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

---

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

Activation of c-Jun N-terminal kinases (JNKs)/stress-activated protein kinases is an early response of cells upon exposure to DNA-damaging agents. JNK-mediated phosphorylation of c-Jun is currently understood to stimulate the transactivating potency of AP-1 (e.g., c-Jun/c-Fos; c-Jun/ATF-2), thereby increasing the expression of AP-1 target genes. Here we show that stimulation of JNK1 activity is not a general early response of cells exposed to genotoxic agents. Treatment of NIH 3T3 cells with UV light (UV-C) as well as with methyl methanesulfonate (MMS) caused activation of JNK1 and an increase in c-Jun protein and AP-1 binding activity, whereas antineoplastic drugs such as mafosfamide, mitomycin C, N-hydroxyethyl-N-chloroethylnitrosourea, and treosulfan did not elicit this response. The phosphatidylinositol 3-kinase inhibitor wortmannin specifically blocked the UV-stimulated activation of JNK1 but did not affect UV-driven activation of extracellular regulated kinase 2 (ERK2). To investigate the significance of JNK1 for transactivation of c-jun, we analyzed the effect of UV irradiation on c-jun expression under conditions of wortmannin-mediated inhibition of UV-induced stimulation of JNK1. Neither the UV-induced increase in c-jun mRNA, c-Jun protein, and AP-1 binding nor the activation of the collagenase and c-jun promoters was affected by wortmannin. In contrast, the mitogen-activated protein kinase/ERK kinase inhibitor PD98056, which blocked ERK2 but not JNK1 activation by UV irradiation, impaired UV-driven c-Jun protein induction and AP-1 binding. Based on the data, we suggest that JNK1 stimulation is not essential for transactivation of c-jun after UV exposure, whereas activation of ERK2 is required for UV-induced signaling leading to elevated c-jun expression.
...
PMID:Activation of c-Jun N-terminal kinase 1 by UV irradiation is inhibited by wortmannin without affecting c-iun expression. 1002 64

Macrocyclic nonaketide compounds, radicicol and its two analogues, 87-250904-F1 and LL-Z1640-2, have various biological activities. Here we show that these compounds inhibit signal-dependent transcriptional activation with different specificity with distinct mechanism. Although all three compounds inhibited PMA-induced AP-1 transcriptional activity in cell-based reporter assay, these compounds exhibited differential effects in separate transcriptional reporter assays for NF-kappaB and glucocorticoid receptor. Next we found that one of these compounds, LL-Z1640-2, was a signal-specific inhibitor of the JNK/p38 pathways. In contrast to LL-Z1640-2, radicicol and 87-250904-F1 did not inhibit JNK/p38 activation. Recently, radicicol was reported as an inhibitor of activated-Ras-induced ERK activation. These results indicated that radicicol and LL-Z1640-2 showed distinct specificity to various MAP kinase pathways despite their structural similarity. Furthermore, LL-Z-1640-2 inhibited anisomycin-induced but not TNF-induced JNK/p38 activation, indicating that the inhibition mechanism is signal-specific.
...
PMID:A radicicol-related macrocyclic nonaketide compound, antibiotic LL-Z1640-2, inhibits the JNK/p38 pathways in signal-specific manner. 1009 3

Endothelin is a 21-amino acid peptide with a striking diversity of important biological responses, including, vasoconstriction, bronchoconstriction, and mitogenesis. Endothelin-1 binding to the endothelin B receptor (ETB), a member of the superfamily of G-protein-coupled receptors, was associated with catalytic activation of the extracellular-regulated kinase 2 (ERK2) and stimulation of AP-1 transcriptional reporter activity. A panel of single point mutations in transmembrane helix 6 (TM6), intracellular loop 3, and transmembrane helix 7 (TM7) were developed to study the structural requirements for ETB activation. Point mutations within highly conserved regions of TM6 and intracellular loop 3 were without effect on agonist-stimulated ERK activation. However, mutations within TM7 of the ETB significantly impacted ligand-stimulated downstream signaling. For example, nine point mutations within TM7 of the ETB were identified that prevented endothelin-stimulated ERK activation. Interestingly, the TM7 mutants fell into two classes; several exhibited greatly decreased AP-1 activity, relative to wild type ETB, whereas others displayed augmented endothelin-stimulated AP-1 transcriptional activity relative to wild type ETB. Our results suggest that TM7 of the ETB is involved in its activation mechanism and regulates agonist-stimulated ERK activation.
...
PMID:Transmembrane helix 7 of the endothelin B receptor regulates downstream signaling. 1018 21

The AP-1 transcription factor, which is composed of various combinations of Fos and Jun proteins, is believed to be a key participant in molecular processes that guide activity-dependent changes in gene expression. In this study, we investigated the activity of different MAP kinases that have been implicated in AP-1 activation. We examined the activities of ERK, JNK/SAPK, and p38 MAPK along with their nuclear targets (Elk-1 and c-Jun) in rat visual cortex after light stimulation. The transcription factor Elk-1 (a possible regulator of c-fos expression) was found to be transiently modified by phosphorylation when visual stimulation was applied after a period of dark rearing. In vitro kinase assay with Elk-1 as substrate showed that light stimulation activated MAPK/ERK in visual cortex but not frontal cortex. Furthermore, ERK activation was temporally matched to onset of Elk-1 phosphorylation. The activity of JNK1 (c-Jun N-terminal kinase 1) was elevated at 2-6 h after visual exposure and was also temporally correlated to increase of endogenous P-c-Jun levels and its appearance within the AP-1 DNA-binding complex. The activities of p38 MAP kinases did not change significantly. These results demonstrate the differential engagement of MAPK signaling pathways following sensory stimulation and their relative effects upon AP-1 expression in the intact brain.
...
PMID:Rapid phosphorylation of Elk-1 transcription factor and activation of MAP kinase signal transduction pathways in response to visual stimulation. 1038 26

Receptors coupled to pertussis toxin (PTX)-sensitive Gi proteins regulate T lymphocyte cytokine secretion, proliferation, and chemotaxis, yet little is known about the molecular mechanisms of Gi protein signaling in mammalian lymphocytes. Using the Jurkat T lymphocyte cell line, we found that a stably expressed Gi protein-coupled receptor (the delta-opioid receptor (DOR1)) stimulates MEK-1 and extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2) and transcriptional activity by an ERK target, Elk-1, via a mechanism requiring a PTX-sensitive Gi protein. Levels of beta-adrenergic receptor kinase-1 C-terminal fragment that inhibited signaling by Gi protein beta gamma subunits in these cells had no effect on DOR1 stimulation of either MEK-1- or Elk-1-dependent transcription, indicating that this pathway is independent of beta gamma. Analysis of this betagamma-independent pathway indicates a role for a herbimycin A-sensitive tyrosine kinase. Unlike beta gamma-mediated pathways, the beta gamma-independent pathway was insensitive to RasN17, inhibitors of phosphatidylinositol 3-kinase (PI 3-kinase), and constitutive PI 3-kinase activity. The beta gamma-independent pathway regulates downstream events, since blocking it abrogated both Elk-1-dependent transcription and mobilization of the mitogenic transcription factor, AP-1, in response to DOR1 signaling. These results characterize a novel, Ras- and PI 3kinase-independent pathway for ERK activation by Gi protein signaling that is distinct from ERK activation by beta gamma and may therefore be mediated by the alphai subunit.
...
PMID:Gi proteins use a novel beta gamma- and Ras-independent pathway to activate extracellular signal-regulated kinase and mobilize AP-1 transcription factors in Jurkat T lymphocytes. 1039 49

Invasion is an essential cellular response that plays an important role in a number of physiological and pathological processes. Matrix metalloproteinase (MMP) production and cell movement are diverse cellular responses integral to the process of invasion. The complexity of the invasive process suggests the necessity of coordinate activation of more than one signaling pathway in order to activate specific factors responsible for regulating these cellular responses. In this report, we demonstrate that cell movement and MMP-9 production are both directly dependent on the activation of endogenous ERK signaling in hepatocyte growth factor (HGF)-or epidermal growth factor (EGF)-stimulated human epidermal keratinocytes. The kinetic profiles of endogenous MEK and ERK activity suggest that prolonged activation of these signal transducers is an underlying mechanism involved in stimulating cell motility and MMP-9 production. In support of this finding, a transient MEK/ERK signal elicited by keratinocyte growth factor (KGF) or insulin-like growth factor-1 (IGF-1) fails to stimulate these invasion-related responses. Specific inhibition of MEK leads to suppression of ERK activation, marked reduction in steady-state levels of c-Fos, and inhibition of cell movement and MMP-9 production. This occurs despite continued activation of JNK and c-Jun signaling in the presence of MEK-specific inhibition. In contrast, when JNK activity is specifically inhibited in HGF-stimulated cells, AP-1 activity is suppressed but cell motility is not affected. This evidence suggests that while ERK and JNK activity are necessary for AP-1 activation, ERK but not JNK is sufficient in stimulating cell motility.
...
PMID:Role of ERK and JNK pathways in regulating cell motility and matrix metalloproteinase 9 production in growth factor-stimulated human epidermal keratinocytes. 1039 97

Although the kidney represents a target for the accumulation and toxicity of arsenic, little is known about the molecular targets of arsenic in this organ. Therefore, these studies were designed to examine the molecular impact of arsenite [As(III)] and arsenate [As(V)] at low (nanomolar) concentrations. Precision-cut rabbit renal cortical slices were challenged with As(III) or As(V) for up to 8 h. Neither form of the metal induced overt cytotoxicity as assessed by intracellular K+ levels over this time period at concentrations from 0.01-10 microM. In addition, no alterations in the expression of Hsp 60, 70, or 90 were observed. However, induction of heme oxygenase-1 (Hsp 32) was seen following a 4-h challenge with As(III), but not with As(V). As(III) and As(V) induced DNA binding of AP-1 at 2- and 4-h exposure; following a 6-h exposure there was no difference. Although no alteration in the DNA binding activity of ATF-2 was induced by As(III) or As(V), both forms enhanced the DNA binding activity of Elk-1. Enhanced DNA binding activity of AP-1 and Elk-1 correlated with increased gene expression of c-fos, but not c-jun, at 2 h. c-myc gene expression was also induced by As(III) and As(V), albeit at a later time point (6 h). These results suggest that acute arsenic challenge, by either As(III) or As(V), is associated with discrete alterations in the activity of signaling pathways and gene expression in renal tissue.
...
PMID:Enhanced transcription factor DNA binding and gene expression induced by arsenite or arsenate in renal slices. 1044 58

Cell-cell and cell-matrix interactions play important regulatory roles in lymphocyte homeostasis. Thrombospondin-1 (TSP1) is a matricellular protein that differentially promotes the adhesion of resting and activated T cells. In this work, we show that adhesion of Jurkat T cells on substrates coated with TSP1 or TSP1-derived peptides is mediated by beta 1 integrins, CD47, and heparan sulfate proteoglycans. Interactions with TSP1 or TSP1 peptides stimulated CD3-induced Ras activation and tyrosine phosphorylation of several T cell proteins. The signals from TSP1 and its derived peptides differentially synergized with activation of the TCR to induce phosphorylation of linker for activation of T cells (LAT) and extracellular signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinase, and p38 kinases. The phosphorylation of ERK in the presence of full-length TSP1 was transient and dependent on a beta 1 integrin receptor. Interestingly, peptides derived from the type 1 repeats of TSP1 and a CD47-binding peptide from the carboxyl-terminal domain of TSP1 also stimulated mitogen-activated protein (MAP) kinase phosphorylation. Moreover, the TSP1 heparin-binding peptide synergized with Ab-ligated TCR to transduce signals to the nucleus, detected by activation of AP-1- and Elk-dependent transcription. This TSP1 peptide-dependent activation of AP-1 was inhibited by both heparin and the MAP/ERK kinase inhibitor PD98059, providing a functional link between adhesion molecule interaction and nuclear transactivation events via the MAP kinase pathways. These findings have implications for the role of extracellular TSP1 and TSP1 fragments in the regulation of T cell function during hemostasis, wound repair, and other inflammatory responses.
...
PMID:Beta 1 integrin- and proteoglycan-mediated stimulation of T lymphoma cell adhesion and mitogen-activated protein kinase signaling by thrombospondin-1 and thrombospondin-1 peptides. 1049 Sep 55

Two types of rat TRH receptor (TRH-R1 and TRH-R2) have been identified and shown previously to exhibit similar binding and stimulated signaling activity via the phosphoinositide-calcium transduction pathway. Since mouse TRH-R1 exhibits basal (or constitutive or ligand-independent) signaling activity, we compared basal signaling by TRH-R1 and TRH-R2. Basal signaling was measured as receptor-mediated reporter gene induction via different transcription factors. We found that TRH-R2 exhibited higher basal signaling activity than TRH-R1 via pathways mediated by transcription factors AP-1, Elk-1 and CREB. Furthermore, CREB-mediated transcription was directly dependent on the level of TRH-R2 expression and was inhibited by midazolam, a specific inverse agonist of basal TRH-R signaling. Since TRH-R1 and TRH-R2 exhibit distinct anatomic distributions in the rat, it is possible that TRH ligand-independent signaling is more important in tissues/cells in which TRH-R2 is expressed and less important in tissues in which TRH-R1 is found.
...
PMID:Rat TRH receptor type 2 exhibits higher basal signaling activity than TRH receptor type 1. 1049 53

Phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) and all-trans-retinoic acid (trans-RA) are potent regulators of growth of cancer cells. In this study, we investigated the effect of TPA and trans-RA alone or their combination on proliferation of human breast cancer ZR75-1 and T47D and lung cancer H460 and H292 cell lines. trans-RA caused various degrees of growth inhibition of these cell lines. However, TPA showed inhibition of proliferation of H460 and H292 cells and induction of ZR75-1 cell growth. Although trans-RA did not significantly regulate the growth inhibitory effect of TPA, it completely prevented its growth stimulating function. The divergent effects of TPA were associated with specific disruption of cell cycle events, an induction of G(0)/G(1) arrest in H460 and H292 cells and inhibition of G(0)/G(1) arrest with increase of S phase in ZR75-1 cells. Induction of G(0)/G(1) arrest was accompanied by induction of p21(WAF1) and ERK activity, whereas inhibition of G(0)/G(1) arrest was associated with enhanced activity of JNK and AP-1 but not ERK. trans-RA did not affect TPA-induced p21(WAF1) expression. However, it inhibited TPA-induced AP-1 activity in ZR75-1 cells and the constitutive AP-1 activity in H460 and H292 cells. Thus, trans-RA modulates TPA activity through its interaction through TPA-induced JNK/AP-1 pathway but not TPA-induced ERK/p21(WAF1) pathway.
...
PMID:Differential effect of retinoic acid on growth regulation by phorbol ester in human cancer cell lines. 1051 54


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---