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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the CNS, astrocytes play a key role in immunological and inflammatory responses through ICAM-1 expression, cytokine secretion (including TNF-alpha), and regulation of blood-brain barrier permeability. Because ICAM-1 transduces intracellular signals in lymphocytes and endothelial cells, we investigated in the present study ICAM-1-coupled signaling pathways in astrocytes. Using rat astrocytes in culture, we report that ICAM-1 binding by specific Abs induces TNF-alpha secretion together with phosphorylation of the transcription factor cAMP response element-binding protein. We show that ICAM-1 binding induces cAMP accumulation and activation of the mitogen-activated protein kinase extracellular signal-regulated kinase. Both pathways are responsible for cAMP response element-binding protein phosphorylation and TNF-alpha secretion. Moreover, these responses are partially dependent protein kinase C, which acts indirectly, as a common activator of cAMP/protein kinase A and extracellular signal-regulated kinase pathways. These results constitute the first evidence of ICAM-1 coupling to intracellular signaling pathways in glial cells and demonstrate the convergence of these pathways onto transcription factor regulation and TNF-alpha secretion. They strongly suggest that ICAM-1-dependent cellular adhesion to astrocytes could contribute to the inflammatory processes observed during leukocyte infiltration in the CNS.
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PMID:ICAM-1-coupled signaling pathways in astrocytes converge to cyclic AMP response element-binding protein phosphorylation and TNF-alpha secretion. 1039 56

Cytokine secretion by mesangial cells (MC) plays a major role in the pathogenesis of glomerulonephritis. To define signaling events that occur during the activation of MC, the cell-specific transcriptional regulation of the interleukin-6 (IL-6) gene was studied. Stimulation with lipopolysaccharide and IL-1beta resulted in the full induction of IL-6 expression only if the cells were coincubated with cAMP agonists; this effect was attenuated by protein kinase A inhibitors. In reporter gene experiments, the IL-6 promoter showed a stimulation pattern comparable to that of the endogenous gene. Elimination of individual transcription factor binding sites provided evidence for functional roles for four cis-acting elements, i.e., activator protein-1, cAMP response element-binding protein (CREB), nuclear factor for IL-6 expression (NF-IL6), and nuclear factor-kappaB (NF-kappaB). Electrophoretic mobility shift assays using nuclear extracts from MC revealed that the DNA-binding activities of activator protein-1 and NF-KB were inducible, whereas no change could be observed for CREB and NF-IL6. The presence of several transcription factor proteins, including JunB, JunD, c-Fos, Fra-1, CREB-1, activating transcription factor-2, NF-KB p50, p52, and p65, and CAAT/enhancer-binding protein-delta, was demonstrated by supershift analysis. Of particular interest was the novel finding of the participation of NF-kappaB p65 in the NF-IL6 complex. In summary, a signal transduction pathway in MC that requires protein kinase A activation in addition to a second signal provided by lipopolysaccharide or IL-1beta was identified.
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PMID:Transcriptional regulation of the interleukin-6 gene in mesangial cells. 1040 2

Brown adipose tissue contains both beta(1)- and beta(3)-adrenergic receptors (beta-ARs), and whereas both receptor subtypes can activate adenylyl cyclase, recent studies suggest that these subtypes have different pharmacological properties and may serve different signaling functions. In this study, primary brown adipocyte cultures were used to determine the role of beta-AR subtypes in mediating lipolysis and uncoupling protein-1 (UCP1) gene expression, elicited by the physiological neurohormone norepinephrine (NE). NE increased both lipolysis and UCP1 mRNA levels in brown adipocyte cultures; the beta(1)-receptor-selective antagonist CGP-20712A strongly antagonized the increase in UCP1 gene expression but had little effect on lipolysis. The beta(3)-receptor-selective agonist CL-316243 (CL) also increased lipolysis and UCP1 mRNA levels, yet CL was more potent in stimulating lipolysis than UCP1 gene expression. NE also increased the phosphorylation of cAMP response element-binding protein (CREB) and perilipin (PL), both of which are protein kinase A substrates that are differentially targeted to the nucleus and lipid droplets, respectively. beta(1)-receptor blockade inhibited NE-stimulated phosphorylation of CREB but not PL. The results suggest that beta-AR subtypes regulate different physiological responses stimulated by NE in brown adipocyte cultures in part by differentially transducing signals to subcellular compartments.
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PMID:Differential regulation of functional responses by beta-adrenergic receptor subtypes in brown adipocytes. 1040 68

The fungal metabolite balanol is a potent inhibitor of protein kinase A (PKA) and protein kinase C (PKC) in vitro that acts by competing with ATP for binding (K(i) approximately 4 nM); congeners of balanol show specificity for PKA over PKC. We have characterized the effects of balanol and 10"-deoxybalanol in intact cells to determine whether these compounds cross the cell membrane and whether the potency and specificity noted in vitro are preserved in vivo. In neonatal rat myocytes and cultured A431 cells transiently transfected with a cyclic AMP response element-luciferase reporter construct, balanol inhibits the induction of luciferase activity by isoproterenol, indicating inhibition of PKA. Western analysis shows that both balanol and 10"-deoxybalanol reduce phosphorylation of cAMP response element-binding protein in isoproterenol-stimulated A431 cells; inhibition is concentration dependent with an IC(50) value of approximately 3 microM. Balanol, but not 10"-deoxybalanol, inhibits phosphorylation of the myristoylated alanine-rich C kinase substrate protein, a PKC substrate, in phorbol ester-stimulated A431 cells (IC(50) approximately 7 microM). Our data demonstrate that balanol is a potent inhibitor of PKA and PKC in several whole-cell systems and causes no obvious toxicity. In addition, balanol congeners inhibit PKA and PKC with the specificity and potency predicted by in vitro experiments.
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PMID:Differential and selective inhibition of protein kinase A and protein kinase C in intact cells by balanol congeners. 1041 57

Activated endothelial cells can directly participate in immune responses by interacting with immunocompetent cells via class II MHC proteins. We show here that, after induction of MHC class II molecule expression by IFN-gamma, rat brain endothelial cells responded to MHC class II ligands, anti-MHC class II Abs, or superantigens by expression of IL-6 transcript and IL-6 secretion. This response was not affected by protein kinase C depletion but was mimicked by the cAMP-elevating agent forskolin and completely blocked by H89, an inhibitor of cAMP-dependent protein kinase (PKA). Involvement of a cAMP/PKA signaling pathway in response to MHC class II ligands was further demonstrated by measure of a dose-dependent increase in cAMP level and phosphorylation of the transcription factor cAMP response element-binding protein (CREB). Our results indicate that MHC class II engagement in brain endothelial cells is directly coupled to IL-6 production via a cAMP/PKA-dependent intracellular pathway.
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PMID:MHC class II engagement in brain endothelial cells induces protein kinase A-dependent IL-6 secretion and phosphorylation of cAMP response element-binding protein. 1049 Sep 57

Dopamine, by activating D(1)- and D(2)-class receptors, plays a significant role in regulating gene expression. Although much is known about D(1) receptor-regulated gene expression, there has been far less information on gene regulation mediated by D(2) receptors. In this study, we show that D(2) receptors can activate the mitogen-activated protein kinase (MAPK) and the cAMP response element-binding protein (CREB) in neurons. Treatment of brain slices with the D(2) receptor agonist quinpirole induced rapid phosphorylation of MAPK and CREB. The neuroleptic drug eticlopride, a highly selective D(2) receptor antagonist, blocked the quinpirole-induced phosphorylation of MAPK and CREB. D(2) receptor-induced MAPK phosphorylation depended on intracellular Ca(2+) elevation, protein kinase C activation, and MAPK kinase activation, but not on the protein tyrosine kinase Pyk2, even though quinpirole stimulated Pyk2 phosphorylation. D(2) receptor-induced CREB phosphorylation was mediated by activation of protein kinase C and Ca(2+)/calmodulin-dependent protein kinase, but not MAPK. The dopamine and cAMP-regulated phosphoprotein DARPP-32 also was required for the regulation of MAPK and CREB phosphorylation by D(2) receptors. Our results suggest that MAPK and CREB signaling cascades are involved in the regulation of gene expression and other long-term effects of D(2) receptor activation.
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PMID:D(2) dopamine receptors induce mitogen-activated protein kinase and cAMP response element-binding protein phosphorylation in neurons. 1050 Feb 24

The type 2 iodothyronine deiodinase (D2) catalyzes T4 activation. In humans, unlike rodents, it is widely expressed, and its action probably contributes to both intracellular and plasma T3 pools. We have isolated the 6.5-kb 5'-flanking region (FR) and the previously uncloned 553 nucleotides (nt) of the 5'-untranslated region (UTR) of hdio2. The 5'-UTR is complex, with three transcription start sites (TSS) (708, 31, and approximately 24 nt 5' to the ATG), an alternatively spliced approximately 300-nt intron in the 5'-UTR, and three short open reading frames 5' to the initiator ATG. The previously reported approximately 7.5-kb D2 messenger RNA (mRNA) is actually an approximately 7-kb doublet that is present in thyroid, pituitary, cardiac and skeletal muscle, and possibly brain, but with only the longer transcript in placenta. A canonical cAMP response element-binding protein-binding site is present at about 90 bp 5' to the most 5'-TSS. It accounts for the robust response of the 6.8-kb hdio2 5'-FR to protein kinase A. Forskolin increases D2 mRNA in human thyroid cells, which may explain the high D2 mRNA in Graves' thyroid and thyroid adenomas. The hdio2 gene structure and Northern blot results suggest that D2 expression is tightly controlled and tissue specific.
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PMID:Characterization of the 5'-flanking and 5'-untranslated regions of the cyclic adenosine 3',5'-monophosphate-responsive human type 2 iodothyronine deiodinase gene. 1061 43

Activation of extracellular signal-regulated kinase (ERK) has been shown to be necessary for NMDA receptor-dependent long-term potentiation (LTP). We studied the role of ERK in three forms of NMDA receptor-independent LTP: LTP induced by very high-frequency stimulation (200 Hz-LTP), LTP induced by the K(+) channel blocker tetraethylammonium (TEA) (TEA-LTP), and mossy fiber (MF) LTP (MF-LTP). We found that ERK was activated in area CA1 after the induction of both 200 Hz-LTP and TEA-LTP and that this activation required the influx of Ca(2+) through voltage-gated Ca(2+) channels. Inhibition of the ERK signaling cascade with either PD 098059 or U0126 prevented the induction of both 200 Hz-LTP and TEA-LTP in area CA1. In contrast, neither PD 098059 nor U0126 prevented MF-LTP in area CA3 induced by either brief or long trains of high-frequency stimulation. U0126 also did not prevent forskolin-induced potentiation in area CA3. However, incubation of slices with forskolin, an activator of the cAMP-dependent protein kinase (PKA) cascade, did result in increases in active ERK and cAMP response element-binding protein (CREB) phosphorylation in area CA3. The forskolin-induced increase in active ERK was inhibited by U0126, whereas the increase in CREB phosphorylation was not, which suggests that in area CA3 the PKA cascade is not coupled to CREB phosphorylation via ERK. Overall, our observations indicate that activation of the ERK signaling cascade is necessary for NMDA receptor-independent LTP in area CA1 but not in area CA3 and suggest a divergence in the signaling cascades underlying NMDA receptor-independent LTP in these hippocampal subregions.
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PMID:The extracellular signal-regulated kinase cascade is required for NMDA receptor-independent LTP in area CA1 but not area CA3 of the hippocampus. 1077 69

Developmental changes in the signaling properties of NMDA receptors have been proposed to underlie the loss of plasticity that accompanies brain maturation. Calcium influx through postsynaptic NMDA receptors can stimulate neuronal gene expression via signaling pathways such as the Ras-MAP kinase (MAPK) pathway and the transcription factor cAMP response element-binding protein (CREB). We analyzed MAPK (Erk1/2) and CREB activation in response to NMDA receptor stimulation during the development of hippocampal neurons in culture. At all stages of development NMDA stimulation induced a rapid phosphorylation of CREB on Ser-133 (phospho-CREB). However, the time course of decline in phospho-CREB changed dramatically with neuronal maturation. At 7 d in vitro (7 DIV) phospho-CREB remained elevated 2 hr after strong NMDA stimulation, whereas at 14 DIV phospho-CREB rose only transiently and fell back to below basal levels within 30 min. Moreover, at 14 DIV, but not at 7 DIV, NMDA receptor stimulation induced a dephosphorylation of CREB that previously had been phosphorylated by KCl depolarization or forskolin, suggesting an NMDA receptor-dependent activation of a CREB phosphatase. There was no developmental change in the time course of phospho-CREB induction that followed KCl depolarization or PKA activation, nor was there a developmental change in the time course of phospho-Erk1/2 induced by NMDA receptor activation. We suggest that, during neuronal maturation, NMDA receptor activation becomes linked specifically to protein phosphatases that act on Ser-133 of CREB. Such a developmentally regulated switch in the mode of NMDA receptor coupling to intracellular signaling pathways may contribute to the changes in neural plasticity observed during brain development.
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PMID:Developmentally regulated NMDA receptor-dependent dephosphorylation of cAMP response element-binding protein (CREB) in hippocampal neurons. 1080 93

Insulin plays a crucial role in the regulation of glucose-homeostasis, and its synthesis is regulated by several stimuli. The transcription of the human insulin gene, enhanced by an elevated intracellular concentration of calcium ions, was completely blocked by Ca2+/calmodulin-dependent protein kinase inhibitor. The activity of the transcription factor activating transcription factor-2 (ATF-2), which binds to the cAMP responsive elements of the human insulin gene, was enhanced by Ca2+/calmodulin-dependent protein kinase IV (CaMKIV). Mutagenesis studies showed that Thr69, Thr71, and Thr73 of ATF-2 are all required for activation by CaMKIV. CaMKIV-induced ATF-2 transcriptional activity was not altered by activation of cJun NH2-terminal protein kinase (JNK) or p38 mitogen-activated protein (MAP) kinase. Furthermore, when transfected into rat primary cultured islets, ATF-2 enhanced glucose-induced insulin promoter activity, whereas cAMP response element-binding protein (CREB) repressed it. These results suggest a mechanism in which ATF-2 regulates insulin gene expression in pancreatic beta-cells, with the transcriptional activity of ATF-2 being increased by an elevated concentration of calcium ions.
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PMID:Activating transcription factor-2 is a positive regulator in CaM kinase IV-induced human insulin gene expression. 1090 71


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