Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II (Ang II) receptors of the AT1 subtype are coupled to heterotrimeric G nucleotide-binding proteins, G(q/11), to activate phospholipase C-beta isoforms with production of inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol. The resultant release of intracellular Ca2+ and increased Ca2+ influx are major determinants of several acute cellular responses initiated by Ang II, including secretion of aldosterone from the adrenal cortex and smooth muscle contraction. However, cellular events related to more prolonged effects of Ang II, such as hypertrophic and hyperplastic responses, are triggered by intracellular signaling cascades that are less dependent on Ca2+ signals. The Ang II-induced activation of Raf-1 kinase, p42 MAP-kinase and c-fos expression in response to Ang II in adrenal glomerulosa cells does not require Ca2+ influx. Moreover, the dose-response relationships for Raf-1 activation, MAP-kinase activation and mitogenesis show significantly higher sensitivity to Ang II than the InsP3, Ca2+-release and aldosterone secretory responses. The sensitivities of both Raf-1 kinase and MAP-kinase stimulation by Ang II to the inhibitors of phosphoinositide kinases, wortmannin and LY 294002, suggest that inositol phospholipids may play a role in these activation events unrelated to their role in Ca2+ signaling. To investigate the changes of various inositides after stimulation at the single cell level, fluorescent probes were developed in which pleckstrin homology domains with distinct binding specificities to inositol phospholipids were fused to the green fluorescent protein and expressed in NIH 3T3 cells. The use of these probes revealed heterogeneity of the inositol lipid pools and their complex relationship to Ca2+ signals. The use of these tools will help to further clarify the complex role of these lipids in initiating Ca2+-dependent and -independent signaling responses.
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PMID:Signaling events activated by angiotensin II receptors: what goes before and after the calcium signals. 988 5

Adult rat ventricular cardiomyocytes contain alpha1A- and alpha1B-adrenoceptors (ARs, 20%:80%, assessed by [3H]prazosin binding). We studied which alpha1-AR subtype mediates noradrenaline (NA)-induced increase in rate of protein synthesis, and which signalling pathway is involved. NA (10-9-10-4 M) concentration-dependently increased inositol phosphate (IP) formation (pEC50-value=6.1+/-0.1, n=5) and protein synthesis (assessed as [3H]phenylalanine incorporation; pEC50-value=6.6+/-0.1, n=6). NA-induced IP-formation was partly inhibited by the alpha1B-AR antagonist chloroethylclonidine (CEC, 30 microM; 33+/-9% inhibition, n=5); following CEC-treatment the alpha1A-AR-selective 5-methyl-urapidil (5-MU) inhibited NA-induced IP-formation with a pKi-value of 9.2+/-0.2 (n=6); the alpha1D-AR-selective BMY 7378 was only a weak antagonist (pKi-value <7). NA-induced increase in protein synthesis was insensitive to CEC whereas 5-MU inhibited it with a pKi-value of 9.1+/-0.2 (n=6). NA (1 microM)-induced increase in protein synthesis was inhibited by the protein kinase C (PKC) inhibitor bisindolylmaleimide (IC50-value: 206 nM), the PI 3-kinase inhibitors wortmannin (IC50=3.4 nM) and LY 294002 (IC50=10 microM), and p70s6-kinase inhibitor rapamycin (IC50=123 pM) but not by the p38 MAP-kinase inhibitor SB 203580 (10 microM) or the MEK-inhibitor PD 98059 (25 microM). Moreover, 5-MU (30 nM) but not CEC inhibited NA-induced activation of p70s6-kinase. We conclude that, in adult rat cardiomyocytes, alpha1A- and alpha1B-AR mediate NA-induced IP-formation but only alpha1A-ARs mediate increase in protein synthesis. Alpha1A-AR-mediated increase in protein synthesis involves activation of a PKC, PI 3-kinase and p70s6-kinase but not of ERK- or p38 MAP-kinase.
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PMID:Noradrenaline-induced increase in protein synthesis in adult rat cardiomyocytes: involvement of only alpha1A-adrenoceptors. 1169 28

NGF activates several signaling cascades in sympathetic neurons. We examined how activation of one of these cascades, the ERK/MAP (extracellular signal-regulated kinase/mitogen-activated protein) kinase pathway, affects dendritic growth in these cells. Dendritic growth was induced by exposure to NGF and BMP-7 (bone morphogenetic protein-7). Exposure to NGF increased phosphorylation of ERK1/2. Unexpectedly, two MEK (MAP kinase kinase) inhibitors (PD 98059 and U 0126) enhanced dendritic growth, and a ligand, basic FGF, that activates the ERK pathway inhibited the growth of these processes. The enhancement of dendritic growth by PD 98059 was associated with an increase in the number of axo-dendritic synapses, and it appeared to represent a specific morphogenic effect because neither axonal growth nor cell survival was affected. In addition, increased dendritic growth was not observed after exposure to inhibitors of other signaling pathways, including the phosphatidylinositol-3-kinase inhibitor LY 294002. Dendritic growth was also increased in cells transfected with dominant-negative mutants of MEK1 and ERK2 but not with dominant-negative mutants of MEK5 and ERK5, suggesting that ERK1/2 is the primary mediator of this effect. Exposure to BMP-7 induces nuclear translocation of Smad1 (Sma- and Mad-related protein 1), and PD 98059 treatment potentiated nuclear accumulation of Smad-1 induced by BMP-7 in sympathetic neurons, suggesting a direct enhancement of BMP signaling in cells treated with an MEK inhibitor. These observations indicate that one of the signaling cascades activated by NGF can act in an antagonistic manner in sympathetic neurons and reduce the dendritic growth induced by other NGF-sensitive pathways.
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PMID:Extracellular signal-regulated kinases regulate dendritic growth in rat sympathetic neurons. 1505 10

ATP induces the proliferation of chick retinal cells in culture through the activation of P2Y1 receptors, PKC and MAP kinases. Together with MAP kinases, the PI3K/AKT pathway has also been implicated as an important mediator in proliferative events during development. Here we investigated the participation of the PI3K/AKT signal pathway on ATP-induced proliferation of chick embryo retinal cells in culture. When retinal cultures obtained from 7-day-old embryos were cultivated for 1 day and treated with ATP, a transient and dose-dependent phosphorylation of both ERK and AKT was observed, an effect that could be mimicked by 500 microM ADP and blocked by 100 microM PPADS, a P2 receptor antagonist. Maximal stimulation of both enzymes was obtained with 100 microM ATP in 5 min, decreasing thereafter. Activation of these pathways by ATP seemed to be independent, since LY294002 and U0126, inhibitors of PI3K and MEK, did not block the activation of ERK and AKT, respectively, although each compound blocked its respective target. Moreover, when the cultures were incubated with ATP in the presence of LY294002, a decreased incorporation of [(3)H]-thymidine was observed, as compared to cultures treated only with ATP, a decline that was also obtained by incubating the cells with ATP plus 0.5 microM API-59CJ-Ome, an inhibitor of AKT. No decrease in cell viability was observed with this concentration of API-59CJ-Ome. An increase in cyclin D1 expression, that could be inhibited by 10 microM LY 294002 or 20 microM U0126, was observed when cells were incubated with 500 microM ADP. No effect of PI3K and MEK inhibitors was observed in the expression of p27kip1 in the cultures. These results suggest that, besides the involvement of the MAP kinases pathway, ATP-induced cell cycling of late developing retinal progenitors in culture also involves the activation of the PI3K/AKT pathway.
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PMID:Involvement of the PI3K/AKT pathway in ATP-induced proliferation of developing retinal cells in culture. 2054 6