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)

We previously reported that both hypoxia and hypoxia followed by reoxygenation (hypoxia/reoxygenation) rapidly activate Src family tyrosine kinases and p21ras in cultured rat cardiac myocytes. This was followed by the sequential activation of mitogen-activated protein kinase kinase kinase (MAPKKK) activity of Raf-1, MAP kinase kinase (MAPKK), MAPKs (p44mapk and p42mapk, also called extracellular signal-regulated protein kinase [ERK]1 and ERK2, respectively), and S6 kinase (p90rsk). In this study, we demonstrated that both hypoxia and hypoxia/reoxygenation caused rapid activation of stress-activated MAPK signaling cascades involving p65PAK, p38MAPK, and SAPK. These stimuli also caused phosphorylation of activating transcription factor (ATF)-2. Because p65PAK is known to be upstream of p38MAPK and also be a target of p21rac-1, which belongs to the rho subfamily of p21ras-related small GTP-binding proteins, these results strongly suggested that two different stress-activated MAPK pathways distinct from the classical MAPK pathway were activated in response to hypoxia and hypoxia/reoxygenation in cardiac myocytes.
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PMID:Hypoxia and hypoxia/reoxygenation activate p65PAK, p38 mitogen-activated protein kinase (MAPK), and stress-activated protein kinase (SAPK) in cultured rat cardiac myocytes. 936 56

UVC irradiation activates mitogen-activated protein kinases (MAPKs), including ERK, JNK, and P38. This study examined the role of protein kinase C (PKC) in the regulation of UVC-stimulated MAPKs activation. Either the depletion of PKC by prolonged treatment of cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) or the inhibition of PKC by a selective PKC inhibitor, UCN-01-ME, attenuated UVC-activation of ERK1/2, keeping the activation of JNK1/2 intact. However, K252a, a non-selective PKC inhibitor, inhibited the activation of both ERK1/2 and JNK1/2 by UVC. In three isoforms of PKC (alpha, delta, epsilon) examined, PKC epsilon shows the most evident translocation, a temporal association with cell membrane, upon the UVC irradiation of NIH 3T3 cells. These results suggest that PKC is acting in the UVC-dependent activation of ERK1/2, and PKC epsilon is one of the PKC isozymes playing such a role.
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PMID:Involvement of protein kinase C in the activation of extracellular signal-regulated kinase 1/2 by UVC irradiation. 938 66

The observation that mitogen-activated protein (MAP) kinases ERK1 and ERK2 are constitutively activated in a number of oncogene-transformed cell lines has led to the hypothesis that prolonged activation of these enzymes is required for the transformation process. To investigate this question, we have examined the regulation of the ERK pathway in Rat1 fibroblasts transformed with activated c-Raf-1 (Raf22W), v-Ha-Ras, and v-Src. Expression of these oncoproteins had no effect on the enzymatic activity of ERK1 and ERK2 in either serum-starved or exponentially growing cells. Moreover, the stimulatory effect of serum on ERK1/ERK2 activity was substantially reduced or abrogated in these cells; this impairment was associated with a strong attenuation of c-fos gene induction. In contrast, expression of Raf22w, v-Ha-Ras, or v-Src resulted in the constitutive activation of the upstream kinases MEK1 and MEK2. Treatment of the cells with vanadate completely restored the activation of ERK1/ERK2 in oncogene-transformed cells, suggesting the involvement of a vanadate-sensitive tyrosine phosphatase. Northern blot analysis of VH1-like dual-specificity MAP kinase phosphatases did not reveal any significant difference in the mRNA expression pattern of these genes between parental and transformed Rat1 cells. Phosphoamino acid analysis indicated that ERK1 is phosphorylated on threonine, but not on tyrosine, in oncogene-transformed cells and that vanadate treatment restores tyrosine phosphorylation. We conclude from these results that ERK1/ERK2 activity is repressed by a single-specificity tyrosine phosphatase in oncogene-transformed rat fibroblasts.
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PMID:Repression of mitogen-activated protein kinases ERK1/ERK2 activity by a protein tyrosine phosphatase in rat fibroblasts transformed by upstream oncoproteins. 939 54

In this report we show that extracellular signal-regulated kinase-1 and -2 (ERK-1 and -2) respond differently to signals that elicit proliferation and/or differentiation of myoblasts using the C2C12 cell line and nondifferentiating mutant NFB4 cells derived from them. Induction of differentiation by withdrawal of serum rendered ERKs in C2C12 myoblasts relatively insensitive to restimulation by serum. Instead, myogenic differentiation of C2C12 cells was associated with sustained activation of ERK-2 dependent on the insulin-like growth factor II (IGF-II) autocrine loop. By contrast, mutant NFB4 cells cultured under the same conditions remained proliferative and demonstrated robust activation of ERKs in response to serum. Similarly, a Gi-dependent signaling pathway induced activation of ERKs in NFB4 cells, but not in C2C12 cells, after stimulation by lysophosphatidic acid (LPA). In NFB4 cells partially rescued by prolonged IGF-I treatment, ERK activity remained responsive to Gi-dependent LPA stimulation, whereas rescue of NFB4 cells by constitutive expression of myogenin or MyoD, associated with activation of the IGF-II autocrine loop, rendered the Gi-signaling pathway refractory to LPA stimulation. Relatively high levels of G(alpha i2) were detected in NFB4 cells and IGF-I treated NFB4 cells, which correlated with responsive Gi signaling. Activation of the IGF-II autocrine loop in C2C12 and NFB4 myoblasts or treatment with IGF-II was associated with loss of G(alpha i2) and inhibition of Gi-dependent signaling. Thus, IGF-I and IGF-II activate distinct signaling cascades, with IGF-II eliciting a stronger differentiation effect correlated with down-regulation of G(alpha i2) protein. Short-term stimulation of NFB4 cells with IGF-I, a mitogenic signal for myoblasts, also induced ERK-1 and -2 activation. Transient stimulation of NFB4 cells with IGF-I while blocking activation of Gi-proteins is with pertussis toxin resulted in preferential activation of ERK-2 characteristic of differentiated C2C12 cells, suggesting that proliferation induced by IGF-I is Gi-dependent and separable from the IGF-I-signaling pathway that leads to differentiation.
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PMID:Extracellular signal-regulated kinase-1 and -2 respond differently to mitogenic and differentiative signaling pathways in myoblasts. 941 7

In renal cells, hypertonicity induces genes for heat shock proteins (HSP70, alpha B-crystallin), as well as enzymes and transporters directly involved in the metabolism and transport of protective organic osmolytes. While heat shock proteins are induced by many stresses including osmotic stress, the induction of the osmolytes genes appears to be specific to osmotic stress. These two adaptive mechanisms allow kidney cells to survive and function in the hypertonic environment that exists on routine basis in kidney medulla. In mammalian cells, hypertonicity induces three mitogen-activated protein kinase pathways: ERK (extracellular regulated kinase), JNK (Jun N-terminal kinase), and p38. ERK activation by osmotic stress is a consistent finding in many cells, but it is not essential for transcriptional regulation of mRNA for transporter of organic osmolyte betaine. While the growth of yeast cells on NaCl-supplemented medium is dependent on HOG1 pathway, it is still unclear which pathway mediates the adaptation to osmotic stress in mammalian cells. Here, we show that inhibition of p38 kinase activity, using the specific inhibitor SB203580 (4-(fluorophenyl)-2-(4-methylsulfonyl-phenyl)-5-(4-pyridyl) imidazole), abolishes the hypertonicity-mediated induction of mRNAs for HSP70 and betaine transporter in Madin-Darby canine kidney cells. The inhibition is dose-dependent and correlates with the in situ activity of native p38 kinase, determined as MAPKAPK-2 activity in cell extracts. As reported previously, the activities of ERK-1 and -2 were not affected by SB203580, but surprisingly, inhibition of native p38 kinase activity correlates with up-regulation of native JNK-1 activity in osmotically stressed cells. p38 mRNA is induced by hypertonic stress and is attenuated with p38 kinase inhibition. We also find that thermal induction of HSP70 mRNA is not affected by p38 kinase inhibition. Such findings suggest that p38 kinase activity is essential for the induction of genes involved in the adaptation of mammalian cells to osmotic stress and that the increased activity of JNK-1 during p38 kinase inhibition is consistent with regulation of JNK-1 by p38 kinase in osmotically stressed cells. In addition, the transduction pathways mediating HSP70 mRNA induction by different stresses appear to be divergent; osmotic induction of HSP70 is p38 kinase-dependent, while thermal induction is not.
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PMID:p38 kinase activity is essential for osmotic induction of mRNAs for HSP70 and transporter for organic solute betaine in Madin-Darby canine kidney cells. 943 Jul 35

We have developed an assay using permeabilized cells to monitor fragmentation of the Golgi complex that occurs during mitosis. Golgi stacks, in permeabilized interphase normal rat kidney (NRK) cells, upon incubation with mitotic extracts undergo extensive fragmentation, and the fragmented Golgi membranes are dispersed throughout the cytoplasm. We find that the continued presence of p34cdc2, the mitosis initiation kinase, is not necessary for Golgi fragmentation. Instead, fragmentation depends on cytosolic mitogen-activated protein kinase kinase 1 (MEK1 or MAPKK1). However, the known cytoplasmic substrates for MEK1, ERK1, and ERK2 are not required for this process. Interestingly, we find a Golgi-associated ERK, which we propose as the likely target for MEK1 in Golgi fragmentation.
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PMID:Signaling via mitogen-activated protein kinase kinase (MEK1) is required for Golgi fragmentation during mitosis. 945 43

Prosaposin, the precursor of saposins A, B, C, and D, was recently reported to be a neurotrophic factor in vivo and in vitro. The neurotrophic region of prosaposin has been localized to a 12-amino acid sequence within the saposin C domain and has been used to derive biologically active synthetic peptides (14-22 residues), called prosaptides. Treatment of primary Schwann cells and an immortalized Schwann cell line, iSC, with a 14-mer prosaptide, TX14(A) (10 nM), enhanced phosphorylation of mitogen-activated kinases ERK1 (p44 MAPK) and ERK2 (p42 MAPK) within 5 min, which was blocked by 4 h pretreatment with pertussis toxin. Furthermore, incubation of Schwann cells with the nonhydrolyzable GDP analog GDP-betaS inhibited TX14(A)-induced ERK phosphorylation. TX14(A) enhanced the sulfatide content of primary Schwann cells by 2.5-fold, which was inhibited by pretreatment with pertussis toxin or the synthetic MAP kinase kinase inhibitor PD098059. In addition, TX14(A) increased the tyrosine phosphorylation of all three isoforms of the adapter molecule, Shc, which coincided with the association of p60Src and PI(3)K. Inhibition of PI3(K) by wortmannin blocked TX14(A)-induced ERK phosphorylation. These data demonstrate that TX14(A) uses a pertussis toxin-sensitive G-protein pathway to activate ERKs, which is essential for enhanced sulfatide synthesis in Schwann cells.
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PMID:Prosaptide activates the MAPK pathway by a G-protein-dependent mechanism essential for enhanced sulfatide synthesis by Schwann cells. 950 74

Expression of the c-fos proto-oncogene is induced by numerous stimuli some of which are transmitted through the Ras/Raf/MAP kinase or the cAMP-dependent protein kinase (PKA) pathways. The effect of cell-specific interactions between these pathways on c-fos expression was investigated by exposing quiescent NIH3T3 cells to serum, forskolin, or a combination. Co-stimulation with serum and forskolin resulted in a more than additive increase in c-fos transcription. Synergistic increase in c-fos promoter activity was also observed in transient transfection studies after co-stimulation with serum plus forskolin or co-transfection with c-Raf and PKA expression plasmids. Analysis of the cAMP signaling pathway revealed that the synergy was neither due to an increase in PKA activity nor to Ser-133 phosphorylation/activation of CREB. The activation status of the MAP kinases ERK1 and ERK2 in co-treated cells was comparable to that in serum-treated cells. Co-stimulation with forskolin did not alter the phosphorylation state of Elk-1 compared to serum-induced phosphorylation of Elk-1. Deletion of c-fos promoter elements previously shown to be important for regulation of c-fos expression in response to mitogens indicates a role for SRE and FAP-1 elements.
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PMID:Synergistic increase in c-fos expression by simultaneous activation of the ras/raf/map kinase- and protein kinase A signaling pathways is mediated by the c-fos AP-1 and SRE sites. 951 70

We recently demonstrated the activation of extracellular signal- regulated protein kinase 1 and 2 (ERK1 and ERK2) by IGF-1, FGF-2, and PDGF-BB in normal human osteoblastic (HOB) cells as well as in rat and mouse osteoblastic cells. In this report, we have examined whether c-Jun NH2-Terminal Kinase (JNK) pathway is activated by growth factors and interleukin-1 beta (IL-1 beta) in normal HOB and rat UMR-106 cells using immune-complex kinase assay and anti-active JNK antibody, which recognizes activated forms of both JNK1 and JNK2. Results have demonstrated the presence of JNK1 and JNK2 proteins in normal HOB and UMR-106 cells. Both JNK1 and JNK2 were activated by IL-1 beta. IL-1 beta preferentially activated JNK pathway in a dose- and time-dependent manner and had little effect on ERK pathway. On the other hand, FGF-2 did not activate JNK but most strongly activated ERK pathway. The activation of JNK was maximal at 20 min whereas maximal activation of ERK1 and ERK2 was observed within 10 min. Results have clearly demonstrated that IL-1 beta preferentially activates JNK pathway whereas FGF-2 activates ERK pathway in normal human and rat UMR-106 osteoblastic cells.
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PMID:Activation of c-Jun NH2-terminal kinases by interleukin-1 beta in normal human osteoblastic and rat UMR-106 cells. 951 50

Activation and recruitment of eosinophils in allergic inflammation is in part mediated by chemoattractants and T-helper 2 (Th2)-derived cytokines. However, little is known concerning the signal transduction mechanisms by which this activation occurs. We have investigated tyrosine kinase-mediated activation of phosphatidylinositol 3-kinase (PI3K) and compared this with the activation of the p21ras-ERK signaling pathway in human eosinophils. The related cytokines interleukin-3 (IL-3), IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF), all induced PI3K activity detected in antiphosphotyrosine immunoprecipitates. Furthermore, the chemoattractants platelet-activating factor (PAF), RANTES, and C5a were also able to induce phosphotyrosine-associated PI3K activity. Protein kinase B (PKB) is a downstream target of PI3K activation by growth factors. Induction of PKB phosphorylation in human eosinophils was transiently induced on activation with the cytokines IL-4 and IL-5, as well as the chemoattractants PAF, C5a, and RANTES showing a broad activation profile. Surprisingly, analysis of the activation of the mitogen-activated protein (MAP) kinases p44(ERK1) and p42(ERK2), showed that ERK2, but not ERK1, was transiently activated in human eosinophils after stimulation with IL-5 or PAF. Activation kinetics correlated with activation of p21ras by both cytokines and chemoattractants as measured by a novel assay for guanosine triphosphate (GTP)-loading. Finally, using specific inhibitors of both the p21ras-ERK and PI3K signaling pathways, a role was demonstrated for PI3K, but not p21ras-ERK, in activation of the serum-treated zymosan (STZ)-mediated respiratory burst in IL-5 and PAF-primed eosinophils. In summary, these data show that in human eosinophils, Th2-derived cytokines differentially activate both PI3K and MAP kinase signal transduction pathways with distinct functional consequences showing complex regulation of eosinophil effector functions.
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PMID:Analysis of signal transduction pathways in human eosinophils activated by chemoattractants and the T-helper 2-derived cytokines interleukin-4 and interleukin-5. 951 56


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