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)

Neutrophils are short-lived leukocytes that die by apoptosis. Whereas stress-induced apoptosis is mediated by the p38 mitogen-activated protein (MAP) kinase pathway (Frasch, S. C., Nick, J. A., Fadok, V. A., Bratton, D. L., Worthen, G. S., and Henson, P. M. (1998) J. Biol. Chem. 273, 8389-8397), signals regulating spontaneous neutrophil apoptosis have not been fully determined. In this study we found increased activation of protein kinase C (PKC)-beta and -delta in neutrophils undergoing spontaneous apoptosis, but we show that only activation of PKC-delta was directly involved in the induction of apoptosis. PKC-delta can be proteolytically activated by caspase 3. We detected the 40-kDa caspase-generated fragment of PKC-delta in apoptotic neutrophils and showed that the caspase 3 inhibitor Asp-Glu-Val-Asp-fluoromethylketone prevented generation of the 40-kDa PKC-delta fragment and delayed neutrophil apoptosis. In a cell-free system, removal of PKC-delta by immunoprecipitation reduced DNA fragmentation, whereas loss of PKC-alpha, -beta, or -zeta had no significant effect. Rottlerin and LY379196 inhibit PKC-delta and PKC-beta, respectively. Only Rottlerin was able to delay neutrophil apoptosis. Inhibitors of MAP-ERK kinase 1 (PD98059) or p38 MAP kinase (SB202190) had no effect on neutrophil apoptosis, and activation of p42/44 and p38 MAP kinase did not increase in apoptotic neutrophils. We conclude that spontaneous neutrophil apoptosis involves activation of PKC-delta but is MAP kinase-independent.
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PMID:Spontaneous neutrophil apoptosis involves caspase 3-mediated activation of protein kinase C-delta. 1060

The effects of p38 MAP kinase and ERK on UVB induced c-fos gene expression were studied in a human keratinocyte cell line, FL30. UVB significantly increased c-fos gene expression at both the transcriptional and protein levels. p38 and ERK were also significantly activated after UVB irradiation. Treating the cells with p38 inhibitor SB202190 inhibited p38 activation, but not ERK; treating the cells with MEK-1 inhibitor PD98059 inhibited ERK activation without suppressing p38 activation. The kinase activation was determined by Western blots using phospho-p38 or ERK antibodies, or an in vivo p38 activity assay. Further studies demonstrated that blocking p38 almost completely abrogated UVB induced c-fos gene transcription and c-Fos protein synthesis. Inhibiting ERK partially abrogated UVB induced c-fos transcriptional and protein levels. Suppression of both p38 and ERK not only completely blocked UVB induced c-fos expression, but also decreased c-fos gene basal expression. Our data indicated that p38 may play a more important role than ERK in UVB induced c-fos expression in human keratinocytes. Since c-fos expression may play an important role in UVB induced AP-1 activation, and AP-1 activation is known to play a role in tumor promotion, both p38 and ERK could be potential targets for chemoprevention of skin cancer.
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PMID:Activation of p38 MAP kinase and ERK are required for ultraviolet-B induced c-fos gene expression in human keratinocytes. 1060 6

We demonstrate here that p38 mitogen-activated protein (MAP) kinase is activated in response to cellular stimulation by human GH (hGH) in Chinese hamster ovary cells stably transfected with GH receptor cDNA. This activation requires the proline-rich box 1 region of the GH receptor required for JAK2 association and is prevented by pretreatment of cells with the JAK2-specific inhibitor AG490. ATF-2 is both phosphorylated and transcriptionally activated by hGH, and its transcriptional activation also requires the proline-rich box 1 region of the GH receptor. Expression of wild type JAK2 can further enhance hGH-induced ATF-2-, CHOP-, and Elk-1-mediated transcriptional activation, whereas pretreatment with AG490 is inhibitory. Use of either specific pharmacological inhibitors or transient transfection of cells with p38alpha MAP kinase cDNA or a dominant negative variant demonstrated that hGH-stimulated transcriptional activation of ATF-2 and CHOP, but not Elk-1, is regulated by p38 MAP kinase. Both the p38 MAP kinase and p44/42 MAP kinase are critical for hGH-stimulated mitogenesis, whereas only p38 MAP kinase is required for hGH-induced actin cytoskeletal re-organization. p38 MAP kinase is therefore an important regulator in coordinating the pleiotropic effects of GH.
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PMID:Janus kinase 2-dependent activation of p38 mitogen-activated protein kinase by growth hormone. Resultant transcriptional activation of ATF-2 and CHOP, cytoskeletal re-organization and mitogenesis. 1063 15

The potential role of p38 mitogen-activated protein (MAP) kinase in platelet-derived growth factor receptor-alpha (PDGF-Ralpha) gene expression was investigated using cultured rat pulmonary myofibroblasts. p38 MAP kinase was constitutively expressed in myofibroblasts and activated by interleukin (IL)-1beta. A pyridinylimidazole compound, SB203580, completely inhibited the ability of p38 MAP kinase activity to phosphorylate PHAS-1 substrate. SB203580 inhibited IL-1beta-induced up-regulation of PDGF-Ralpha mRNA and protein in a concentration-dependent manner. Other kinase inhibitors, including the mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor PD98059, did not block up-regulation of PDGF-Ralpha. The IL-1beta-induced increase in the number of (125)I-PDGF-AA-binding sites at the cell surface was reduced >70% by pretreatment with SB203580. Accordingly, an enhancement of PDGF-AA-stimulated DNA synthesis following IL-1beta pretreatment was blocked >70% by SB203580. SB203580 did not affect IL-1beta-induced ERK activation, yet enhanced IL-1beta-induced JNK activation approximately 2-fold. Treatment of cells with SB203580 after inhibition of transcription by actinomycin D decreased the half-life of IL-1beta-induced PDGF-Ralpha mRNA from >4 to approximately 1.5 h. Moreover, pretreatment of cells with cycloheximide blocked induction of PDGF-Ralpha mRNA by IL-1beta, suggesting that de novo protein synthesis was required for PDGF-Ralpha mRNA stabilization. These data indicate that p38 MAP kinase regulates PDGF-Ralpha expression at the translational level by signaling the synthesis of an mRNA-stabilizing protein.
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PMID:Regulation of interleukin-1beta -induced platelet-derived growth factor receptor-alpha expression in rat pulmonary myofibroblasts by p38 mitogen-activated protein kinase. 1080 32

Hsp27 kinase activities were studied in adult rat ventricular myocytes following sequential chromatography on Mono Q and Mono S. A basal level of activity was present following cell isolation. FPLC on Mono Q revealed three peaks of activity, peaks 'a', 'b', and 'c'. A fourth peak, 'd', was detected upon subsequent chromatography of the Mono Q flow-through on Mono S. Immunoblotting revealed that peaks 'a', 'b', and 'c' contained predominantly a 49 kDa form of MAPKAP kinase-2. Peak 'd' contained a 43 kDa form. 'In-gel' kinase assays using hsp27 indicated both forms of MAPKAP kinase-2 were active. No other bands of hsp27 kinase activity were detected. Both forms of hsp27 kinase immunoprecipitated with a MAPKAP kinase-2 antibody and have therefore been named MAPKAP kinase-2alpha (p49) and MAPKAP kinase-2beta (p43). MAPKAP kinase-2beta chromatographed on Superose 12 as a 60.7 kDa monomer whereas the behavior of MAPKAP kinase-2alpha suggested both a 65.7 kDa monomer and higher molecular mass complexes. Both activities phosphorylated hsp27 on serine residues, and two-dimensional phosphopeptide mapping indicated the same sites were phosphorylated. A tumor-promoting phorbol ester, phorbol 12-myristate 13-acetate (PMA), stimulated both MAPKAP kinase-2alpha and MAPKAP kinase-2beta activity. Inhibition of MEK activation with PD 98059 or p38alpha/beta MAP kinase activity with SB203580 blocked activation by PMA. However, whereas PD 98059 inhibited only the PMA-stimulated activation, SB203580 inhibited both PMA-stimulated and basal hsp27 phosphorylation. These data demonstrate the presence of two forms of MAPKAP kinase-2 in adult ventricular myocytes. Both forms are activated indirectly by the ERK MAP kinase pathway and directly by p38 MAP kinase but independently regulated.
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PMID:Two distinct forms of MAPKAP kinase-2 in adult cardiac ventricular myocytes. 1082 88

Lipopolysaccharide (LPS) of Gram-negative bacteria interacts with a CD14-independent receptor of mouse bone marrow granulocytes (BMC), and triggers in these cells the expression of CD14, an inducible type of LPS receptor (iLpsR). This particular response of BMC to LPS required the activation of protein tyrosine kinase and p38 MAP kinase. The inhibition of the LPS effect by the MEK inhibitor PD-98059 suggested that the ERK pathway was also involved. Unexpectedly, protein kinase C, myosin light chain kinase, cAMP-, cGMP-, and Ca(2+)/calmodulin-dependent kinases, as well as ecto-protein kinases, were not required for iLpsR expression. However, other yet unidentified serine/threonine protein kinase(s) were implied since the BMC response to LPS was markedly reduced after exposure to three inhibitors of such kinases (K-252a, H-7, and KT-5823). The atypical kinase requirements observed in this study may be due either to a novel signaling LPS receptor complex present in BMC, or to the particular events involved in CD14 biosynthesis.
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PMID:Protein phosphorylation pathways involved during lipopolysaccharide-induced expression of CD14 in mouse bone marrow granulocytes. 1086 78

Lipopolysaccharide (LPS) stimulates multiple signaling events, including nuclear factor-kappaB (NF-kappaB) activity and the mitogen-activated protein (MAP) kinases, ERK, JNK, and p38 in LPS-responsive cells, resulting in transcriptional activation and cytokine generation. LPS-induced signaling via toll-like receptor 4 (TLR4) results in the activation of the transcription factor NF-kappaB. Since LPS activates other signaling cascades in responsive cells, the objective of this study was to determine whether such events are mediated by TLR4 in response to LPS. We generated human embryonic kidney cells (HEK293) that stably express TLR4 (HEK-TLR4) and examined their responsiveness to LPS by measuring NF-kappaB activity and production of interleukin-8 (IL-8). A trans-reporting system was used to measure the activity of Elk-1, an ETS-domain transcription factor targeted by MAP kinase pathways. LPS stimulated NF-kappaB reporter activity and IL-8 production but not Elk-1 activity in HEK-TLR4 cells. When MD-2, a protein associated with the extracellular domain of TLR4, was expressed in these cells, there was a marked increase in Elk-1 activity as well as ERK, JNK, and p38 MAP kinase phosphorylation in response to LPS. TLR4-mediated NF-kappaB reporter activity and IL-8 production was enhanced by the expression of MD-2. This study demonstrates that expression of both TLR4 and MD-2 is required for LPS to activate or augment the MAP kinase pathways, Elk-1 stimulation, and IL-8 generation.
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PMID:Cellular events mediated by lipopolysaccharide-stimulated toll-like receptor 4. MD-2 is required for activation of mitogen-activated protein kinases and Elk-1. 1087 45

Endotoxin-induced cytokine gene expression is regulated, in part, by NF-kappaB. We have shown that both the ERK and p38 mitogen-activated protein (MAP) kinases are necessary for cytokine gene transcription and that the p38 MAP kinase is required for NF-kappaB-driven transcription, so we hypothesized that the MEK --> ERK pathway regulated NF-kappaB-driven transcription as well. We found that a constitutive active MEK --> ERK pathway inhibited NF-kappaB-driven transcription. In addition, both PD 98059 and a dominant negative ERK2 augmented NF-kappaB-driven transcription; however, neither PD 98059 nor MEK1 altered NF-kappaB activation at any level. The constitutive active MEK --> ERK pathway inhibited the phosphorylation of TBP, which is necessary for both interaction with RelA and binding to the TATA box. Due to the fact that we have shown that the p38 MAP kinase modulates TBP activation, we evaluated the effect of the constitutive active MEK --> ERK pathway on p38 MAP kinase activity. We found that the MEK --> ERK pathway negatively regulates NF-kappaB-driven transcription, in part, by inhibiting p38 MAP kinase activity. Thus, the ERK and p38 MAP kinases have differential effects on NF-kappaB-driven transcription.
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PMID:A constitutive active MEK --> ERK pathway negatively regulates NF-kappa B-dependent gene expression by modulating TATA-binding protein phosphorylation. 1087 13

Differentiation therapy for neoplastic diseases has potential for supplementing existing treatment modalities but its implementation has been slow. One of the reasons is the lack of full understanding of the complexities of cellular pathways through which signals for differentiation lead to cell maturation. This was addressed in this study using HL60 cells, a well-established model of differentiation of neoplastic cells. SB 203580 and SB 202190, specific inhibitors of a signaling protein p38 MAP kinase, were found to markedly accelerate monocytic differentiation of HL60 cells induced by low concentrations of 1,25-dihydroxyvitamin D(3) (1,25D(3)). Surprisingly, inhibition of p38 activity resulted in sustained enhancement of p38 phosphorylation and of its in vitro activity in the absence of the inhibitor, indicating up-regulation of the upstream components of the p38 pathway. In addition, SB 203580 or SB 202190 treatment of HL60 cells resulted in a prolonged activation of the JNK and, to a lesser extent, the ERK pathways. The data are consistent with the hypothesis that in HL60 cells an interruption of a negative feedback loop from a p38 target activates a common regulator of multiple MAPK pathways. The possibility also exists that JNK and/or ERK pathways amplify a differentiation signal provided by 1,25D(3).
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PMID:Inhibition of p38 MAP kinase activity up-regulates multiple MAP kinase pathways and potentiates 1,25-dihydroxyvitamin D(3)-induced differentiation of human leukemia HL60 cells. 1089 94

We have used an antibody that specifically recognizes eukaryotic initiation factor 4E (eIF4E) when it is phosphorylated at Ser(207) to characterize eIF4E phosphorylation in the nervous system of APLYSIA: The level of phosphorylated eIF4E, but not the level of total eIF4E, was significantly correlated with the basal rate of translation measured from different animals. Serotonin (5-HT), a transmitter that regulates the rate of translation in APLYSIA: neurons, had mixed effects on eIF4E phosphorylation. 5-HT decreased eIF4E phosphorylation in sensory cell clusters through activation of protein kinase C. 5-HT increased eIF4E phosphorylation in the whole pleural ganglia. In the APLYSIA: nervous system, eIF4E phosphorylation correlated with phosphorylation of the p38 MAP kinase, but not the p42 MAP kinase (ERK). Furthermore, an inhibitor of the p38 MAP kinase significantly decreased basal eIF4E phosphorylation, but an inhibitor of the MAP or ERK kinase (MEK) did not. Despite the correlation of eIF4E phosphorylation with the basal rate of translation, inhibition of eIF4E phosphorylation by an inhibitor of the p38 MAP kinase did not significantly decrease the rate of translation.
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PMID:Regulation of eukaryotic initiation factor 4E phosphorylation in the nervous system of Aplysia californica. 1089 66


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