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)

Urokinase-type plasminogen activator (uPA) expression is induced upon cytoskeletal reorganization (CSR) by a mechanism independent of protein kinase C and cAMP protein kinase in nontransformed renal epithelial (LLC-PK1) cells. This CSR-dependent uPA gene activation is mediated by an AP-1-recognizing element located 2 kilobases upstream of the transcription initiation site. The phosphorylation of c-Jun, a component of AP-1, is induced by CSR, which seems to increase both the activity and stability of c-Jun (Lee, J. S., von der Ahe, D., Kiefer, B., and Nagamine, Y. (1993) Nucleic Acids Res. 21, 3365-3372). It has been shown that c-Jun is phosphorylated by members of the mitogen-activated protein kinase family, i.e. ERKs and JNKs. ERKs are activated through a growth factor-coupled Ras/Raf-dependent signaling pathway, while JNKs are activated through a stress-induced signaling pathway. Although CSR induces both ERK-2 and JNK activity, JNK does not seem to be involved in the uPA gene induction because UV irradiation, which activates JNK as efficiently as CSR, does not activate the uPA promoter. Further analysis showed the involvement of SOS, Ras, and Raf-1 in the pathway induced by CSR. Our results suggest that cells sense changes in cell morphology using the cytoskeleton as a sensor and respond by activating the ERK-involving signaling pathway from within the cell.
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PMID:Cytoskeleton reorganization induces the urokinase-type plasminogen activator gene via the Ras/extracellular signal-regulated kinase (ERK) signaling pathway. 899 79

Epstein-Barr virus (EBV) initiates infection of normal B lymphocytes by binding to CD21, a complement receptor. Since EBV, unlike most viruses, preferentially infects resting (non-activated) cells, the present studies were undertaken to evaluate the hypothesis that intracellular signalling pathway(s) triggered by EBV binding to CD21 activate the expression of certain cellular genes, as well as the initially expressed viral genes, and thus enable EBV to infect resting B cells. Experiments with nontransforming EBV, recombinant virus ligand and anti-CD2 1 MAbs show that EBV binding to CD21 on resting B cells increases CD23 mRNA levels independently of viral gene expression. A panel of five protein kinase C (PKC) and tyrosine kinase (PTK) inhibitors, all with different modes of action, exhibited a distinctive pattern of effects on the EBV induced induction of CD23 expression, ranging from nearly complete inhibition to no influence. The results suggest that distinct PKC isoforms and PTKs are involved in the signalling pathway(s) triggered by EBV binding to CD21. Significantly, the five inhibitors showed the same pattern of effects on the earliest stages of infection (EBNA-2 transcription) and B cell transformation (mitogenesis and colony formation). The identical pattern of effects of these PKC and PTK inhibitors with diverse mechanisms of action on the EBV induced increase in both CD23 and EBNA-2 mRNA levels strongly suggests that their transcription is mediated by an intracellular signalling pathway which shares, at least in part, common members.
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PMID:Epstein-Barr virus binding to CD21, the virus receptor, activates resting B cells via an intracellular pathway that is linked to B cell infection. 900 Jan

IL-1-activated chondrocytes express a large number of genes which contribute to cartilage degradation. The signaling pathways activated in response to IL-1 in these cells are not well-defined. We examined the effects of IL-1 and other stimuli on the mitogen activated protein kinase (MAPK) pathways in rabbit articular chondrocytes. We demonstrate that IL-1 activates three MAPKs, ERK, JNK and p38, in a time and dose-dependent manner. Activation is maximal by 15 minutes and returns to baseline levels by 1 hour. Maximal activation of ERK and p38 occurs with 1 ng/ml IL-1 whereas activation of JNK requires 10-fold higher levels. In contrast to IL-1, the PKC activator, PDBu preferentially activates ERK while TNF alpha preferentially activates JNK. LPS and TGF beta fail to stimulate any of the kinases examined. These results suggest that activation of the various MAPK pathways is important in the response of chondrocytes to IL-1, cytokines and growth factors.
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PMID:The effects of IL-1 on mitogen-activated protein kinases in rabbit articular chondrocytes. 901 64

Members of three classes of pyridinylimidazoles bind with varying affinities to CSBP (p38) kinase which is a member of a stress-induced signal transduction pathway. Based upon SAR and protein homology modeling, the pharmacophore and three potential modes of binding to the enzyme are presented. For a subset of pyridinylimidazoles, binding is shown to correlate with inhibition of CSBP kinase activity, whereas no significant inhibition of PKA, PKC alpha and ERK kinase activity is observed.
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PMID:Regulation of stress-induced cytokine production by pyridinylimidazoles; inhibition of CSBP kinase. 904 57

The mechanism of mitogen-activated protein kinase (MAPK, ERK) stimulation by the GnRH analog [D-Trp6]GnRH (GnRH-a) was investigated in the gonadotroph-derived alphaT3-1 cell line. GnRH-a as well as the protein kinase C (PKC) activator 12-O-tetradecanoyl phorbol-13-acetate (TPA) stimulated a sustained response of MAPK activity, whereas epidermal growth factor (EGF) stimulated a transient response. MAPK kinase (MEK) is also activated by GnRH-a, but in a transient manner. GnRH-a and TPA apparently activated mainly the MAPK isoform ERK1, as revealed by Mono-Q fast protein liquid chromatography followed by Western blotting as well as by gel kinase assay. GnRH-a and TPA stimulated the tyrosine phosphorylation of several proteins, and this effect as well as the stimulation of MAPK activity were inhibited by the PKC inhibitor GF 109203X. Similarly, down-regulation of TPA-sensitive PKC subspecies nearly abolished the effect of GnRH-a and TPA on MAPK activity. Furthermore, the protein tyrosine kinase (PTK) inhibitor genistein inhibited protein tyrosine phosphorylation and reduced GnRH-a-stimulated MAPK activity by 50%, suggesting the participation of genistein-sensitive and insensitive pathways in GnRH-a action. Although Ca2+ ionophores have only a marginal stimulatory effect, the removal of Ca2+ markedly reduced MAPK activation by GnRH-a and TPA, but had no effect on GnRH-a and TPA stimulation of protein tyrosine phosphorylation. Interestingly, the removal of Ca2+ also partly inhibited the activation of MAPK by EGF and vanadate/H2O2. Thus, a calcium-dependent component(s) downstream of PKC and PTK might also participate in MAPK activation. Elevation of cAMP by forskolin exerted partial inhibition on EGF, but not on TPA or GnRH-a action, suggesting that MEK activators other than Raf-1 might be involved in GnRH action. We conclude that Ca2+, PTK, and PKC participate in the activation of MAPK by GnRH-a, with Ca2+ being necessary downstream to PKC and PTK.
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PMID:Mechanism of mitogen-activated protein kinase activation by gonadotropin-releasing hormone in the pituitary of alphaT3-1 cell line: differential roles of calcium and protein kinase C. 907 30

Inner medullary collecting duct (IMCD) cells adapt to a hypertonic environment by synthesizing transporters that allow for accumulation of organic osmolytes. To examine for activation of additional mitogen-activated protein (MAP) kinases, extracts of IMCD-3 cells subjected to a hypertonic medium (600 mosmol/kgH2O) for 15 min were fractionated by Mono Q fast-performance liquid chromatography and assayed with the epidermal growth factor receptor [EGFR-(662-681)] peptide as substrate. Three peaks of activity were identified. Western blotting revealed that these peaks coincided with Jun NH2-terminal kinase (JNK), extracellular signal-regulated protein kinases, ERK1 and ERK2, and p38 MAP kinase. To assess the functional significance of ERK2 activation in IMCD-3 cells, the effect of PD-098059, an inhibitor of the upstream regulatory protein kinase MAP/ERK kinase (MEK) was assessed. PD-098059 inhibited ERK activation by hypertonicity. Yet, the stimulation of inositol uptake, a marker of adaptation, after 16 h was unaltered. Direct measurements of JNK activity [phosphorylation of GST-cJun-(1-79)] revealed a marked (20- to 40-fold) increase in activity as medium osmolality was increased from 300 to 900 mosmol/kgH2O with either NaCl or mannitol. Urea induced a more modest increase in activity. The response is prompt and detected as early as 2 min after exposure, reaching a maximum activation at 10-15 min. Downregulation of cellular protein kinase C (PKC) by chronic exposure to phorbol esters only minimally attenuated the JNK response to hyperosmolality, indicating a lack of involvement of PKC. We conclude that, in IMCD-3 cells, inhibition of ERK activation by hyperosmolality does not prevent osmoregulatory increase in inositol transport. This is not consistent with a role for ERKs in the response. The roles for JNK and p38 have not been ruled out, and these pathways may represent the initiating event in the subsequent transcription of organic osmolyte transporter genes and adaptation to extracellular hypertonicity.
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PMID:Multiple mitogen-activated protein kinases are regulated by hyperosmolality in mouse IMCD cells. 908 72

We have characterized signaling pathways involving the related adhesion focal tyrosine kinase (RAFTK, also known as PYK2 or CAK-beta) in CMK human megakaryocytic cells. Stem cell factor, which potentiates the growth of megakaryocytes and their progenitors, and phorbol myristate acetate, which causes differentiation of megakaryocytic cell lines, induced the tyrosine phosphorylation of RAFTK but not of focal adhesion kinase. Stimulation of CMK cells with stem cell factor resulted in an increase in the autophosphorylation and kinase activity of RAFTK. Phosphorylation of RAFTK under these conditions was mediated by a protein kinase C-dependent pathway. Cytochalasin D, which disrupts the cytoskeleton, abolished the phosphorylation of RAFTK upon phorbol myristate acetate and stem cell factor stimulation, indicating that RAFTK association with the actin cytoskeleton appears to be critical for its phosphorylation. In addition, we observed an association of RAFTK with paxillin, a 68-kDa cytoskeleton protein. Using in vitro binding assays, RAFTK and paxillin were shown to bind directly through the C-terminal proline-rich domain. Transient overexpression of a dominant-negative mutant of RAFTK inhibited significantly the tyrosine phosphorylation of paxillin upon phorbol myristate acetate stimulation. These observations indicate that RAFTK might play an important role in the phosphorylation of signaling pathways within the focal adhesions and that RAFTK participates in signaling events that link signals from the cell surface to the cytoskeleton. Furthermore, this study suggests that RAFTK might be involved in megakaryocyte proliferation and differentiation.
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PMID:Tyrosine phosphorylation of the related adhesion focal tyrosine kinase in megakaryocytes upon stem cell factor and phorbol myristate acetate stimulation and its association with paxillin. 909 34

Short chain fatty acids (propionate and butyrate) and deoxycholic acid (DCA) are able to induce apoptosis in HT-29 colonic tumor cell line, but DCA induces a much higher level of apoptosis than butyrate and propionate. Mixtures of DCA with butyrate or propionate enhance the effect of the single components. Apoptosis is not affected by the PKC, PTK or de novo mRNA and protein synthesis inhibitors, so that the involvement of these enzymes and processes is ruled out. In contrast, DCA-induced apoptosis is directly related to [Ca2+]i concentration as demonstrated by the apoptosis inhibition caused by [Ca2+]i chelator BAPTA/AM.
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PMID:Deoxycholic acid and SCFA-induced apoptosis in the human tumor cell-line HT-29 and possible mechanisms. 910 63

The transformed phenotype of v-Ras- or Bacillus cereus phosphatidylcholine-hydrolyzing phospholipase C (PC-PLC)-expressing NIH 3T3 cells is reverted by expressing a kinase-defective mutant of protein kinase C lambda (lambdaPKC). We report here that extracellular signal-regulated kinase (ERK)-1 and -2 are constitutively activated in v-Ras- and PC-PLC-transformed cells in the absence of added growth factors. Interestingly, the activated ERKs were exclusively localized to the cell nucleus. Consistently, the transactivating potential of the C-terminal domain of Elk-1, which is activated upon ERK-mediated phosphorylation, was strongly induced in serum-starved cells expressing v-Ras or PC-PLC. Reversion of v-Ras- or PC-PLC-induced transformation by expression of dominant negative lambdaPKC abolished the nuclear ERK activation suggesting lambdaPKC as a novel, direct or indirect, activator of mitogen-activated protein kinase/ERK kinase in response to activated Ras or elevated levels of phosphatidylcholine-derived diacylglycerol. Transient transfection experiments confirmed that lambdaPKC acts downstream of Ras but upstream of mitogen-activated protein kinase/ERK kinase. We found both the v-Ras- and PC-PLC-transformed cells to be insensitive to stimulation with platelet-derived growth factor (PDGF). No detectable receptor level, autophosphorylation, or superinduction of DNA synthesis could be observed in response to treatment with PDGF. Reversion of the transformed cell lines by expression of dominant negative lambdaPKC restored the receptor level and the ability to respond to PDGF in terms of receptor autophosphorylation, ERK activation, and induction of DNA synthesis.
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PMID:Reversion of Ras- and phosphatidylcholine-hydrolyzing phospholipase C-mediated transformation of NIH 3T3 cells by a dominant interfering mutant of protein kinase C lambda is accompanied by the loss of constitutive nuclear mitogen-activated protein kinase/extracellular signal-regulated kinase activity. 911 Oct 71

The activation of protein kinase C (PKC) found in diabetic glomeruli and glomerular mesangial cells cultured under high glucose conditions has been proposed to contribute to the development of diabetic nephropathy. However, the abnormalities distal to PKC have not been fully elucidated yet. Herein, we provide the evidence that mitogen-activated protein kinase (MAPK) cascade, an important kinase cascade downstream to PKC and an activator of cytosolic phospholipase A2 (cPLA2) by direct phosphorylation, is activated in glomeruli isolated from streptozotocin-induced diabetic rats. MAPK cascade was also activated in glomerular mesangial cells cultured under high glucose (27.8 mmol/l) conditions for 5 days, and the activation of MAPK cascade was inhibited by treating the cells with calphostin C, an inhibitor of PKC. Furthermore, the activities of cPLA2 also increased in cells cultured under the same conditions and this activation was inhibited by both calphostin C and PD 098059, an inhibitor of MEK (MAPK or extracellular signal-regulated kinase [ERK] kinase). These results indicate that MAPK cascade is activated in glomeruli and mesangial cells under the diabetic state possibly through the activation of PKC. Activated MAPK, in turn, may induce various functional changes of mesangial cells at least through the activation of cPLA2 and contribute to the development of diabetic nephropathy.
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PMID:Mitogen-activated protein kinase cascade is activated in glomeruli of diabetic rats and glomerular mesangial cells cultured under high glucose conditions. 913 54


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