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)

Glucagon-like peptide-2 (GLP-2) promotes the expansion of the intestinal epithelium through stimulation of the GLP-2 receptor, a recently identified member of the glucagon-secretin G protein-coupled receptor superfamily. Although activation of G protein-coupled receptors may lead to stimulation of cell growth, the mechanisms transducing the GLP-2 signal to mitogenic proliferation remain unknown. We now report studies of GLP-2R signaling in baby hamster kidney (BHK) cells expressing a transfected rat GLP-2 receptor (BHK-GLP-2R cells). GLP-2, but not glucagon or GLP-1, increased the levels of cAMP and activated both cAMP-response element- and AP-1-dependent transcriptional activity in a dose-dependent manner. The activation of AP-1-luciferase activity was protein kinase A (PKA) -dependent and markedly diminished in the presence of a dominant negative inhibitor of PKA. Although GLP-2 stimulated the expression of c-fos, c-jun, junB, and zif268, and transiently increased p70 S6 kinase in quiescent BHK-GLP-2R cells, GLP-2 also inhibited extracellular signal-regulated kinase 1/2 and reduced serum-stimulated Elk-1 activity. Furthermore, no rise in intracellular calcium was observed following GLP-2 exposure in BHK-GLP-2R cells. Although GLP-2 stimulated both cAMP accumulation and cell proliferation, 8-bromo-cyclic AMP alone did not promote cell proliferation. These findings suggest that the GLP-2R may be coupled to activation of mitogenic signaling in heterologous cell types independent of PKA via as yet unidentified downstream mediators of GLP-2 action in vivo.
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PMID:Identification of glucagon-like peptide-2 (GLP-2)-activated signaling pathways in baby hamster kidney fibroblasts expressing the rat GLP-2 receptor. 1052 25

Growing evidence suggests that activation of mitogen-activated protein kinase (MAPK) signal transduction mediates changes in muscle gene expression in response to exercise. Nevertheless, little is known about upstream or downstream regulation of MAPK in response to muscle contraction. Here we show that ex vivo muscle contraction stimulates extracellular signal-regulated kinase 1 and 2 (ERK1/2), and p38(MAPK) phosphorylation. Phosphorylation of ERK1/2 or p38(MAPK) was unaffected by protein kinase C inhibition (GF109203X), suggesting that protein kinase C is not involved in mediating contraction-induced MAPK signaling. Contraction-stimulated phosphorylation of ERK1/2 and p38(MAPK) was completely inhibited by pretreatment with PD98059 (MAPK kinase inhibitor) and SB203580 (p38(MAPK) inhibitor), respectively. Muscle contraction also activated MAPK downstream targets p90 ribosomal S6 kinase (p90(Rsk)), MAPK-activated protein kinase 2 (MAPKAP-K2), and mitogen- and stress-activated protein kinase 1 (MSK1). Use of PD98059 or SB203580 revealed that stimulation of p90(Rsk) and MAPKAP-K2 most closely reflects ERK and p38(MAPK) stimulation, respectively. Stimulation of MSK1 in contracting skeletal muscle required the activation of both ERK and p38(MAPK). These data demonstrate that muscle contraction, separate from systemic influence, activates MAPK signaling. Furthermore, we are the first to show that contractile activity stimulates MAPKAP-K2 and MSK1.
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PMID:Effect of contraction on mitogen-activated protein kinase signal transduction in skeletal muscle. Involvement Of the mitogen- and stress-activated protein kinase 1. 1062 98

Expression of an activated extracellular signal-regulated kinase 1 (ERK1) construct in yeast cells was used to examine the conservation of function among mitogen-activated protein (MAP) kinases. Sequence alignment of the human MAP kinase ERK1 with all Saccharomyces cerevisiae kinases reveals a particularly strong kinship with Kss1p (invasive growth promoting MAP kinase), Fus3p (pheromone response MAP/ERK kinase), and Mpk1p (cell wall remodeling MAP kinase). A fusion protein of constitutively active human MAP/ERK kinase 1 (MEK) and human ERK1 was introduced under regulated expression into yeast cells. The fusion protein (MEK/ERK) induced a filamentation response element promoter and led to a growth retardation effect concomitant with a morphological change resulting in elongated cells, bipolar budding, and multicell chains. Induction of filamentous growth was also observed for diploid cells following MEK/ERK expression in liquid culture. Neither haploids nor diploids, however, showed marked penetration of agar medium. These effects could be triggered by either moderate MEK/ERK expression at 37 degrees C or by high level MEK/ERK expression at 30 degrees C. The combination of high level MEK/ERK expression and 37 degrees C resulted in cell death. The deleterious effects of MEK/ERK expression and high temperature were significantly mitigated by 1 m sorbitol, which also enhanced the filamentous phenotype. MEK/ERK was able to constitutively activate a cell wall maintenance reporter gene, suggesting misregulation of this pathway. In contrast, MEK/ERK effectively blocked expression from a pheromone-responsive element promoter and inhibited mating. These results are consistent with MEK/ERK promoting filamentous growth and altering the cell wall through its ability to partially mimic Kss1p and stimulate a pathway normally controlled by Mpk1p, while appearing to inhibit the normal functioning of the structurally related yeast MAP kinase Fus3p.
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PMID:Human ERK1 induces filamentous growth and cell wall remodeling pathways in Saccharomyces cerevisiae. 1078 25

Matrix metalloproteinase-1 (MMP-1) plays an important role in the degradation of extracellular matrix components under several physiological and pathological conditions. The expression of this protease is upregulated by mitogenic growth factors and proinflammatory cytokines, which have been shown to activate different sets of mitogen-activated protein (MAP) kinase pathways. Here we provide evidence that activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) or the p38 MAP kinase pathway is sufficient to induce transcription from the MMP-1 promoter in human primary fibroblasts, whereas modulation of mRNA stability seems to be of minor importance. Upregulation of MMP-1 expression by mitogenic or inflammatory stimuli is blocked by specific small molecular weight inhibitors of the ERK pathway or the p38 pathway, respectively, and constitutively active kinases within the ERK1/2 pathway (MEKK1, MEK1) or the p38 pathway (ASK1, MEKK1, MKK3) are potent activators of the MMP-1 promoter. The current study provides evidence that distinct extracellular signals leading to upregulation of MMP-1 expression in fibroblasts are relayed independently through different MAP kinase pathways and are integrated at the level of the promoter.
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PMID:Independent role of p38 and ERK1/2 mitogen-activated kinases in the upregulation of matrix metalloproteinase-1. 1091 95

The p53 tumor suppressor protein is a transcription factor that plays a major role in the DNA damage response. After DNA damage, p53 levels increase due primarily to stabilization of the protein. The molecular mechanisms leading to stabilization of p53 after DNA damage have not been completely elucidated. Recently we reported that cisplatin treatment activated extracellular signal-regulated kinase 1 and 2 (ERK1/2) and that inhibition of ERK1/2 resulted in enhanced sensitivity to cisplatin. In the present study, we examined the potential role of ERK1/2 activation in regulation of the p53 response to cisplatin. In the ovarian carcinoma cell line A2780, inhibition of ERK1/2 activation with the mitogen-activated protein kinase/ERK kinase 1 (MEK1) inhibitor PD98059 resulted in decreased p53 protein half-life and diminished accumulation of p53 protein during exposure to cisplatin. We also demonstrated that p53 protein co-immunoprecipitated with ERK1/2 protein and was phosphorylated by activated recombinant murine ERK2 in vitro. Furthermore, PD98059 decreased the phosphorylation of p53 at serine 15 during cisplatin exposure, suggesting that ERK1/2 mediates in part phosphorylation of p53 during the cisplatin DNA response. These results strongly suggest that cisplatin-induced ERK activation is an up-stream regulator of the p53 response to DNA damage caused by cisplatin.
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PMID:Effect of extracellular signal-regulated kinase on p53 accumulation in response to cisplatin. 1095 92

Glomerular hypertension and hyperglycemia are major determinants of diabetic nephropathy. We sought to identify the mechanisms whereby stretch-induced activation of mesangial cell extracellular signal-regulated kinase 1 and 2 (ERK1/ERK2) is enhanced in high glucose (HG). Mesangial cells cultured on fibronectin Flex I plates in normal glucose (NG; 5.6 mM) or HG (30 mM), were stretched by 15% elongation at 60 cycles/min for up to 60 min. In HG, a 5-min stretch increased ERK1/ERK2 phosphorylation by 6.4 +/- 0.4/4.3 +/- 0.3-fold (P < 0.05 vs. NG stretch). In contrast, p38 phosphorylation was increased identically by stretch in NG and HG. Unlike many effects of HG, augmentation of ERK activity by HG was not dependent on protein kinase C (PKC) as indicated by downregulation of PKC with 24-h phorbol ester or inhibition with bisindolylmaleimide IV. In both NG and HG, pretreatment with arginine-glycine-aspartic acid peptide (0.5 mg/ml) to inhibit integrin binding or with cytochalasin D (100 ng/ml) to disassemble filamentous (F) actin, significantly reduced phosphorylation of ERK1/ERK2 and p38. To determine whether the rate of mitogen-activated protein kinase dephosphorylation is affected by HG, cellular kinase activity was inhibited by depleting ATP. Post-ATP depletion, phosphorylation of ERK1/ERK2 was reduced to 36 +/- 9/51 +/- 14% vs. 9 +/- 5/7 +/- 6% in NG (P < 0.05, n = 5). Thus stretch-induced ERK1/ERK2 and p38 activation in both NG and HG is beta(1)-integrin and F-actin dependent. Stretch-induced ERK1/ERK2 is enhanced in high glucose by diminished dephosphorylation, suggesting reduced phosphatase activity in the diabetic milieu. Enhanced mesangial cell ERK1/ERK2 signaling in response to the combined effects of mechanical stretch and HG may contribute to the pathogenesis of diabetic nephropathy.
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PMID:Stretch-induced mesangial cell ERK1/ERK2 activation is enhanced in high glucose by decreased dephosphorylation. 1099 19

Extracellular signal-regulated kinase 1 (ERK1) and ERK2 are important components in signal transduction pathways involved in many cellular processes, including cell differentiation and proliferation. These proteins consist of a central kinase domain flanked by short N- and C-terminal noncatalytic domains. While the regulation of ERK2 by sequences within the kinase domain has been extensively studied, little is known about the small regions outside of the kinase domain. We performed mutational analysis on the N-terminal, noncatalytic domain of ERK2 in an attempt to determine its role in ERK2 function and regulation. Deleting or mutating amino acids 19 to 25 (ERK2-Delta19-25) created an ERK2 molecule that could be phosphorylated in response to growth factor and serum stimulation in a MEK (mitogen-activated protein kinase kinase or ERK kinase)-dependent manner but had little kinase activity and was unable to bind to MEK in vivo. Since MEK acts as a cytoplasmic anchor for the ERKs, the lack of a MEK interaction resulted in the aberrant nuclear localization of ERK2-Delta19-25 mutants in serum-starved cells. Assaying these mutants for their ability to affect ERK signaling revealed that ERK2-Delta19-25 mutants acted in a dominant-negative manner to inhibit transcriptional signaling through endogenous ERKs to an Elk1-responsive promoter in transfected COS-1 cells. However, ERK2-Delta19-25 had no effect on the phosphorylation of RSK2, an ERK2 cytoplasmic substrate, whereas a nonactivatable ERK (T183A) that retained these sequences could inhibit RSK2 phosphorylation. These results suggest that the N-terminal domain of ERK2 profoundly affects ERK2 localization, MEK binding, kinase activity, and signaling and identify a novel dominant-negative mutant of ERK2 that can dissociate at least some transcriptional responses from cytoplasmic responses.
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PMID:Biochemical and biological functions of the N-terminal, noncatalytic domain of extracellular signal-regulated kinase 2. 1111 99

Activation of the extracellular signal-regulated kinase 1 (ERK1) and ERK2 by neurotrophins, neuronal activity, or cAMP has been strongly implicated in differentiation, survival, and adaptive responses of neurons during development and in the adult brain. Recently, a new member of the mitogen-activated protein (MAP) kinase family, ERK5, was discovered. Like ERK1 and ERK2, ERK5 is expressed in neurons, and ERK5 stimulation by epidermal growth factor is blocked by the MAP kinase/ERK kinase 1 (MEK1) inhibitors PD98059 and U0126. This suggests the interesting possibility that some of the functions attributed to ERK1/2 may be mediated by ERK5. However, the regulatory properties of ERK5 in primary cultured neurons have not been reported. Here we examined the regulation of ERK5 signaling in primary cultured cortical neurons. Our data demonstrate that, similar to ERK1/2, ERK5 is activated by neurotrophins including brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and NT-4. BDNF stimulation of ERK5 required the activity of MEK5. Surprisingly, ERK5 was not stimulated by cAMP or neuronal activity induced by glutamate or membrane depolarization. In contrast to ERK1/2, ERK5 strongly activated the transcriptional activity of myocyte enhancer factor 2C (MEF2C) in pheochromocytoma 12 (PC12) cells and was required for neurotrophin stimulation of MEF2C transcription in both PC12 cells and cortical neurons. Furthermore, ERK1/2, but not ERK5, induced transcription from Elk1 and the cAMP/ Ca(2+) response element in PC12 cells. Our data suggest that mechanisms for regulation of ERK5 and downstream transcriptional pathways regulated by ERK5 are distinct from those of ERK1/2 in neurons. Furthermore, ERK5 is the first MAP kinase identified whose activity is stimulated by neurotrophins but not by neuronal activity.
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PMID:Differential regulation of mitogen-activated protein kinases ERK1/2 and ERK5 by neurotrophins, neuronal activity, and cAMP in neurons. 1116 Apr 24

Stimulation of aldosterone biosynthesis by angiotensin II (AII) is thought to be mediated via the PLC, IP3 and intracellular calcium signalling pathway. MAPK (p42/p44) is involved in cell proliferation, and is also activated by AII, but its role in the adrenal response to dietary sodium is unclear. To study the relationship between AII receptor (ATR), MAPK and PKC isoforms, PKCalpha and PKCepsilon, mature Wistar rats were maintained on low or high sodium diets for 1 week. In adrenals from animals on a sodium deplete diet, total ligand binding to both ATR subtypes decreased in the zona glomerulosa (ZG). Under these conditions, active MAPK in the ZG decreased paralleling a decrease in active PKCalpha. In the inner zones (IZ), largely reflecting medullary events, low sodium did not affect MAPK activity. However active PKCalpha decreased. In adrenals from sodium-loaded animals, type 2 ATR (AT2R) binding was reduced in the ZG, while type 1 ATR (AT1R) increased in the IZ. Active MAPK increased in ZG, as did active PKCalpha and PKCepsilon. In IZ, ERK, PKCalpha and PKCepsilon were unchanged. These results suggest that in the ZG and IZ, two different modes of MAPK regulation may exist, utilising different PKC isoforms.
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PMID:Regulation of MAPK activity in response to dietary sodium in the rat adrenal gland. 1119 66

The somatostatin receptor subtype sst2A is highly expressed, non-mutated and functionally active in gliomas. After stimulation of cultivated human U343 glioma cells with somatostatin, octreotide (sst2-, sst3- and sst5-selective peptide agonist) or the sst2-selective non-peptide agonist L-054,522 multiple signal transduction pathways are induced: elevated cAMP levels are reduced, protein tyrosine phosphatases (especially SHP2) are activated and mitogen-activated protein kinases are inhibited. Stimulation of the phosphatases resulted in dephosphorylation of activated receptors for EGF and PDGF (epidermal and platelet-derived growth factor), and as a consequence the mitogen-activated protein kinases ERK 1 and 2 (p42/p44) were de-phosphorylated in co-stimulation experiments. Furthermore, somatostatin or sst2-selective agonists reduced EGF-stimulated expression of the AP-1 complex (c-jun/c-jun) on the transcriptional and translational level. These experiments show that the interaction of stimulatory and inhibitory receptors are important mechanisms for the regulation of signal cascades and gene expression.
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PMID:Influence of the somatostatin receptor sst2 on growth factor signal cascades in human glioma cells. 1122 55


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