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)

Although processes involved in mRNA degradation play a significant role in dictating steady state mRNA levels, the influence of cell surface signaling on mRNA stability control is understood incompletely. In this study, the effects of cAMP-elevating agents on type I angiotensin II receptor (AT1-R) mRNA levels were assessed in cultured rat aortic vascular smooth muscle cells (VSMCs). AT1-R mRNA levels are rapidly reduced by forskolin treatment, in which the maximal effect yields an 80% reduction in AT1-R mRNA levels after 6 hr of treatment. The rate of AT1-R mRNA decay in response to forskolin is greater than its apparent intrinsic decay, as assessed in the presence of the transcriptional inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole, suggesting forskolin treatment destabilizes the AT1-R mRNA. Nuclear run-on analysis indicates forskolin treatment does not affect transcription of the AT1-R gene in VSMCs, implying induced AT1-R mRNA destabilization accounts for the entire effect of forskolin in decreasing AT1-R mRNA levels. Dose-effect studies that assessed AT1-R mRNA levels and cAMP production were conducted using forskolin and the beta-adrenergic receptor agonist isoproterenol as agonists. Isoproterenol is almost 3 orders of magnitude more potent at eliciting the reduction in AT1-receptor mRNA levels than it is at stimulating cAMP production. Similarly, forskolin elicits reductions in AT1-R mRNA, which occur at concentrations that fail to elicit a detectable production of cAMP. However, protein kinase A activity is stimulated maximally by isoproterenol and forskolin concentrations that do not stimulate detectable cAMP production. These data provide evidence that the mechanism for down-regulation of AT1-R mRNA levels by cAMP-elevating agents in VSMCs occurs via a PKA-regulated mRNA destabilization pathway.
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PMID:The vascular smooth muscle type I angiotensin II receptor mRNA is destabilized by cyclic AMP-elevating agents. 935 68

Angiotensin II (Ang II) interacts with the neuronal AT1 receptor subtype and initiates a cascade of signaling events involving activation of Ras-Raf-1-MAP kinase. Raf-1-dependent activation of mitogen-activated protein kinase (MAPK) is the key in the chronic norepinephrine neuromodulatory actions of Ang II and is associated with the translocation of MAPK into the nucleus. In view of these observations, this study was designed to determine if Ang II causes cellular redistribution of Raf-1 in neuronal cells. Most of Raf-1 was localized in the cytoplasmic compartment in neurons. Ang II treatment resulted in a time-dependent increase in the translocation of immunoreactive Raf-1 from the cytoplasm into the nucleus. A fourfold increase was observed in 15 min. The nuclear sequestration of Raf-1 was blocked by losartan, an AT1 receptor-specific antagonist, and not by PD123319, an AT2 receptor-specific antagonist. Confocal microscopic analysis of immunofluorescence data confirmed the nuclear translocation and further showed that Raf-1 was exclusively localized into the nucleolus. These observations demonstrate, for the first time, that Ang II stimulates Raf-1 targeting into the neuronal nucleus, and they suggest that this translocation may play a direct role in the transcriptional regulation of Ang II actions.
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PMID:AT1 receptor-mediated nuclear translocation of Raf-1 in brain neurons. 942 90

A polyclonal antibody was raised in rabbits against a fusion protein immunogen consisting of bacterial maltose-binding protein coupled to a 92-amino acid C-terminal fragment of the rat AT1b angiotensin II (Ang II) receptor. The antibody immunoprecipitated the photoaffinity-labeled bovine AT1 receptor (AT1-R), but not the rat AT2 receptor, and specifically stained bovine adrenal glomerulosa cells and AT1a receptor-expressing Cos-7 cells, as well as the rat adrenal zona glomerulosa and renal glomeruli. The antibody was employed to analyze Ang II-induced phosphorylation of the endogenous AT1-R immunoprecipitated from cultured bovine adrenal glomerulosa cells. Receptor phosphorylation was rapid, sustained for up to 60 min, and enhanced by pretreatment of the cells with okadaic acid. Its magnitude was correlated with the degree of ligand occupancy of the receptor. Activation of protein kinase A and protein kinase C (PKC) also caused phosphorylation of the receptor, but to a lesser extent than Ang II. Inhibition of PKC by staurosporine augmented Ang II-stimulated AT1-R phosphorylation, suggesting a negative regulatory role of PKC on the putative G protein-coupled receptor kinase(s) that mediates the majority of AT1-R phosphorylation. The antibody should permit further analysis of endogenous AT1-R phosphorylation in Ang II target cells.
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PMID:Agonist-induced phosphorylation of the endogenous AT1 angiotensin receptor in bovine adrenal glomerulosa cells. 960 26

Angiotensin II (Ang II) is a potent pressor hormone, a stimulus for vascular smooth muscle hypertrophy and an activator of multiple tyrosine kinases. The physiological effects of Ang II are mediated through activation of AT1 and AT2 receptors, receptors that have been coupled to tyrosine kinase(s) and tyrosine phosphatases, respectively. Agonists of G protein-coupled receptors, of which Ang II is one, have recently been shown to stimulate smooth muscle contraction in part via activation tyrosine kinases. We tested the hypothesis that Ang II-induced contraction in the rat aorta was dependent on activation of tyrosine kinase(s) and specifically investigated the role of the tyrosine kinase mitogen-activated protein kinase kinase (MEK), a kinase important to the mitogen activated protein kinase (MAPK) pathway. Rat thoracic aortic strips denuded of endothelium and cultured aortic smooth muscle cells were used in isolated tissue baths for measurement of isometric contractile force and Western analyses of protein tyrosyl-phosphorylation. Ang II (0.1-100 nM)-induced contraction in the aorta was completely blocked by the AT1 receptor antagonist losartan (1 microM) but unaffected by the AT2 receptor antagonist PD123319 (100 nM) or tyrosine phosphatase inhibitor sodium orthovanadate (1 microM), indicating an AT1 receptor mediates aortic contraction to Ang II. Neither the tyrosine kinase inhibitor genistein (5 microM), inactive tyrosine kinase inhibitor daidzein (5 microM) nor MEK inhibitor PD098059 (10 microM) reduced Ang II-induced contraction; the concentrations of inhibitors used maximally reduced contraction stimulated by other agonists of G protein-coupled receptors such as serotonin. Moreover, Ang II-induced contraction was not altered by the combination of PD098059 and PD123319, indicating that it is unlikely AT2 receptor stimulation masks activation of the MAPK pathway through AT1 receptor activation. The nonflavone tyrosine kinase inhibitor tyrphostin B42 (30 microM) reduced Ang II-induced maximal contraction (to 11.2% control) but, unlike the other tyrosine kinase inhibitors, also reduced KCl-induced contraction (to 55.2% control), indicating a probable nonselectivity of tyrphostin B42. Ang IIinduced maximal contraction was reduced by the L-type voltage gated calcium channel antagonist nifedipine (50 nM), consistent with the activation of calcium channels by Ang II. In cultured rat aortic smooth muscle cells, Ang II (0.1-1000 nM) stimulated concentration-dependent tyrosyl-phosphorylation of the extracellular signal regulated kinase (Erk) mitogen activated protein kinases (maximal stimulation, fold basal: Erk-1 = 17-fold, Erk-2 = 3-fold), indicating that Ang II can activate MEK. Losartan (1 microM) abolished Ang II (10 nM)-induced Erk tyrosyl-phosphorylation and PD098059 (10 microM), which did not diminish Ang II-induced aortic contraction, reduced Ang II (10 nM)-stimulated phosphorylation of Erk-2 by 72%. Finally, Ang II (1 microM) increased tyrosyl-phosphorylation of the Erk proteins in isolated aorta exposed to Ang II for 5 min. Thus, while Ang II can stimulate both MEK activation and vascular contraction via interaction with AT1 receptors, stimulation of MEK does not appear to be important for Ang II-induced contraction. These findings dissociate the process of Ang II-stimulated Erk protein tyrosyl-phosphorylation from Ang II-induced contraction in the rat aorta.
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PMID:Dissociation of angiotensin II-stimulated activation of mitogen-activated protein kinase kinase from vascular contraction. 973 8

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

Little is known of the mechanisms leading to mitogen-activated protein kinase (MAPK) activation via Gq-coupled receptors. We therefore examined the pathways by which angiotensin II (Ang II) activates Raf-1 kinase, an upstream intermediate in the pathway to MAPK, via the Gq-coupled AT1 angiotensin receptor in bovine adrenal glomerulosa (BAG) cells. Ang II caused a rapid and transient activation of Raf-1 that reached a peak at 5-10 min. Ang II was a potent stimulus of Raf-1 activation with an ED50 of 10 pM and a maximal response at 1 nM, although higher Ang II concentrations elicited a submaximal response. Ang II-stimulated Raf-1 activity was unaffected by down-regulation of protein kinase C and intracellular Ca2+ chelation (using BAPTA) but was partially inhibited by pertussis toxin, and was abolished by manumycin A. Removal of extracellular Ca2+ (by EGTA) or blockade of L type Ca2+ channels (by nifedipine), as well as inhibition of MEK-1 kinase (by PD98059), enhanced Raf-1 activity, whereas wortmannin (100 nM) inhibited approximately one half of Ang II-stimulated Raf-1 activity. Hence, Raf-1 kinase activation by Ang II in BAG cells is dependent on Ras, is mediated in part via Gi and phosphatidylinositol 3-kinase, and is negatively regulated via Ca2+ influx and a downstream signaling element(s).
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PMID:Raf-1 kinase activation by angiotensin II in adrenal glomerulosa cells: roles of Gi, phosphatidylinositol 3-kinase, and Ca2+ influx. 1006 66

Nck is a small adaptor protein consisting exclusively of three SH3 domains and one SH2 domain. Nck is thought to have an important role in cell signalling by coupling receptor tyrosine kinases, via its SH2 domain, to downstream SH3-binding effectors. We report here that angiotensin II, working through the AT1 receptor subtype, stimulates the phosphorylation of Nck in rat aortic smooth muscle cells. Phosphopeptide mapping analysis revealed that Nck is phosphorylated on four peptides containing exclusively phosphoserine in quiescent cells. Treatment with angiotensin II resulted in increased phosphorylation of these four peptides, without the appearance of new phosphopeptides. We show that Nck, via its SH3 domains, specifically binds three major phosphoproteins of 95, 82 and 66 kDa both in vitro and in intact cells. Notably, the phosphorylation of these Nck-binding proteins was found to increase in parallel with that of Nck on stimulation by angiotensin II. One candidate for the 66 kDa phosphoprotein is the serine/threonine kinase p21-activated kinase 1 (Pak1), which was found to form a stable complex with Nck in aortic smooth muscle cells. We have also identified the gamma2 isoform of casein kinase I as another protein kinase that associates with Nck in these cells. These findings indicate that Nck is a target of G-protein-coupled receptors and suggest a role for Pak1 and casein kinase I-gamma2 in downstream signalling or regulation of the AT1 receptor.
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PMID:Angiotensin II stimulates serine phosphorylation of the adaptor protein Nck: physical association with the serine/threonine kinases Pak1 and casein kinase I. 1037 65

The mechanism by which Ang II stimulates the growth of vascular smooth muscle cells was investigated by measuring the phosphorylation of mitogen-activated protein kinases ERK 1 and ERK 2. Ca2+ ionophore was found to have effects practically analogous to Ang II. We found that the signaling pathway involves the activation of epidermal growth factor receptor (EGFR) kinase, activation of the adaptor proteins Shc and Grb2, and the small G-protein Ras. Although the mechanism of AT1- (or Ca2+)-induced activation of EGFR is not yet clear, we have found that calcium-dependent protein kinase CAKss/PYK2 and c-Src are involved in this process. These studies indicate a transactivation mechanism that utilizes EGFR as a bridge between a Gq-coupled receptor and activation of phosphotyrosine generation.
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PMID:Angiotensin II-mediated vascular smooth muscle cell growth signaling. 1082 89

We used whole-cell patch clamp to investigate steady-state activation of ATP-sensitive K+ channels (KATP) of rat arterial smooth muscle by protein kinase A (PKA) and the pathway by which angiotensin II (Ang II) inhibits these channels. Rp-cAMPS, an inhibitor of PKA, did not affect KATP currents activated by pinacidil when the intracellular solution contained 0.1 mM ATP. However, when ATP was increased to 1.0 mM, inhibition of PKA reduced KATP current, while the phosphatase inhibitor calyculin A caused a small increase in current. Ang II (100 nM) inhibited KATP current activated by the K+ channel opener pinacidil. The degree of inhibition was greater with 1.0 mM than with 0.1 mM intracellular ATP. The effect of Ang II was abolished by the AT1 receptor antagonist losartan. The inhibition of KATP currents by Ang II was abolished by a combination of PKA inhibitor peptide 5-24 (5 microM) and PKC inhibitor peptide 19-27 (100 microM), while either alone caused only partial block of the effect. In the presence of PKA inhibitor peptide, the inhibitory effect of Ang II was unaffected by the PKC inhibitor Go 6976, which is selective for Ca2+-dependent isoforms of PKC, but was abolished by a selective peptide inhibitor of the translocation of the epsilon isoform of PKC. Our results indicate that KATP channels are activated by steady-state phosphorylation by PKA at normal intracellular ATP levels, and that Ang II inhibits the channels both through activation of PKCepsilon and inhibition of PKA.
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PMID:Angiotensin II inhibits rat arterial KATP channels by inhibiting steady-state protein kinase A activity and activating protein kinase Ce. 1120 68

Angiotensin (Ang) II has been shown to enhance the development of atherosclerotic lesions. Migration of monocytes is an early critical step in the atherosclerotic process. To elucidate mechanisms by which Ang II promotes atherogenesis, we investigated its effects on human monocyte migration. Ang II induced migration of human peripheral blood monocytes (HPBM) and human THP-1 monocytes at concentrations between 0.01 and 1 micromol/L, with a 3.6+/-0.6-fold induction in HPBM and a 4.8+/-0.9-fold induction in THP-1 cells at 1 micromol/L Ang II (both P<0.01 versus unstimulated cells). Addition of the Ang II receptor type 1 (AT1-R) antagonist losartan (1 to 100 micromol/L) suppressed Ang II-induced migration of HPBM and THP-1 monocytes in a dose-dependent manner, demonstrating an AT1-R-mediated mechanism. Ang II-directed migration was also blocked by the Src kinase inhibitor PP2 (10 micromol/L), by the extracellular-regulated protein kinase (ERK 1/2) inhibitor PD98059 (30 micromol/L), and by the p38-MAPK inhibitor SB203580 (10 micromol/L), indicating that Src, ERK 1/2, and p38 are all involved in Ang II-induced migration of HPBM and human THP-1 monocytes. The proline-rich tyrosine kinase 2 (Pyk2) and paxillin are 2 cytoskeleton-associated proteins involved in cell movement, phosphorylated by Ang II in other cell types, and abundantly expressed in monocytes. Ang II (1 micromol/L) induced Pyk2 and paxillin phosphorylation in human THP-1 monocytes, peaking after 10 minutes for Pyk2 with a 6.7+/-0.9-fold induction and after 2 minutes for paxillin with a 3.2+/-0.4-fold induction. Ang II-induced phosphorylation of both proteins was suppressed by losartan and the Src inhibitor PP2, whereas no effect was observed with PD98059 and SB203580. This study demonstrates a novel proatherogenic action of Ang II on human monocytes by stimulating their migration, through an AT1-R-dependent process, involving signaling through Src, ERK 1/2, and p38. Furthermore, the promigratory actions of Ang II in human monocytes are associated with the phosphorylation of 2 cytoskeleton-associated proteins, Pyk2 and paxillin.
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PMID:Angiotensin II induces migration and Pyk2/paxillin phosphorylation of human monocytes. 1123 Mar 39


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