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)

SB 203580 has been widely used to specifically shut down the p38 MAP kinase-dependent pathway, although it is capable of inducing c-Raf kinase activity in cells. The present study demonstrates that SB 203580 activates members of the ERK cascade, c-Raf, MEK, and ERK, in human monocytic THP-1 cells. The activation of these kinases was sustained for at least 24 h after SB 203580 treatment and was also observed in U937 cells, suggesting that c-Raf efficiently transduces the signal even in the presence of the inhibitor in these cells. However, the expression of ERK cascade-dependent genes, such as c-fos and IL-1beta, was extremely limited. Analysis of the cellular distribution of ERK in SB 203580-treated cells indicated that nuclear translocation of phosphorylated ERK was impaired. Also, nuclear translocation of ERK induced by 12-O-tetradecanoyl-phorbol-13-acetate (TPA) was inhibited by SB 239063, which does not associate with c-Raf and is highly selective for p38 MAP kinase. In addition, the forced expression of the dominant negative mutant of p38 MAP kinase suppressed serum responsive element-dependent transactivation induced by TPA. These results suggest that the steady-state level of p38 MAP kinase activity modulates ERK signaling.
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PMID:Regulation of ERK-mediated signal transduction by p38 MAP kinase in human monocytic THP-1 cells. 1280 11

Matrix metalloproteinases (MMPs) contribute to the pathophysiology of brain injury and inflammation but little is known about their regulatory signaling pathways in brain cells. Here we examine the role of mitogen-activated protein (MAP) kinase pathways in MMP-9 regulation in cortical rat astrocytes. The protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) induced MMP-9 but not MMP-2 secretion as measured by gelatin zymography. Northern blot and RT-PCR analysis showed that MMP-9 responses occurred at the mRNA level. Although PMA increased phosphorylation in all three major MAP kinase pathways (ERK, p38 MAP kinase, and JNK), only inhibition of the ERK pathway by the MEK/ERK inhibitor U0126 (0.1-10 microM) significantly reduced MMP-9 upregulation, even when treatment was delayed for 4 h after PMA exposure. Inhibitors of p38 MAP kinase (SB203580) and JNK (SP600125) had no effect. This PKC pathway was compared to a cytokine response by exposing astrocytes to TNFalpha, which also activated MAP kinase and induced MMP-9 upregulation. But in this case, all three MAP kinase inhibitors (U0126, SB203580, and SP600125) reduced TNFalpha-induced MMP-9 upregulation. Taken together, these results suggest that the ERK MAP kinase is essential for MMP-9 upregulation via PKC and cytokine pathways in astrocytes.
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PMID:Essential role for ERK mitogen-activated protein kinase in matrix metalloproteinase-9 regulation in rat cortical astrocytes. 1289 4

Inhaled hexavalent chromium (Cr(VI)) promotes pulmonary disease and lung cancer through poorly defined mechanisms. These mechanisms were studied in A549 lung epithelial cells to investigate the hypothesis that nontoxic Cr(VI) exposures selectively activate cell signaling that shifts the balance of gene transcription. These studies demonstrated that nontoxic doses of Cr(VI) (10 microM) increased reactive oxygen species and selectively activated c-Jun N-terminal kinase (JNK), relative to ERK or p38 MAP kinase. In contrast, only toxic, nonselective levels of exogenous oxidants stimulated JNK. However, JNK activation in response to Cr(VI) and exogenous H(2)O(2) (1 mM) shared requirements for intracellular thiol oxidation, activation of Src family kinases, and p130(cas) (Cas). Cr(VI) did not mimic H(2)O(2)-mediated stimulation of JNK in fibroblasts containing only Src and did not activate Src or Yes in A549 cells. Instead, Fyn and Lck were activated in A549 cells, indicating activation of specific Src family kinases in response to Cr(VI). Finally, Cr(VI) was demonstrated to directly activate purified Fyn in vitro and the majority of this activation did not require oxidant generation. These data suggest that nontoxic levels of Cr(VI), which can shift patterns of gene transcription, are selective in their activation of cell signaling and that Cr(VI) can directly activate Src family kinases independently of reactive oxygen species generation.
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PMID:Selective activation of Src family kinases and JNK by low levels of chromium(VI). 1290 92

Because selective inhibition of cyclooxygenase-2 (COX-2) suppressed the induction of skin tumors in mice by UV and as UV has been shown to induce expression of COX-2 in skin and cells, COX-2 may be crucial for photocarcinogenesis of the skin. We studied the mechanism of UVB-induced expression of COX-2 focusing on the signal transduction pathway involved. Hydrogen peroxide (H2O2) treatment of HaCaT cells induced expression of COX-2 and pretreatment with the antioxidant N-acetylcysteine (NAC) partly inhibited the UVB-induced expression of COX-2 protein in HaCaT cells, suggesting that oxidative stress contributes to COX-2 induction. To examine the signaling pathways involved in the UVB-induced expression of COX-2 in HaCaT cells, we analysed the expression of COX-2 protein after treatment with various inhibitors of signaling molecules. Inhibition of EGFR by a specific inhibitor and by a neutralizing antibody suppressed the induction of COX-2 expression by UV. Although a neutralizing antibody to transforming growth factor-alpha (TGF-alpha) suppressed COX-2 expression induced by TGF-alpha, it did not suppress COX-2 expression by UV, indicating that a direct activation of EGFR is involved. Treatment of cells at low temperature (4 degrees C) inhibited UVB-induced JNK activation, but it did not inhibit COX-2 expression by UV. Inhibitors of MEK, p38 MAP kinase and PI3-kinase, suppressed the induction of COX-2 expression by UV. In contrast, an erbB-2 inhibitor augmented the UVB-induced increase of COX-2 protein. These data indicate that oxidative stress in association with activation of EGFR, ERK, p38 MAP kinase, and PI3-kinase plays crucial roles in the UVB induction of expression of COX-2.
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PMID:Involvement of EGF receptor activation in the induction of cyclooxygenase-2 in HaCaT keratinocytes after UVB. 1293 Mar 1

Deactivation of brain macrophages (microglia) by transforming growth factor-beta (TGF-beta) is characterized by enhanced Kv1.3 K+ channel expression. The intracellular mechanisms by which TGF-beta causes K+ channel upregulation in microglia have remained unclear. We show here that the protein kinase inhibitor H7 abolishes TGF-beta-induced increases in delayed rectifier K+ current density. However, this effect cannot be related to inhibition of protein kinase C (PKC) or protein kinase A (PKA) activity, because specific PKC and PKA inhibitors did not exhibit effects identical to H7. TGF-beta-induced Kv1.3 channel expression was also unaffected by inhibitors of tyrosine kinase, Ca2+/calmodulin kinase II and mitogen-activated protein (MAP) kinase ERK. In contrast, delayed rectifier K+ current density was larger in TGF-beta-stimulated cells pretreated with the p38 MAP kinase inhibitor SB203580 or the phosphatidylinositol 3-OH (PI3) kinase inhibitor wortmannin, suggesting that both p38 MAP kinase and PI3 kinase regulate negatively the upregulation of Kv1.3 K+ channels in TGF-beta-treated microglial cells.
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PMID:Effects of kinase inhibitors on TGF-beta induced upregulation of Kv1.3 K+ channels in brain macrophages. 1296 Oct 89

Inflammatory osteolysis induced by implant-derived wear debris is associated with infiltration of various cell-types to the implant-bone interface leading to abundant secretion of pro-inflammatory cytokines and activation of proteinases that together lead to propagation of the localized inflammatory response and periprosthetic bone erosion. Tumor necrosis factor family members are considered to be direct mediators of inflammation and osteolysis. These cytokines exert their osteoclastic effects via activation of the transcription factor NF-kappaB and certain MAP kinases, including c-Jun, Erks and p38, all known to be essential for the development of osteoclasts. We have recently documented that the osteoclastogenic cytokines TNF and RANKL play a pivotal role in the development of inflammatory osteolysis. We have also found that PMMA particles stimulate osteoclastogenesis, at least in part, by induction of RANKL, TNF, and by activation of the transcription factor NF-kappaB. More importantly, our data indicate that inhibitors of the osteoclastogenic factors, TNF and RANKL abrogate particle-induced osteoclastogenesis. In the current study, we investigated if PMMA particles activate MAP kinases, and the potential role of these kinases as mediators of osteolysis. Using kinase assays, we show that in osteoclast precursors, PMMA particles markedly and rapidly activate p38 and ERK MAP kinases. This activation was specific, evident by complete blockade with specific inhibitory compounds. Similarly, we show that PMMA particles activate the JNK pathway, which is known to be involved in inflammatory and osteoclastogenic events. We also show that p38 MAP kinase regulates PMMA-activation of NF-kappaB, thus providing a possible mechanism for particle action in osteoclast precursors. Finally, we provide evidence that specific inhibitors of MAP kinases are capable of inhibiting PMMA-stimulated osteoclastogenesis. These data provide evidence that MAP kinases are potent mediators of particle-induced osteoclastogenesis.
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PMID:Mitogen-activated protein (MAP) kinases mediate PMMA-induction of osteoclasts. 1455 17

The role of lysophosphatidylcholine (LPC) in the induction of MCP-1, IL-8 and RANTES, which are chemotactic factors to monocytes, neutrophils and lymphocytes, respectively, by human vascular endothelial cells (EC), was examined. LPC induced the expression of MCP-1 and IL-8 in a concentration- and time-dependent manner in microvascular EC (MVEC) and in large vessel EC from aorta, pulmonary artery and umbilical vein. LPC also induced RANTES in MVEC but not in large vessel EC. Signaling pathways responsible for LPC induction of chemokines were examined in MVEC. LPC and TNFalpha, a cytokine secreted in sites of inflammation, additively stimulated RANTES expression. LPC did not augment TNFalpha induction of MCP-1 or IL-8. A platelet-activating factor receptor antagonist (BN52021) failed to block LPC induction of MVEC chemokines, but the G(i)-protein inhibitor pertussis toxin partially blocked LPC induction of RANTES and IL-8. LPC activated multiple kinases in MVEC; it increased the phosphorylation of ERK1/2, AKT and p38 MAP kinase in a time-dependent manner. An inhibitor of the MAPK/ERK pathway, PD98059, blocked the phosphorylation of ERK1/2 and RANTES induction by LPC, but augmented IL-8 induction. LY294002, a specific inhibitor of phosphoinositide 3 kinase (PI3 kinase), blunted the phosphorylation of AKT and inhibited LPC induction of RANTES more strongly than IL-8. Inhibition of p38 MAP kinase pathway by SB202190 also blocked LPC-induced expression of IL-8 and RANTES. Our results suggest that LPC induction of chemokines in MVEC is distinct from that in large vessel EC, and required the activities of MAP kinases and PI3 kinase for the induction of RANTES and IL-8. We speculate that the presence of LPC, a bioactive lipid product of phospholipase A(2) (PLA(2)) and a constituent of oxidized low-density lipoprotein, can differentially influence the chemotaxis of particular leukocyte subpopulations during inflammation.
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PMID:Lysophosphatidylcholine regulates human microvascular endothelial cell expression of chemokines. 1459 94

Angiotensin II (Ang II) stimulates protein synthesis in vascular smooth muscle cells (VSMCs), possibly secondary to regulatory changes at the initiation of mRNA translation. Mitogen-activated protein (MAP) kinase signal-integrating kinase-1 (Mnk1), a substrate of ERK and p38 MAP kinase, phosphorylates eukaryotic initiation factor 4E (eIF4E), an important factor in translation. The goal of the present study was to investigate the role of Mnk1 in Ang II-induced protein synthesis and to characterize the molecular mechanisms by which Mnk1 and eIF4E is activated in rat VSMCs. Ang II treatment resulted in increased Mnk1 activity and eIF4E phosphorylation. Expression of a dominant-negative Mnk1 mutant abolished Ang II-induced eIF4E phosphorylation. PD98059 or introduction of kinase-inactive MEK1/MKK1, but not SB202190 or kinase-inactive p38 MAP kinase, inhibited Ang II-induced Mnk1 activation and eIF4E phosphorylation, suggesting that ERK, but not p38 MAP kinase, is required for Ang II-induced Mnk1-eIF4E activation. Further, dominant-negative constructs for Ras, but not for Rho, Rac, or Cdc42, abolished Ang II-induced Mnk1 activation. Finally, treatment of VSMCs with CGP57380, a novel specific kinase inhibitor of Mnk1, resulted in dose-dependent decreases in Ang II-stimulated phosphorylation of eIF4E, protein synthesis, and VSMC hypertrophy. In summary, these data demonstrated that (1) Ang II-induced Mnk1 activation is mediated by the Ras-ERK cascade in VSMCs, and (2) Mnk1 is involved in Ang II-mediated protein synthesis and hypertrophy, presumably through the activation of translation-initiation. The Mnk1-eIF4E pathway may provide new insights into molecular mechanisms involved in vascular hypertrophy and other Ang II-mediated pathological states.
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PMID:Mnk1 is required for angiotensin II-induced protein synthesis in vascular smooth muscle cells. 1460 21

Although LPS receptor (CD14) signaling is mediated in part by beta2 integrins, the role of beta2 integrins in macrophage LPS signaling postinjury remains unknown. To study this, splenic macrophages were isolated from mice 7 days postburn, and inflammatory mediator production was determined. Macrophages isolated from injured mice produced higher levels of PGE2, TNF-alpha, IL-6, and IL-10 and lower levels of IL-12 in response to LPS stimulation than did cells from sham-treated mice. Blockade of beta2 integrin signaling by addition of antibodies against the CD11b (alphaCD11b) to the cultures increased IL-10 production by macrophages from injured mice without affecting other mediators. In contrast, sham macrophage responses to LPS were unaffected by alphaCD11b. Inhibition of p38 MAP kinase activity attenuated IL-10 production and abrogated the enhanced IL-10 response induced by alphaCD11b, whereas ERK 1/2 inhibition had no effect. Burn injury was associated with increased levels of total and phosphorylated p38 MAP kinase. These findings indicate that LPS signaling via beta2 integrins acts to attenuate the exaggerated induction of IL-10 by macrophages postinjury. Moreover, this effect of beta2 integrin signaling postinjury appears to be downstream of the p38 MAP kinase pathway and is independent of other markers of macrophage hyperactivity.
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PMID:Regulation of macrophage IL-10 production postinjury via beta2 integrin signaling and the P38 MAP kinase pathway. 1462 77

Lipopolysaccharide (LPS) and porins of Gram-negative outer membranes are the main pathogenic factors implicated in the clinical syndrome of septic shock. The biological activity of porins and LPS are similar, but they occur by different mechanisms. It seems that porins act through different intracellular pathways with respect to LPS. In this study we analyzed the role of several inhibitors of the MEK/ERK signal pathway on the induction of proinflammatory and immunological cytokines in U937 cell line stimulated by Salmonella typhimurium porins and compared it to the cytokine induction after LPS stimulation. We investigated the effects of p38 MAP kinase inhibitor SB-203580, MEK/ERK kinase inhibitor PD-098059 and Raf-1 inhibitor forskolin, and demonstrated that they modulate cytokine mRNA expression in a different manner as a consequence of the use of porins or LPS as stimuli. TNF-alpha and IL-1beta mRNA expression is decreased by PD-098059 after stimulation with LPS but not with porins in differentiated U937 cells. IL-10 mRNA expression is inhibited by SB-203580 and PD-098059 after stimulation with porins in U937 cells. IL-6 and IL-8 mRNA expression is not changed by PD-098059 or SB-203580, after stimulation either with porins or LPS. Furthermore, mRNA expression of the studied cytokines, except for GM-CSF, is not changed using forskolin.
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PMID:Induction of cytokine mRNA expression in U937 cells by Salmonella typhimurium porins is regulated by different phosphorylation pathways. 1462 44


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