Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously showed that sphingosine 1-phosphate acts as a second messenger for tumor necrosis factor alpha-induced interleukin-6 synthesis in osteoblast-like MC3T3-E1 cells and that the synthesis by sphingosine 1-phosphate is dependent on p42/p44 mitogen-activated protein (MAP) kinase activation. In the present study, we investigated the effect of sphingosine 1-phosphate on the induction of heat shock protein 27 (HSP27) in MC3T3-E1 cells. Not C2-ceramide, but sphingosine and sphingosine 1-phosphate significantly induced HSP27 accumulation dose dependently in the range between 1microM and 30 microM. DL-threo-dihydrosphingosine, an inhibitor of sphingosine kinase, markedly inhibited the sphingosine-induced HSP27 accumulation. Sphingosine 1-phosphate induced increase in the levels of the mRNA for HSP27. Sphingosine 1-phosphate stimulated the phosphorylation of p38 MAP kinase. The sphingosine 1-phosphate-induced HSP27 accumulation was dose dependently suppressed by SB203580, an inhibitor of p38 MAP kinase, but not PD98059, an inhibitor of the upstream kinase that activates p42/p44 MAP kinase. SB203580 reduced the sphingosine 1-phosphate-induced increase of mRNA for HSP27. These results strongly suggest that sphingosine 1-phosphate-stimulated HSP27 induction is mediated via p38 MAP kinase activation in osteoblasts.
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PMID:Sphingosine 1-phosphate induces heat shock protein 27 via p38 mitogen-activated protein kinase activation in osteoblasts. 1049 Dec 24

Tetanic stimuli to layer I-II afferents in rat prefrontal cortex induced long-term depression (LTD) of layer I-II to layer V pyramidal neuron glutamatergic synapses when tetani were coupled to bath application of dopamine. This LTD was blocked by the following metabotropic glutamate receptor (mGluR) antagonists coapplied with dopamine: (S)-alpha-methyl-4-carboxyphenylglycine (MCPG; group I and II antagonist), (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA; group I antagonist), or (RS)-alpha-methylserine-O-phosphate monophenyl ester (MSOPPE; group II antagonist). This suggests that the dopamine-facilitated LTD requires synaptic activation of groups I and II mGluRs during tetanus. LTD could also be induced by coupling tetani to bath application of groups I and II mGluR agonist (1S, 3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD). In the next series of experiments, coapplication of dopamine and 1S,3R-ACPD, but not application of either drug alone, consistently induced LTD without tetani or even single test stimuli during drug application, suggesting that coactivation of dopamine receptors and the mGluRs is sufficient for LTD induction. Immunoblot analyses with anti-active mitogen-activated protein kinases (MAP-Ks) revealed that D1 receptors, D2 receptors, group I mGluRs, and group II mGluRs all contribute to MAP-K activation in prefrontal cortex, and that combined activation of dopamine receptors and mGluRs synergistically or additively activate MAP-Ks. Consistently, LTD by dopamine + 1S, 3R-ACPD coapplication, as well as the two other forms of LTD (LTD by dopamine + tetani and LTD by 1S,3R-ACPD + tetani), was blocked by bath application of MAP-K kinase inhibitor PD98059. LTD by dopamine + 1S,3R-ACPD coapplication was also blocked by postsynaptic injection of synthetic MAP-K substrate peptide. Our results suggest that dopamine receptors and groups I and II mGluRs cooperate to induce LTD through converging postsynaptic activation of MAP-Ks.
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PMID:Dopamine receptors and groups I and II mGluRs cooperate for long-term depression induction in rat prefrontal cortex through converging postsynaptic activation of MAP kinases. 1055 88

Physiological and pathological observations indicate that basic fibroblast growth factor (bFGF) is an important regulator of osteoblastic cell differentiation and in particular of cranial ossification. Experimental evidence suggests that inorganic phosphate (Pi) transport could be an important function of bone matrix calcification. In the present study, we address the influence of bFGF on Pi transport activity in MC3T3-E1 osteoblast-like cells derived from mouse calvaria. The results indicate that bFGF is a potent and selective stimulator of sodium-dependent Pi transport in these cells. The change in Pi transport activity induced by bFGF depends on transcription and translation and corresponds to a change in the maximum velocity of the Pi transport system (Vmax). These observations suggest that enhanced Pi transport activity in response to bFGF may result from insertion of newly synthesized Pi transporters into the plasma membrane. A selective inhibitor of fibroblast growth factor receptor (FGFR) tyrosine kinase, SU5402, blunted the stimulation of Pi transport induced by bFGF. It also prevented the increase in protein tyrosine phosphorylation induced by bFGF, including phosphorylation of FGFR-1, FGFR-2, phospholipase C-gamma (PLC-gamma), and Shc as well as the recruitment of the Grb2/Sos signaling complex. In addition, bFGF-induced the activation of the mitogen-activated protein (MAP) kinases extracellular signal-regulated kinase (ERK) and p38, effects that were prevented by SU5402. Both the protein kinase C (PKC) inhibitor calphostin C and PKC down-regulation suppressed the stimulatory effect of bFGF on Pi transport. Selective inhibitors of ERK and p38 MAP kinases slightly reduced this cellular response with a significant effect observed with the highest concentration of the p38 MAP kinase inhibitor. In conclusion, the results of this study indicate that bFGF selectively stimulates Pi transport in calvaria-derived osteoblastic cells. The main signaling mechanism responsible for this effect involves tyrosine phosphorylation of PLC-gamma and activation of PKC, with a possible contribution of the p38 MAP kinase pathway.
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PMID:Stimulation of sodium-dependent phosphate transport and signaling mechanisms induced by basic fibroblast growth factor in MC3T3-E1 osteoblast-like cells. 1064 18

The stress-activated kinases c-Jun N-terminal kinase (JNK) and p38 are members of the mitogen-activated protein (MAP) kinase family and take part in signalling cascades initiated by various forms of stress. Their targets include the microtubule-associated protein tau, which becomes hyperphosphorylated in Alzheimer's disease. It is necessary, as a forerunner for in vivo studies, to identify the protein kinases and phosphatases that are responsible for phosphate turnover at individual sites. Using nanoelectrospray mass spectrometry, we have undertaken an extensive comparison of phosphorylation in vitro by several candidate tau kinases, namely, JNK, p38, ERK2, and glycogen synthase kinase 3beta (GSK3beta). Between 10 and 15 sites were identified for each kinase. The three MAP kinases phosphorylated Ser202 and Thr205 but not detectably Ser199, whereas conversely GSK3beta phosphorylated Ser199 but not detectably Ser202 or Thr205. Phosphorylated Ser404 was found with all of these kinases except JNK. The MAP kinases may not be strictly proline specific: p38 phosphorylated the nonproline sites Ser185, Thr245, Ser305, and Ser356, whereas ERK2 was the most strict. All of the sites detected except Thr245 and Ser305 are known or suspected phosphorylation sites in paired helical filament-tau extracted from Alzheimer brains. Thus, the three MAP kinases and GSK3beta are importantly all strong candidates as tau kinases that may be involved in the pathogenic hyperphosphorylation of tau in Alzheimer's disease.
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PMID:Phosphorylation sites on tau identified by nanoelectrospray mass spectrometry: differences in vitro between the mitogen-activated protein kinases ERK2, c-Jun N-terminal kinase and P38, and glycogen synthase kinase-3beta. 1073 16

Muscarinic acetylcholine receptors (mAChRs) in exocrine tissue from the avian nasal salt gland are coupled to phospholipase C and generate inositol phosphate and Ca(2+) signals upon activation. An early effect of receptor activation in the secretory cells is a transient accumulation of c-Fos protein. In cooperation with constitutively expressed Jun, Fos presumably serves as a transcription factor altering gene expression during cell growth and differentiation processes in the gland associated with adaptation to osmotic stress in animals. Nothing is known, however, about the mAChR-dependent signaling pathways leading to Fos expression in these cells. By incubation of isolated nasal gland tissue in short-term culture with activators or inhibitors of signaling pathways and quantitative Western blot analysis of Fos abundance, we have now identified the sustained elevation of the intracellular Ca(2+) concentration and the activation of the p38 mitogen-activated protein (MAP) kinase as intermediate signaling elements for the regulation of c-Fos by muscarinic receptor activation. It is suggested that p38 MAP kinase, rather than exclusively mediating stress responses, is involved in the regulation of cellular growth and differentiation controlled by G protein-coupled receptors.
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PMID:Ca(2+) and p38 MAP kinase regulate mAChR-mediated c-Fos expression in avian exocrine cells. 1079 61

Members of the transforming growth factor (TGF)-beta family are important regulators of skeletal development. In this study, we investigated the effect of TGF-beta1 on inorganic phosphate (Pi) transport and on expression of the type III Pi carriers Glvr-1 and Ram-1 in murine ATDC5 chondrocytes. TGF-beta1 induced a selective, dose- and time-dependent increase in sodium-dependent Pi transport in ATDC5 cells. This response was dependent on RNA and protein synthesis and reflected a change in the maximal rate of the transport system, suggesting that TGF-beta1 induces the synthesis of new Pi carriers and their insertion into the plasma membrane. Consistently, Northern blotting analysis showed a dose-dependent increase in Glvr-1 messenger RNA expression in response to TGF-beta1, which preceded the maximal stimulation of Pi transport by several hours. Glvr-1 thus likely mediates at least part of the increase in Pi uptake induced by TGF-beta1. Ram-1 messenger RNA expression was not affected by TGF-beta1. TGF-beta1 activated the Smad signaling pathway and the mitogen-activated protein kinases ERK and p38 in ATDC5 cells. Unlike the regulation of Pi transport by receptor tyrosine kinase agonists in osteoblasts, the effect of TGF-beta1 on Pi uptake in ATDC5 cells did not involve protein kinase C or mitogen-activated protein kinases, suggesting that a specific, possibly Smad-dependent, signal mediates this response. In conclusion, TGF-beta1 stimulates Pi transport and Glvr-1 expression in chondrocytes, suggesting that, like proliferation, differentiation, and matrix synthesis, Pi handling is subject to regulation by TGF-beta3 family members in bone-forming cells.
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PMID:Transforming growth factor-beta stimulates inorganic phosphate transport and expression of the type III phosphate transporter Glvr-1 in chondrogenic ATDC5 cells. 1083 Mar 13

Catecholamines modulate cardiac function at least in part through alpha(1)-adrenergic receptors linked to the activation of protein kinase C (PKC). This study examines the molecular forms of the alpha(1)-receptor and PKC that mediate norepinephrine's actions in cardiomyocytes; distinct approaches (activation-dependent down-regulation of PKC isoforms) and novel reagents (A61603, an alpha(1A/c)-receptor agonist) are used to resolve this issue which has been the focus of dispute in previous studies. Norepinephrine (NE) induces a rise in diacylglycerol levels which is sustained for 24 h and is associated with the translocation (at 5 min) and down-regulation (at 24 h) of PKC delta and PKC xi (but not PKC alpha). The selective targeting of the alpha(1)-adrenergic receptor to activate novel PKC isoforms is remarkable, given an 8-fold greater abundance of PKC alpha relative to PKC xi in this preparation. NE activates the extracellular signal-regulated protein kinase (ERK) subfamily of mitogen-activated protein kinases through a PKC delta/PKC xi -dependent pathway. WB-4101 (alpha(1A/c)- and alpha(1D)-receptor antagonist) and 5-methylurapidil (alpha(1A/c)-receptor antagonist) inhibit norepinephrine-dependent accumulation of inositol phosphate and diacylglycerol, down-regulation of PKC delta and PKC xi, and activation of ERK. Each of these responses is stimulated by A61603, but not attenuated by high concentrations of chloroethylclonidine (which irreversibly inactivates the alpha(1B)-, and to a lesser extent, the alpha(1D)-receptor) or BMY 7378 (selective alpha(1D)-receptor antagonist). A61603 also activates p38-MAPK and induces hypertrophy. These studies establish that NE's actions in cardiomyocytes can be attributed to the alpha(1A/c)-adrenergic receptor subtype and nPKC isoforms, thereby identifying specific targets for the development of pharmaceuticals to influence cardiac contractile function and/or growth responses.
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PMID:The alpha(1)-adrenoceptor subtype- and protein kinase C isoform-dependence of Norepinephrine's actions in cardiomyocytes. 1086 Jul 63

Over the last few years, sphingolipids have emerged as an additional class of lipids participating in signaling events in various cell types. The best-investigated examples so far are ceramide and sphingosine-1-phosphate. Ceramide-activated protein kinase and sphingosine kinase are two enzymes which respond to and generate these mediators. In particular, sphingosine kinase, its substrate sphingosine and the product sphingosine-1-phosphate have recently been implicated in the signaling cascades initiated at the FcepsilonRI of mast cells. High intracellular levels of sphingosine seem to serve as an 'intracellular' inhibitor which is 'deactivated' by the action of sphingosine kinase, due to the conversion to sphingosine-1-phosphate. One mode of action of the inhibitory process in this cell type is prevention of the activation of the mitogen-activated protein (MAP) kinase pathway. Sphingosine-1-phosphate itself, the product of this enzymatic reaction, is believed to lead to Ca(2+) mobilization and to stimulate the MAP kinase pathway. The existence and function of this second messenger explains the 'IP3 gap' described in mast cells after FcepsilonRI activation. Therefore, a picture emerges whereby the balance of these two lipid molecules seems to be decisive for the activation of mast cells by IgE plus antigen, with sphingosine kinase acting as a permissive switch for stimulation.
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PMID:The role of sphingosine kinase in the signaling initiated at the high-affinity receptor for IgE (FcepsilonRI) in mast cells. 1087 86

We previously showed that sphingosine 1-phosphate phosphorylates p42/p44 mitogen-activated protein (MAP) kinase and p38 MAP kinase in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the effect of sphingosine 1-phosphate on phospholipase C-catalyzing phosphoinositide hydrolysis induced by prostaglandin F2alpha (PGF2 alpha) in these cells. Sphingosine 1-phosphate significantly amplified the inositol phosphates formation by PGF2 alpha. Sphingosine 1-phosphate did not enhance the formation induced by NaF, a direct activator of heterotrimeric GTP-binding proteins. PD98059, an inhibitor of the kinase that activates p42/p44 MAP kinase, had little effect on the amplification by sphingosine 1-phosphate. SB203580, an inhibitor of p38 MAP kinase, reduced the effect of sphingosine 1-phosphate on the formation of inositol phosphates by PGF2 alpha. The phosphorylation of p42/p44 MAP kinase by PGF alpha was attenuated by PD98059. SB203580 suppressed the phosphorylation of p38 MAP kinase by PGF2 alpha. Tumor necrosis factor-alpha enhanced the PGF2 alpha-stimulated formation of inositol phosphates. These results strongly suggest that sphingosine 1-phosphate amplifies PGF2 alpha-induced phosphoinositide hydrolysis by phospholipase C through p38 MAP kinase in osteoblasts.
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PMID:Sphingosine 1-phosphate amplifies phosphoinositide hydrolysis stimulated by prostaglandin f2 alpha in osteoblasts: involvement of p38MAP kinase. 1091 28

Sphingosine-1-phosphate (SPP), produced by sphingosine kinase, has recently been reported to act as an intracellular second messenger for Ca(2+) and mitogenic responses triggered by membrane receptors and as an extracellular ligand for specific SPP receptors. Here, we investigated the signaling pathway leading to SPP production by the G protein-coupled P2Y(2) receptor and its functional implication in human leukemia (HL-60) cells, which do not respond to extracellular SPP. P2Y(2) receptor activation by UTP or ATP resulted in rapid and transient production of SPP, which was insensitive to pertussis toxin and blocked by the sphingosine kinase inhibitor, DL-threo-dihydrosphingosine. Treatment of HL-60 cells with this inhibitor did not affect activation of mitogen-activated protein kinases, but suppressed Ca(2+) mobilization by the P2Y(2) receptor. However, receptor-induced SPP production apparently required an increase in intracellular Ca(2+) concentration, but not Ca(2+) influx, and was mimicked by exposure of cells to Ca(2+) ionophores. Taken together, activation of the P2Y(2) receptor stimulates SPP production in HL-60 cells, a process apparently not required for mitogen-activated protein kinase activation, but most likely representing an amplification system for receptor-mediated Ca(2+) signaling.
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PMID:Stimulation of sphingosine-1-phosphate formation by the P2Y(2) receptor in HL-60 cells: Ca(2+) requirement and implication in receptor-mediated Ca(2+) mobilization, but not MAP kinase activation. 1095 41


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