. Currently, no specific inhibitors of the ERK proteins exist. Moreover, most kinase inhibitors lack specificity because they target the ATP binding region, which is well conserved among the protein kinase families. Taking advantage of recently identified ERK docking domains, which are reported to facilitate substrate protein interactions, we have used computer-aided drug design (CADD) to identify novel small molecular weight ERK inhibitors. Following a CADD screen of over 800 000 molecules, 80 potential compounds were selected and tested for activity in biological assays. Several compounds inhibited ERK-specific phosphorylation of ribosomal S6 kinase-1 (Rsk-1) or the ternary complex factor Elk-1 (TCF/Elk-1), both of which are involved in promoting cell proliferation. Active compounds showed a dose-dependent reduction in the proliferation of several cancer cell lines as measured by colony survival assays. Direct binding between the active compounds and ERK2 was indicated by fluorescence quenching. These active compounds may serve as lead candidates for development of novel specific inhibitors of ERK-substrate interactions involved in cell proliferation.
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PMID:Identification of novel extracellular signal-regulated kinase docking domain inhibitors. 1599 96

Inhibitors of the oncogenic Ras-MAPK pathway have been intensely pursued as therapeutics. Targeting this pathway, however, presents challenges due to the essential role of MAPK in homeostatic functions. The phosphorylation and activation of MAPK substrates is regulated by protein-protein interactions with MAPK docking sites. Active ERK1/2 (extracellular signal-regulated kinase 1/2)-MAPKs localize to effectors containing DEF (docking site for ERK, (F)/(Y) -X-(F)/(Y) -P)- or D-domain (docking domain) motifs. We have examined the in vivo activity of ERK2 mutants with impaired ability to signal via either docking site. Mutations in the DEF-domain binding pocket prevent activation of DEF-domain-containing effectors but not RSK (90 kDa ribosomal S6 kinase), which contains a D domain. Conversely, mutation of the ERK2 CD domain, which interacts with D domains, prevents RSK activation but not DEF-domain signaling. Uncoupling docking interactions does not compromise ERK2 phosphotransferase activity. ERK2 DEF mutants undergo regulated nuclear translocation but are defective for Elk-1/TCF transactivation and target gene induction. Thus, downstream branches of ERK2 signaling can be selectively inhibited without blocking total pathway activity. Significantly, several protooncogenes contain DEF domains and are regulated by ERK1/2. Therefore, disrupting ERK-DEF domain interactions could be an alternative to inhibiting oncogenic Ras-MAPK signaling.
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PMID:Spatially separate docking sites on ERK2 regulate distinct signaling events in vivo. 1605 Nov 77

Internal tandem duplication (ITD) mutations in the FLT3 tyrosine kinase have been detected in approximately 20% of acute myeloid leukemia (AML) patients. Patients harboring FLT3/ITD mutations have a relatively poor prognosis. FLT3/ITD results in constitutive autophosphorylation of the receptor and factor-independent survival. Previous studies have shown that FLT3/ITD activates the signal transducers and activators of transcription 5 (STAT5), p42/p44 mitogen-activated protein kinase [MAPK; extracellular signal-regulated kinase (ERK) 1/2], and phosphatidylinositol 3-kinase/Akt pathways. We herein provide biochemical and biological evidence that ribosomal S6 kinase 1 (RSK1) and protein kinase A (PKA) are the two principal kinases that mediate the antiapoptotic function of FLT3/ITD via phosphorylation of BAD at Ser112. Inhibiting both MAPK kinase (MEK)/ERK and PKA pathways by a combination of U0126 (10 micromol/L) and H-89 (5 micromol/L) reduced most of BAD phosphorylation at Ser112 and induced apoptosis to a level comparable with that induced by FLT3 inhibitor AG1296 (5 micromol/L) in BaF3/FLT3/ITD cells. RNA interference of RSK1 or PKA catalytic subunit reduced BAD phosphorylation and induced apoptosis. The MEK inhibitor U0126 and/or the PKA inhibitor H-89 greatly enhanced the efficacy of the FLT3 inhibitor AG1296, suggesting that combining FLT3/ITD downstream pathway inhibition with FLT3 inhibitors may be a viable therapeutic strategy for AML caused by a FLT3/ITD mutation.
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PMID:The FLT3 internal tandem duplication mutation prevents apoptosis in interleukin-3-deprived BaF3 cells due to protein kinase A and ribosomal S6 kinase 1-mediated BAD phosphorylation at serine 112. 1610 85

Vitamin A (retinol) is essential for normal regulation of cell growth and differentiation. We have shown that the retinol metabolite retinoic acid (RA) induces mucous cell differentiation of normal human tracheobronchial epithelial (NHTBE) cells. However, early biological effects of RA in the differentiation of bronchial epithelia are largely unknown. Here, we showed that RA rapidly activated cAMP response element-binding protein (CREB). However, RA did not use the conventional retinoic acid receptor (RAR)/retinoid X receptor (RXR) to activate CREB. RA activated CREB in NHTBE and H1734 cells in which RARs/RXR were silenced with small interfering RNA (siRNA) targeting RAR/RXR expression or deactivated by antagonist. Inhibition of protein kinase C (PKC) or extracellular regulated kinase (ERK1/2) blocked the RA-mediated activation of CREB. In addition, depletion of p90 ribosomal S6 kinase (RSK) via siRSK1/2 completely abolished the activation, suggesting that PKC, ERK, and RSK are required for the activation. Altogether, this study provides the first evidence that RA rapidly activates CREB transcription factor via PKC, ERK, and RSK in a retinoid receptor-independent manner in normal bronchial epithelial cells. This noncanonical RA signaling pathway may play an important role in mediating early biological effects in the mucociliary differentiation of bronchial epithelia.
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PMID:Nonclassical action of retinoic acid on the activation of the cAMP response element-binding protein in normal human bronchial epithelial cells. 1628 Mar 61

Although p90 ribosomal S6 kinase (RSK) is known as an important downstream effector of the ribosomal protein S6 kinase/extracellular signal-regulated kinase (Ras/ERK) pathway, its endogenous role, and precise molecular function remain unclear. Using gain-of-function and null mutants of RSK, its physiological role was successfully characterized in Drosophila. Surprisingly, RSK-null mutants were viable, but exhibited developmental abnormalities related to an enhanced ERK-dependent cellular differentiation such as ectopic photoreceptor- and vein-cell formation. Conversely, overexpression of RSK dramatically suppressed the ERK-dependent differentiation, which was further augmented by mutations in the Ras/ERK pathway. Consistent with these physiological phenotypes, RSK negatively regulated ERK-mediated developmental processes and gene expressions by blocking the nuclear localization of ERK in a kinase activity-independent manner. In addition, we further demonstrated that the RSK-dependent inhibition of ERK nuclear migration is mediated by the physical association between ERK and RSK. Collectively, our study reveals a novel regulatory mechanism of the Ras/ERK pathway by RSK, which negatively regulates ERK activity by acting as a cytoplasmic anchor in Drosophila.
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PMID:Inhibition of ERK-MAP kinase signaling by RSK during Drosophila development. 1676 54

In cardiac myocytes, sustained (3 min) intracellular acidosis activates the ERK1/2 (extracellular-signal-regulated kinase 1/2) pathway and, through this pathway, increases sarcolemmal NHE (Na+/H+ exchanger) activity [Haworth, McCann, Snabaitis, Roberts and Avkiran (2003) J. Biol. Chem. 278, 31676-31684]. In the present study, we aimed to determine the time-dependence, pH-dependence and upstream signalling mechanisms of acidosis-induced ERK1/2 activation in ARVM (adult rat ventricular myocytes). Cultured ARVM were subjected to intracellular acidosis for up to 20 min by exposure to NH4Cl, followed by washout with a bicarbonate-free Tyrode solution containing the NHE1 inhibitor cariporide. After the desired duration of intracellular acidosis, the phosphorylation status of ERK1/2 and its downstream effector p90(RSK) (90 kDa ribosomal S6 kinase) were determined by Western blotting. This revealed a time-dependent transient phosphorylation of both ERK1/2 and p90(RSK) by intracellular acidosis (intracellular pH approximately 6.6), with maximum activation occurring at 3 min and a return to basal levels by 20 min. When the degree of intracellular acidosis was varied from approximately 6.8 to approximately 6.5, maximum ERK1/2 phosphorylation was observed at an intracellular pH of 6.64. Inhibition of MEK1/2 [MAPK (mitogen-activated protein kinase)/ERK kinase 1/2) by pre-treatment of ARVM with U0126 or adenoviral expression of dominant-negative D208A-MEK1 protein prevented the phosphorylation of ERK1/2 by sustained intracellular acidosis, as did inhibition of Raf-1 with GW 5074 or ZM 336372. Interference with Ras signalling by the adenoviral expression of dominant-negative N17-Ras protein or with FPT III (farnesyl protein transferase inhibitor III) also prevented acidosis-induced ERK1/2 phosphorylation, whereas inhibiting G-protein signalling [by adenoviral expression of RGS4 or Lsc, the RGS domain of p115 RhoGEF (guanine nucleotide-exchange factor)] or protein kinase C (with bisindolylmaleimide I) had no effect. Our data show that, in ARVM, sustained intracellular acidosis activates ERK1/2 through proximal activation of the classical Ras/Raf/MEK pathway.
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PMID:Ras triggers acidosis-induced activation of the extracellular-signal-regulated kinase pathway in cardiac myocytes. 1683 Nov 26

Klebsiella pneumoniae (KP), an enterobacterium, usually causes urinary tract infection or pneumonia; however, it has caused severe liver abscess in diabetic patients in recent years. How this emerging virulent KP strain causes liver abscess is not known. This study investigates signalling pathways in HepG2 cells infected by virulent KP. Cells were infected with bacteria for various durations and harvested to screen for signalling molecules by Western blotting. Our results showed that phosphorylated mitogen-activated protein kinase (MAPK) kinase (MEK) 1/2, p44/p42 MAPK and p90 ribosomal S6 kinase (p90RSK) were observed and this pathway was inhibited by MEK1/2 inhibitors U0126 and PD98059. Phosphorylation of MEK3/6, p38 kinase and ATF-2 was also observed and this pathway was inhibited by p38 kinase inhibitors SB203850 and SB202190. Toll-like receptor (TLR) 2 and 4 expressions were increased and maximized 2-4 h post infection. The JNK pathway, Elk, MAPKAPK-2 and HSP27 were not activated. These results suggest that KP infections induce signal transduction through TLR2 and TLR4 and activate two downstream MAP kinase pathways, MEK1/2-p44/p42 MAPK-p90RSK and MEK3/6-p38 kinase-ATF-2, but not the JNK pathway in HepG2 cells. The infected HepG2 eventually showed apoptosis and died.
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PMID:Mitogen-activated protein kinase (MAPK) signalling pathways in HepG2 cells infected with a virulent strain of Klebsiella pneumoniae. 1692 65

The extracellular signal-regulated kinases (ERK1 and ERK2) are important mediators of cell proliferation. Constitutive activation of the ERK proteins plays a critical role in the proliferation of many human cancers. Taking advantage of recently identified substrate docking domains on ERK2, we have used computer-aided drug design (CADD) to identify novel low molecular weight compounds that interact with ERK2 in an ATP-independent manner and disrupt substrate-specific interactions. In the current study, a CADD screen of the 3D structure of active phosphorylated ERK2 protein was used to identify inhibitory compounds. We tested 13 compounds identified by the CADD screen in ERK-specific phosphorylation, cell proliferation, and binding assays. Of the 13 compounds tested, 4 compounds strongly inhibited ERK-mediated phosphorylation of ribosomal S6 kinase-1 (Rsk-1) and/or the transcription factor Elk-1 and inhibited the proliferation of HeLa cervical carcinoma cells with IC(50) values in the 2-10 microM range. These studies demonstrate that CADD can be used to identify lead compounds for development of novel non-ATP-dependent inhibitors selective for active ERK and its interactions with substrates involved in cancer cell proliferation.
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PMID:Characterization of ATP-independent ERK inhibitors identified through in silico analysis of the active ERK2 structure. 1700 Jan 6


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