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)

Central nervous system (CNS) infections caused by Streptococcus pneumoniae still have a disastrous outcome. Underlying immunological and CNS cellular events are largely enigmatic. We used pneumococcal cells walls (PCW) to investigate microglial responses as these cells are prominent sensors and effectors during neuropathological changes. PCW stimulation of mouse microglia in vitro evoked the release of the cyto- and chemokines, TNF-alpha, IL-6, IL-12, KC, MCP-1, MIP-1alpha, MIP-2 and RANTES as well as soluble TNF receptor II, a potential TNF-alpha antagonist. The release induction followed extremely steep dose-response relations, and short exposure periods (15 min) were already sufficient to trigger substantial responses. PCW signaling controlling the release depended on both p38 and p42/p44 (ERK2/ERK1) MAP kinase activities. The kinase inhibitor, tyrphostin AG126 prevented the PCW-inducible phosphorylation of p42/p44(MAPK), potently blocked cytokine release and drastically reduced the bioavailable TNF-alpha, since it only marginally affected the release of soluble TNF receptors. Moreover, in an in vivo model of pneumococcal meningitis, AG126 significantly attenuated the PCW-induced leukocyte influx to the cerebrospinal fluid. The findings imply that pneumococcal CNS infection can cause a rapid and massive microglial activation and that ERK/MAPK pathway(s) are potential targets for pharmacological interventions.
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PMID:The protein tyrosine kinase inhibitor AG126 prevents the massive microglial cytokine induction by pneumococcal cell walls. 1144 64

Hepatocyte growth factor/scatter factor (HGF/SF) is considered to be a mesenchymal-derived factor that acts via a dual system receptor, consisting of the MET receptor and proteoglycans present on adjacent epithelial cells. Surprisingly, HGS/SF stimulated the migration of rat mammary (Rama) 27 fibroblasts, although it failed to stimulate their proliferation. HGF/SF stimulated a transient activation of mitogen-activated protein kinases p44 and p42 (p42/44(MAPK)), with a maximum level of dual phosphorylation of p42/44(MAPK) occurring 10-15 min after the addition of the growth factor, which was followed by a rapid decrease to near basal levels after 20 min. Interestingly, a second phase of p42/44(MAPK) dual phosphorylation was observed at later times (3 h to 10 h). PD098059, a specific inhibitor of MEK-1, prevented the dual phosphorylation of p42/44(MAPK) and also the phosphorylation of p90(RSK) (ribosomal subunit S6 kinase), which mirrored the kinetics of p42/44(MAPK) phosphorylation. Moreover, PD098059 prevented the HGF/SF-induced migration of Rama 27 cells. HGF/SF also induced an early increase in the phosphorylation of protein kinase B/Akt. Akt phosphorylation was elevated 15 min after the addition of HGF/SF and then declined to basal levels by 30 min. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PtdIns3K), prevented the increase in Akt phosphorylation and abolished HGF/SF-induced migration of fibroblasts. PD098059 also inhibited the stimulation of Akt phosphorylation by HGF/SF and wortmannin similarly inhibited the stimulation of p42/44(MAPK) dual phosphorylation. These results suggest that HGF/SF-induced motility depends on both the transient dual phosphorylation of p42/44(MAPK) and the activation of PtdIns3K in Rama 27 fibroblasts and that these pathways are mutually dependent.
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PMID:Hepatocyte growth factor/scatter factor stimulates migration of rat mammary fibroblasts through both mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt pathways. 1150 2

We have examined the mechanisms regulating prostacyclin (PGI(2)) synthesis after acute exposure of human umbilical vein endothelial cells (HUVEC) to interleukin-1 alpha (IL-1 alpha). IL-1 alpha evoked an early (30 min) release of PGI(2) and [(3)H]arachidonate that was blocked by the cytosolic phospholipase A(2)alpha (cPLA(2)alpha) inhibitor arachidonyl trifluoromethyl ketone. IL-1 alpha-mediated activation of extracellular signal-regulated kinase 1/2 (ERK1/2; p42/p44(mapk)) coincided temporally with phosphorylation of cPLA(2)alpha and with the onset of PGI(2) synthesis. The mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors, PD-98059 and U-0126, blocked IL-1 alpha-induced ERK activation and partially attenuated cPLA(2)alpha phosphorylation and PGI(2) release, suggesting that ERK-dependent and -independent pathways regulate cPLA(2)alpha phosphorylation. SB-203580 treatment enhanced IL-1 alpha-induced MEK, p42/44(mapk), and cPLA(2)alpha phosphorylation but reduced thrombin-stimulated MEK and p42/44(mapk) activation. IL-1 alpha, but not thrombin, activated Raf-1 as assessed by immune-complex kinase assay, as did SB-203580 alone. These results show that IL-1 alpha causes an acute upregulation of PGI(2) generation in HUVEC, establish a role for the MEK/ERK/cPLA(2)alpha pathway in this early release, and provide evidence for an agonist-specific cross talk between p38(mapk) and p42/44(mapk) that may reflect receptor-specific differences in the signaling elements proximal to MAPK activation.
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PMID:Agonist-specific cross talk between ERKs and p38(mapk) regulates PGI(2) synthesis in endothelium. 1154 64

Posttranslational processing of the pro-growth hormone-releasing hormone (proGHRH) peptide can result in the formation of at least two peptide products: GHRH and the C-terminal peptide, GHRH-related peptide (GHRH-RP). While cyclic adenosine monophosphate transduces many of the actions of GHRH, other pathways also have been implicated in its actions. The aims of this study were to examine and characterize the activation of mitogen-activated protein kinase (MAPK) pathways by GHRH, and GHRH-RP in pituitary-derived GH3 cells, as well as the activation of the transcription factors that serve as substrates for these kinases. GHRH rapidly increased p44/p42 MAPK activity in GH3 cells in a protein kinase A-dependent and a protein kinase C-independent manner and stimulated the activation of the transcription factor Elk-1. By contrast, GHRH-RP and p75-92NH2 had no effect on p44/p42 MAPK phosphorylation in these cells. Additionally, we determined that all three peptides, GHRH, GHRH-RP, and p75-92NH2, rapidly and specifically increase phosphorylation of p38 MAPK and stimulate the activation of the nuclear factor CHOP. These are the first studies to demonstrate the activation of Elk-1 by GHRH and the activation of p38 MAPK and CHOP by GHRH, GHRH-RP, and p75-92NH2. We conclude that members of the GHRH family of peptides differentially activate multiple intracellular signaling pathways and suggest that the biologic actions of GHRH may be far more diverse than previously thought.
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PMID:Peptides derived from pro-growth hormone-releasing hormone activate p38 mitogen-activated protein kinase in GH3 pituitary cells. 1157 18

Protein kinase C (PKC) epsilon and PKCdelta translocation in neonatal rat ventricular myocytes (NRVMs) is accompanied by subsequent activation of the ERK, JNK, and p38(MAPK) cascades; however, it is not known if either or both novel PKCs are necessary for their downstream activation. Use of PKC inhibitors to answer this question is complicated by a lack of isoenzyme specificity, and the fact that many PKC inhibitors stimulate JNK and p38(MAPK) activity. Therefore, replication-defective adenoviruses (Advs) encoding constitutively active (ca) mutants of PKCepsilon and PKCdelta were used to test if either or both of these PKCs are sufficient to activate ERKs, JNKs, and/or p38(MAPK) in NRVMs. Adv-caPKCepsilon infection (1 to 25 multiplicities of viral infection (MOI); 4 to 48 hours) increased total PKCepsilon levels in a time- and dose-dependent manner, with maximal expression observed 8 hours after Adv infection. Adv-caPKCepsilon induced a time- and dose-dependent increase in phosphorylated p42 and p44 ERKs, as compared with a control Adv encoding beta-galactosidase (Adv-nebetagal). Maximal ERK phosphorylation occurred 8 hours after Adv infection. In contrast, JNK was only minimally activated, and p38(MAPK) was relatively unaffected. Adv-caPKCdelta infection (1 to 25 MOI, 4 to 48 hours) increased total PKCdelta levels in a similar fashion. Adv-caPKCdelta (5 MOI) induced a 29-fold increase in phosphorylated p54 JNK, and a 15-fold increase in phosphorylated p38(MAPK) 24 hours after Adv infection. In contrast, p42 and p44 ERK were only minimally activated. Whereas neither Adv induced NRVM hypertrophy, Adv-caPKCdelta, but not Adv-caPKCepsilon, induced NRVM apoptosis. We conclude that the novel PKCs differentially regulate MAPK cascades and apoptosis in an isoenzyme-specific and time-dependent manner.
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PMID:Differential activation of mitogen-activated protein kinase cascades and apoptosis by protein kinase C epsilon and delta in neonatal rat ventricular myocytes. 1170 8

Connective tissue growth factor/hypertrophic chondrocyte specific gene product 24 (CTGF/Hcs24) promotes proliferation and differentiation of chondrocytes in culture. We investigated the roles of two major types of mitogen activated protein kinase (MAPK) in the promotion of proliferation and differentiation by CTGF/Hcs24. Here we report the effects of the MAPKK/MEK 1/2 inhibitor, PD098059, and p38 MAPK inhibitor, SB203580, in a human chondrosarcoma-derived chondrocytic cell line (HCS-2/8) and rabbit growth cartilage (RGC) cells treated with CTGF/Hcs24. In the proliferation phase, CTGF/Hcs24 induced a approximately fivefold increase in the phosphorylation of p44/42 MAPK/ERK and a approximately twofold increase in that of p38 MAPK in an in vivo kinase assay. These inhibitors of MAPKK and MAPK suppressed phosphorylation of ets-like gene-1 (Elk-1) and nuclear activating transcription factor-2 (Atf-2) induced by CTGF/Hcs24 in a dose-dependent manner, respectively. Western blot analysis showed that phosphorylation of ERK was induced from 30 to 60 min and phosphorylation of p38 MAPK from 10 to 15 min after the addition of CTGF/Hcs24 in confluence HCS-2/8 cells. PD098059 suppressed the DNA synthesis of HCS-2/8 cells and RGC cells, while SB203580 did not. On the other hand, the p38 MAPK inhibitor, SB203580, completely inhibited the CTGF/Hcs24-induced synthesis of proteoglycans in HCS-2/8 cells and RGC cells but the MEK1/2 inhibitor, PD098059, did not. These results suggest that ERK mediates the CTGF/Hcs24-induced proliferation of chondrocytes, and that p38 MAPK mediates the CTGF/Hcs24-induced differentiation of chondrocytes.
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PMID:CTGF/Hcs24 induces chondrocyte differentiation through a p38 mitogen-activated protein kinase (p38MAPK), and proliferation through a p44/42 MAPK/extracellular-signal regulated kinase (ERK). 1173 99

Protein kinase C (PKC), a family of lipid-activated serine kinases, is involved in multiple functions in the regulation of growth control. The PKC-related isoform PKC mu/PKD has been implicated in mitogenic signal cascades because of the activation of p42/p44 MAPK leading to Elk1-mediated gene transcription, and PKC mu/PKD has been shown to be activated via a PKC-dependent pathway. By using confocal analyses, we demonstrate here that PKC mu partially colocalizes with PKC eta in different cell types. Colocalization depends on the presence of the PKC mu pleckstrin homology domain. Coexpression of constitutively active PKC eta with PKC mu leads to a significant enhancement of the PKC mu substrate phosphorylation capacity as a result of an increased phosphorylation of the activation loop Ser(738/742) of PKC mu, whereas Ser(910) autophosphorylation remains unaffected. In vitro phosphorylation experiments show that PKC eta directly phosphorylates PKC mu on activation loop serines. Consequently, the p42 MAPK cascade is triggered leading to an increase in reporter gene activity driven by a serum-responsive element in HEK293 cells. At the same time, PKC eta-mediated JNK activation is reduced, providing evidence for a mutual regulation of PKC mu/PKC eta affecting different arms of the p38/ERK/JNK pathways. Our data provide evidence for the sequential involvement of selective PKC isoforms in kinase cascades and identify the relevant domains in PKC mu for interaction with and activation by PKC eta as pleckstrin homology domain and activation loop.
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PMID:Protein kinase C (PKC)eta-mediated PKC mu activation modulates ERK and JNK signal pathways. 1174 79

Bryostatin 1 (bryo 1) is known to induce the differentiation and cell cycle arrest of human lymphoid leukemia cells in vitro. The extracellular signal-regulated kinase (ERK), originally identified as a participant in mitogenic signaling, has recently been implicated in the signaling of cellular differentiation. To examine the role of the ERK/mitogen-activated protein (MAP) kinase pathway in B-lymphoid cell differentiation of the Reh Acute Lymphoblastic Leukemia cell line, the effects of bryo 1 on ERK activation were determined. On bryo 1 treatment, the activity of ERK2 (p42) rapidly increased, with ERK1 (p44) protein levels remaining constant. p44/42 immunoprecipitates from lysates of bryo 1-treated cells had increased their ability to phosphorylate the transcription factor Elk-1. Constitutive AP-1 activity was shown to be potentiated after bryo 1 treatment using electrophoretic mobility shift assays. The protein composition of the AP-1 transcription factor complex activated by bryo 1 was analyzed using supershift analysis with specific antibodies against c-Fos, Fos B, c-Jun, Jun B, and Jun D proteins. Supershift analysis revealed that the bryo 1-induced AP-1 complex was composed predominantly of Fos B and Jun D. Therefore, we evaluated the effects of inhibiting MAP/ERK kinase (MEK) on both DNA binding and cellular differentiation. Treatment of Reh cells with 20 microM PD98059, a specific inhibitor of MEK, inhibited bryo 1-induced ERK activity and DNA binding. Furthermore, PD98059 blocked the bryo 1-induced differentiation of Reh cells, as assessed by a number of features associated with lymphoid differentiation, including changes in morphology, cell growth arrest, attachment, and increased expression of the leukocyte integrin CD11c. Moreover, transient transfection of Reh cells with antisense MAP kinase oligonucleotides blocked bryo 1-induced expression of CD11c. Our analysis also shows that CD11c's gene promoter activity is augmented by bryo 1. Therefore, we conclude that activation of the MEK/ERK signaling pathway is necessary for bryo 1-induced differentiation of the pre-B Acute Lymphoblastic Leukemia cell line Reh.
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PMID:Mitogen-activated protein kinase is required for bryostatin 1-induced differentiation of the human acute lymphoblastic leukemia cell line Reh. 1175 59

In transfected cells and non-neuronal tissues many G-protein-coupled receptors activate p44/42 MAP kinase (ERK), a kinase involved in both hippocampal synaptic plasticity and learning and memory. However, it is not clear to what degree these receptors couple to ERK in brain. G(s)-coupled beta-adrenergic receptor activation of ERK in neurons is critical in the regulation of synaptic plasticity in area CA1 of the hippocampus. In addition, alpha(1)- and alpha(2)-adrenergic receptors, present in CA1, could potentially activate ERK. We find that, like the beta-adrenergic receptor, the G(q)-coupled alpha(1)AR activates ERK in adult mouse CA1. However, activation of the G(i/o)-coupled alpha(2)AR does not activate ERK, nor does activation of a homologous G(i/o)-coupled receptor enriched in adult mouse CA1, the 5HT(1A) receptor. In contrast, the nonhomologous G(i/o)-coupled gamma-aminobutyric acid type B receptor does activate ERK in adult mouse CA1. Surprisingly, activation of alpha(2)ARs in CA1 from immature animals where basal phospho-ERK is low induces ERK phosphorylation. These data suggest that although most G-protein-coupled receptor subtypes activate ERK in non-neuronal cells, the coupling of G(i/o) to ERK is tightly regulated in brain.
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PMID:ERK activation by G-protein-coupled receptors in mouse brain is receptor identity-specific. 1178 65

Platelet activating factor (PAF) interacts with cell surface G protein-coupled receptors on leukocytes to induce degranulation, leukotriene C(4) (LTC(4)) generation, and chemokine CCL2 production. Using a basophilic leukemia RBL-2H3 cell line expressing wild-type PAF receptor (PAFR) and a phosphorylation-deficient mutant (mPAFR), we have previously demonstrated that receptor phosphorylation mediates desensitization of PAF-induced degranulation. Here, we sought to determine the role of receptor phosphorylation on PAF-induced LTC(4) generation and CCL2 production. We found that PAF caused a significantly enhanced LTC(4) generation in cells expressing mPAFR when compared with PAFR cells. In contrast, PAF-induced CCL2 production was greatly reduced in mPAFR cells. Pertussis toxin and U0126, which inhibit G(i) and p44/42 mitogen-activated protein kinase (ERK) activation, respectively, caused very little inhibition of PAF-induced CCL2 production (approximately 20% inhibition). In contrast, these inhibitors almost completely blocked both PAF-induced ERK phosphorylation and LTC(4) generation in PAFR cells. However, in mPAFR cells pertussis toxin only partially inhibited PAF-induced ERK phosphorylation. A Ca(2+)/calmodulin inhibitor had no effect on PAF-induced ERK phosphorylation in PAFR cells but completely blocked the response in mPAFR cells. These data demonstrate that receptor phosphorylation, which serves to desensitize PAF-induced LTC(4) generation, is required for chemokine CCL2 production. They also indicate a previously unrecognized selectivity in G protein usage and ERK activation for PAF-induced responses. Whereas PAF-induced CCL2 production is, in large part, mediated independently of G(i) activation or ERK phosphorylation, LTC(4) generation requires ERK phosphorylation, which is mediated by different G proteins depending on the phosphorylation status of the receptor.
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PMID:Distinct roles of receptor phosphorylation, G protein usage, and mitogen-activated protein kinase activation on platelet activating factor-induced leukotriene C(4) generation and chemokine production. 1193 80


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