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 fibroblast growth factor-2 (FGF-2) acts not only on osteoblasts to stimulate osteoclastic bone resorption indirectly but also on mature osteoclasts directly. In this study, we investigated the mechanism of this direct action of FGF-2 on mature osteoclasts using mouse and rabbit osteoclast culture systems. FGF-2 stimulated pit formation resorbed by isolated rabbit osteoclasts moderately from low concentrations (>/=10(-12) m), whereas at high concentrations (>/=10(-9) m) it showed stimulation on pit formation resorbed by unfractionated bone cells very potently. FGF-2 (>/=10(-12) m) also increased cathepsin K and MMP-9 mRNA levels in mouse and rabbit osteoclasts. Among FGF receptors (FGFR1 to 4) only FGFR1 was detected on isolated mouse osteoclasts, whereas all FGFRs were identified on mouse osteoblasts. FGF-2 (>/=10(-12) m) up-regulated the phosphorylation of cellular proteins, including p42/p44 mitogen-activated protein (MAP) kinase, and increased the kinase activity of immunoprecipitated FGFR1 in mouse osteoclasts. The stimulation of FGF-2 on mouse and rabbit osteoclast functions was abrogated by PD-98059, a specific inhibitor of p42/p44 MAP kinase. These results strongly suggest that FGF-2 acts directly on mature osteoclasts through activation of FGFR1 and p42/p44 MAP kinase, causing the stimulation of bone resorption at physiological or pathological concentrations.
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PMID:Fibroblast growth factor (FGF)-2 directly stimulates mature osteoclast function through activation of FGF receptor 1 and p42/p44 MAP kinase. 1089 47

We have used an antibody that specifically recognizes eukaryotic initiation factor 4E (eIF4E) when it is phosphorylated at Ser(207) to characterize eIF4E phosphorylation in the nervous system of APLYSIA: The level of phosphorylated eIF4E, but not the level of total eIF4E, was significantly correlated with the basal rate of translation measured from different animals. Serotonin (5-HT), a transmitter that regulates the rate of translation in APLYSIA: neurons, had mixed effects on eIF4E phosphorylation. 5-HT decreased eIF4E phosphorylation in sensory cell clusters through activation of protein kinase C. 5-HT increased eIF4E phosphorylation in the whole pleural ganglia. In the APLYSIA: nervous system, eIF4E phosphorylation correlated with phosphorylation of the p38 MAP kinase, but not the p42 MAP kinase (ERK). Furthermore, an inhibitor of the p38 MAP kinase significantly decreased basal eIF4E phosphorylation, but an inhibitor of the MAP or ERK kinase (MEK) did not. Despite the correlation of eIF4E phosphorylation with the basal rate of translation, inhibition of eIF4E phosphorylation by an inhibitor of the p38 MAP kinase did not significantly decrease the rate of translation.
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PMID:Regulation of eukaryotic initiation factor 4E phosphorylation in the nervous system of Aplysia californica. 1089 66

The effect of lipopolysaccharide (LPS) on the expression of immediate early genes, such as c-fos and c-jun, was examined in C6 rat glioma cells. LPS (1 microg/ml) alone did not affect c-fos mRNA level. LPS, however, transiently increased c-jun mRNA level. Cycloheximide (CHX, 20 microM), a protein synthesis inhibitor, alone caused increases of c-fos and c-jun mRNA levels. LPS showed a potentiating effect in the regulation of c-fos mRNA level, whereas LPS showed an additive action for the regulation of CHX-induced c-jun mRNA expression. To determine if CREB and mitogen-activated protein kinases (MAPKs) are involved in the regulation of c-fos mRNA expression by LPS and CHX, Western blot was carried out using the phosphorylated form of antibodies against ERK, JNK, p38, and CREB. LPS transiently increased the phosphorylation of p38-MAPK and CREB. In addition, LPS alone elevated phosphorylation of ERK (p44/p42) MAPK in a time-dependent manner. Furthermore, LPS plus CHX enhanced phosphorylation of ERK, p38, and CREB in a synergistic manner. Our results suggest that the phosphorylation of ERK, p38, and CREB may be involved in the regulation of synergistic c-fos mRNA expression induced by LPS plus CHX in C6 rat glioma cells.
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PMID:Regulation of c-fos gene expression by lipopolysaccharide and cycloheximide in C6 rat glioma cells. 1092 99

We have previously shown that protein kinase C (PKC)-epsilon, nuclear factor (NF)-kappaB, and mitogen-activated protein kinases (MAPKs) are essential signaling elements in ischemic preconditioning. In the present study, we examined whether activation of PKCepsilon affects the activation of NF-kappaB in cardiac myocytes and whether MAPKs are mediators of this signaling event. Activation of PKCepsilon (+108% above control) in adult rabbit cardiomyocytes to a degree that has been previously shown to protect myocytes against hypoxic injury increased the DNA-binding activity of NF-kappaB (+164%) and activator protein (AP)-1 (+127%) but not that of Elk-1. Activation of PKCeta did not have an effect on these transcription factors. Activation of PKCepsilon also enhanced the phosphorylation activities of the p44/p42 MAPKs and the p54/p46 c-Jun NH(2)-terminal kinases (JNKs). PKCepsilon-induced activation of NF-kappaB and AP-1 was completely abolished by inhibition of the p44/p42 MAPK pathway with PD98059 and by inhibition of the p54/p46 JNK pathway with a dominant negative mutant of MAPK kinase-4, indicating that both signaling pathways are necessary. Taken together, these data identify NF-kappaB and AP-1 as downstream targets of PKCepsilon, thereby establishing a molecular link between activation of PKCepsilon and activation of NF-kappaB and AP-1 in cardiomyocytes. The results further demonstrate that both the p44/p42 MAPK and the p54/p46 JNK signaling pathways are essential mediators of this event.
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PMID:PKCepsilon modulates NF-kappaB and AP-1 via mitogen-activated protein kinases in adult rabbit cardiomyocytes. 1100 55

Despite recent studies depicting the capacity of G protein-coupled receptors (GPCRs) to activate mitogenic signaling pathways more commonly associated with receptor tyrosine kinases (RTKs), little is known regarding the interactive effects of GPCR and RTK activation on cell growth and signal transduction. Such interactions likely mediate the physiologic growth in most cells in vivo as well as the aberrant, non-neoplastic growth that occurs in diseases such as asthma, where disruptions of the local hormonal or inflammatory state can contribute to significant GPCR activation. In this study, we show that numerous inflammatory or contractile agents, including thrombin, histamine, and carbachol, potentiate epidermal growth factor (EGF)-stimulated proliferation of human airway smooth muscle (ASM), thus demonstrating a clear synergy between RTK and GPCR activation. Alterations in promitogenic nuclear signaling were evidenced by additive or synergistic increases in Elk-1 and activator protein-1 activation, and by increases in cyclin D1 expression. Interestingly, GPCR activation did not cause EGF receptor tyrosine phosphorylation nor did it increase EGF-stimulated autophosphorylation. In the presence of EGF, histamine or carbachol did not alter the time-dependent phosphorylation of p42/p44, whereas thrombin was capable of increasing phospho-p42/p44 levels at selected time points in some, but not all, cultures. In contrast to their relative inability to alter EGF receptor-linked p42/p44 activation, thrombin, histamine, and carbachol consistently increased the late phase (> 1 h) activity of p70 S6 kinase. Collectively, these findings suggest that inflammatory and contractile agents that activate GPCRs can significantly modulate RTK-mediated ASM growth through a p70 S6 kinase-dependent, p42/p44-independent mechanism.
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PMID:Mechanisms of proliferation synergy by receptor tyrosine kinase and G protein-coupled receptor activation in human airway smooth muscle. 1101 21

Phagocytosis of IgG-opsonized particles by macrophages requires the activation of protein kinase C (PKC), a family of protein serine/threonine kinases. In the present study, we have investigated the role of the PKC-alpha isoenzyme in FcgammaR-mediated phagocytosis using clones of the mouse macrophage cell line RAW 264. 7 overexpressing a dominant-negative (DN) mutant of PKC-alpha. Overexpression of DN PKC-alpha had no effect on the attachment of IgG-opsonized sheep red blood cells, but inhibited their internalization. Further analysis of the signaling events induced by IgG-opsonized sheep red blood cells revealed that whereas tyrosine phosphorylation of Syk was normal, phosphorylation of ERK 1/2 (p42/44) was impaired in DN PKC-alpha-overexpressing macrophages. These observations suggest a role for PKC-alpha in the regulation of FcgammaR-induced phagocytosis and signal transduction.
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PMID:Protein kinase C-alpha participates in FcgammaR-mediated phagocytosis in macrophages. 1102 99

While monocyte/macrophage (Mphi) adherence to a matrix is necessary for differentiation and prolonged survival, the effect of adherence on the signaling mechanisms responsible for Mphi activation is unknown. Lipopolysaccharide (LPS) activates Mphi by signaling through members of the mitogen activated protein kinase (MAPK) family thereby inducing transcription of proinflammatory cytokines, such as TNF-alpha. Since adherence has been shown to affect different activities of various myeloid phagocytes, we investigated whether adherence affects intracellular signaling and modulates activation of the Mphi proinflammatory phenotype. We assessed the effect of adherence on activation of rabbit alveolar Mphi by measuring LPS-induced TNF-alpha mRNA and TNF-alpha secreted product in adherent versus nonadherent cells, in vitro. The effect of adherence on LPS-induced activation of MAPK was assessed by western analysis using a dual phosphospecific antibody against p38MAPK, p42,44ERK, and p54SAPK. LPS is known to induce activation of NF-kappaB and AP-1. Modulation of these two transcription factors by LPS under adherent versus nonadherent conditions was evaluated by gel-shift analyses. The results were that adherent cells treated with LPS, 10 ng/mL or 1 microg/ml, elicited a 26- and 132-fold increase, respectively, in TNF-alpha production. Nonadherent cells did not elicit significant TNF-alpha in response to LPS. Adherence alone induced significant ERK and AP-1 activation, but did not stimulate a significant TNF-alpha response and no further activation of ERK and AP-1 was observed with LPS stimulation. Adherence alone did not activate p38MAPK or NF-kappaB, but primed Mphi for an augmented response to LPS in activation of p38, NF-kappaB and in production of TNF-alpha. We conclude that adherence primes Mphi for activation and regulates MAPK signal transduction pathways.
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PMID:Adherence regulates macrophage signal transduction and primes tumor necrosis factor production. 1104 6

The present study investigated the activation of mitogen-activated protein kinases (MAPKs) by a GnRH agonist (GnRHa) in human granulosa-luteal cells (hGLCs). The phosphorylation state of p44 and p42 MAPK was examined using antibodies that distinguish phospho-p44/42 MAPK (Thr(202)/Tyr(204)) from total p44/42 MAPK (activated plus inactivated). Activation of MAPK by GnRHa was observed within 5 min and was sustained for 60 min after treatment. GnRHa stimulated MAPK activation in a dose-dependent manner, with maximum stimulation (6.7-fold over basal levels) at 10(-7) M. Pretreatment with a protein kinase C (PKC) inhibitor, GF109203X, completely blocked GnRHa-induced MAPK activation. In addition, pretreatment with a PKC activator, phorbol-12-myristate 13-acetate, potentiated GnRH-induced MAPK activation. These results indicate that GnRHa stimulates MAPK activation through a PKC-dependent pathway in hGLCs, possibly coupled to G(q)alpha protein. MAPK activation was also observed in response to 8-bromo-cAMP or cholera toxin, but not pertussis toxin. Forskolin (50 microM) substantially stimulated a rapid cAMP accumulation, whereas GnRHa (10(-7) M) or pertussis toxin (100 mg/ml) did not affect basal intracellular cAMP levels. Cotreatment of GnRHa (10(-7) M) did not attenuate forskolin- or hCG-stimulated cAMP accumulation. These results suggest that the GnRH receptor is probably not coupled to G(s)alpha or G(i)alpha in hGLCs. Finally, GnRHa (10(-7) M) stimulated a significant increase in Elk-1 phosphorylation and c-fos messenger RNA expression, as revealed by an in vitro kinase assay and Northern blot analysis, respectively. These results clearly demonstrate that GnRH activates the MAPK cascade through a PKC-dependent pathway in the human ovary.
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PMID:Stimulation of mitogen-activated protein kinase by gonadotropin-releasing hormone in human granulosa-luteal cells. 1115 38

To determine the immediate effect of thiazolidinediones on human skeletal muscle, differentiated human myotubes were acutely (1 day) and myoblasts chronically (during the differentiation process) treated with troglitazone (TGZ). Chronic TGZ treatment resulted in loss of the typical multinucleated phenotype. The increase of muscle markers typically observed during differentiation was suppressed, while adipocyte markers increased markedly. Chronic TGZ treatment increased insulin-stimulated phosphatidylinositol (PI) 3-kinase activity and membranous protein kinase B/Akt (PKB/Akt) Ser-473 phosphorylation more than 4-fold. Phosphorylation of p42/44 mitogen-activated protein kinase (42/44 MAPK/ERK) was unaltered. Basal glucose uptake as well as both basal and insulin-stimulated glycogen synthesis increased approximately 1.6- and approximately 2.5-fold after chronic TGZ treatment, respectively. A 2-fold stimulation of PI 3-kinase but no other significant TGZ effect was found after acute TGZ treatment. In conclusion, chronic TGZ treatment inhibited myogenic differentiation of that human muscle while inducing adipocyte-specific gene expression. The effects of chronic TGZ treatment on basal glucose transport may in part be secondary to this transdifferentiation. The enhancing effect on PI 3-kinase and PKB/Akt involved in both differentiation and glycogen synthesis appears to be pivotal in the cellular action of TGZ.
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PMID:Effects of troglitazone on cellular differentiation, insulin signaling, and glucose metabolism in cultured human skeletal muscle cells. 1116 73

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


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