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:2.7.11.13 (protein kinase C)
49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies using phorbol esters and cell-free preparations suggest that protein kinase C (PKC) may regulate Cl- secretion and apical membrane Cl- channels in airway epithelium. To determine whether PKC may be involved in receptor-mediated control of secretion, we measured the mass of diacylglycerol (DAG) generated by two Cl- secretagogues, isoproterenol and bradykinin. Bradykinin increased cellular DAG at concentrations similar to those that increase inositol phosphates, suggesting that bradykinin stimulates phosphatidylinositol hydrolysis, as observed in other systems. Isoproterenol also increased cellular DAG at concentrations similar to those that stimulate adenosine 3',5'-cyclic monophosphate (cAMP) accumulation. The beta-adrenergic receptor antagonist, nadolol, blocked and cell-permanent analogues of cAMP mimicked the effect of isoproterenol. However, isoproterenol does not stimulate phosphatidylinositol turnover. Simultaneous addition of maximal concentrations of isoproterenol and bradykinin produced additive increases in DAG. To test the possibility that the isoproterenol-induced increase in DAG came from phosphatidylcholine turnover, we measured the release of water-soluble choline metabolites and the incorporation of choline into cellular lipids. Although phorbol ester and bradykinin stimulated phosphatidylcholine turnover, isoproterenol did not. These results suggest that isoproterenol and bradykinin generate DAG from the following different lipid sources: bradykinin stimulates phosphatidylinositol hydrolysis to produce DAG; isoproterenol stimulates an increase in DAG from unknown sources. The data suggest that simultaneous activation of cAMP-dependent protein kinase and PKC may occur during receptor-mediated stimulation of Cl- secretion.
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PMID:Isoproterenol, cAMP, and bradykinin stimulate diacylglycerol production in airway epithelium. 216 9

Mitogenic stimulation of Na(+)-H+ exchange activity, as defined by the level of 5-(N,N-hexamethylene)amiloride (HMA)-sensitive Na+ influx, was compared in WI-38 and SV40 virus-transformed WI-38 fibroblasts. Serum or bradykinin dramatically stimulated HMA-sensitive Na+ influx in WI-38 cells, whereas in SV40-transformed WI-38 cells, serum, but not bradykinin, produced a large increase in HMA-sensitive Na+ influx. This lack of a bradykinin response was traced to a dramatic reduction in the number of bradykinin receptors, from 470 fmol/mg protein in WI-38 cells to 29 fmol/mg protein in the SV40-transformed WI-38 cells. Transformation of WI-38 cells with SV40 virus also altered the mechanism by which HMA-sensitive Na+ influx is stimulated. In WI-38 cells, 12-O-tetradecanoylphorbol 13-acetate (TPA) dramatically stimulated HMA-sensitive Na+ influx. In SV40-transformed WI-38 cells, TPA alone had no effect on HMA-sensitive influx and inhibited serum-stimulated HMA-sensitive Na+ influx. Down-regulation of protein kinase C activity decreased serum- and TPA-stimulated HMA-sensitive Na+ influx in the WI-38 cells and relieved the TPA inhibition of serum-stimulated HMA-sensitive Na+ influx in the SV40-transformed WI-38 cells.
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PMID:Loss of bradykinin receptors and TPA-stimulated Na+ influx in SV40-transformed WI-38 cells. 217 45

In this study we investigated the role of protein kinases in activation of the Na(+)-H+ exchanger in inner medullary collecting duct (IMCD) cells. Monolayers, 24-48 h after achieving confluence, were made quiescent by 24 h incubation in 0.1% serum before study. Changes in pHi were measured with 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein. Phorbol myristate acetate (PMA), a synthetic analogue of diacylglycerol (DAG), was used to stimulate protein kinase C (PKC). In nominally HCO3(-)-free media containing 110 mM Na+ and 1 mM Ca2+, PMA addition increased pHi from 7.29 +/- 0.08 to 7.54 +/- 0.07 after 20 min. The increment in pHi was completely inhibited by 1 mM amiloride or by replacement of extracellular Na+ with choline but not inhibited by 1 mM N-ethylmaleimide, an inhibitor of active proton transport. Downregulation of PKC by overnight incubation of monolayers with PMA also prevented the rise in pHi upon subsequent challenge with PMA. Another active analogue of DAG, 1,2-dioleoyl-rac-glycerol, caused an increment in pHi similar to that produced by PMA, whereas 4 alpha-phorbol, an inactive analogue, did not stimulate Na(+)-H+ exchange. Bradykinin (10(-6) M), a phospholipase C-activating hormone, also induces alkalinization of IMCD cells similar to that produced by phorbol esters. Neither vasopressin (10(-7) M), which induces cellular accumulation of adenosine 3',5'-cyclic monophosphate (cAMP) and activation of protein kinase A (PKA), nor 8-bromo-cAMP (1 mM) changed pHi. Therefore in the IMCD cell activation of PKC but not PKA stimulates a rise in pHi via the Na(+)-H+ exchanger.
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PMID:Na(+)-H+ exchange is stimulated by protein kinase C activation in inner medullary collecting duct cells. 217 60

Ligand stimulation of the platelet-derived growth factor receptor (PDGF-R) results in rapid activation of the receptor tyrosine kinase, stimulation of phosphoinositide hydrolysis, an increase in intracellular free Ca2+ concentration ([Ca2+]i), and, ultimately, cellular proliferation. In a previous study, we demonstrated that staurosporine, a known inhibitor of protein kinase C, blocked PDGF-induced [Ca2+]i increases in Swiss mouse 3T3 fibroblasts by a mechanism that appeared unrelated to inhibition of protein kinase activity (Olsen, R., Melder, D., Seewald, M., Abraham, R., and Powis, G. (1990) Biochem. Pharmacol. 39, 968-972). In the present study, we report that staurosporine inhibits ligand-dependent PDGF-R tyrosine kinase activation in cell-free receptor preparations and in intact Swiss 3T3 cells. At the same concentrations (10(-8)-10(-6) M), staurosporine suppressed both the tyrosine phosphorylation of phospholipase C activity and the hydrolysis of phosphoinositides induced by PDGF stimulation of intact cells. In contrast, guanine nucleotide-binding protein-dependent phospholipase C activation induced by bradykinin or fluoroaluminate anion was relatively insensitive to staurosporine. A preferential inhibitory effect of staurosporine on signal generation by the PDGF-R was indicated by findings that epidermal growth factor receptor (EGF-R) tyrosine kinase activity and EGF-dependent phospholipase C in A-431 carcinoma cells were approximately 100-fold less sensitive to this drug. These data indicate that submicromolar concentrations of staurosporine inhibit PDGF-dependent phosphoinositide hydrolysis and Ca2+ mobilization through a proximal inhibitory effect on ligand-induced activation of the PDGF-R tyrosine kinase.
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PMID:Preferential inhibition of the platelet-derived growth factor receptor tyrosine kinase by staurosporine. 217 5

Bovine pulmonary microvessel endothelial cells grown on a flexible substrate contract upon the addition of angiotensin II, thrombin, bradykinin, and U44069, a stable analogue of thromboxane A2. All these agents promote inflammation and increase paracellular permeability in vivo or in vitro. The contractile response is mediated by intracellular and extracellular free calcium: the response is inhibited by TMB-8, an intracellular Ca2+ chelator, and EGTA. Contraction is inhibited by trifluoroperazine, a Ca2(+)-calmodulin antagonist, and by ML-7, an inhibitor of myosin light-chain kinase. Preincubation with PMA, a protein kinase C activator, prevents contraction by angiotensin II. The inactive analogue 4-alpha-phorbol 12,13-didecanoate does not inhibit contraction. In contrast cAMP, carbacyclin (a stable PGI2 analogue), and isoproterenol, agonists known to stabilize the microvascular barrier against inflammatory agents, relax pulmonary microvessel EC. This direct evidence of the contractile potential of microvessel endothelial cells lends support to the theory that endothelial contraction leads to increased junctional permeability.
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PMID:Inflammatory agonists that increase microvascular permeability in vivo stimulate cultured pulmonary microvessel endothelial cell contraction. 217 9

The effects of bradykinin on activation of phosphoinositide turnover, 1,2-diglyceride formation, and growth of cultured adult human keratinocytes were investigated. Keratinocytes specifically bound [3H]bradykinin with high affinity (kd = 3.4 nM) and displayed 1.5 X 10(5) binding sites/cell. Bradykinin caused a rapid dose-dependent increase in inositol trisphosphate (IP3) inositol bisphosphate, and inositol monophosphate. IP3 was maximally increased (fivefold) at 30 s and remained elevated for at least 10 min. Half maximal stimulation of IP3 formation was observed at 27 nM bradykinin. IP3 accumulation was equally elevated by bradykinin and lys-bradykinin but was not stimulated by des-Arg9-bradykinin, indicating that phospholipase C in cultured keratinocytes is coupled to B2 bradykinin receptors. Treatment of keratinocytes with active phorbol ester (TPA) caused a significant inhibition (50%) of bradykinin-induced IP3 accumulation, suggesting negative regulation of phospholipase C by protein kinase C. Bradykinin also caused a significant elevation in 1,2-diacylglycerol (DAG) content. DAG content was maximally elevated (twofold) at 1 min and remained elevated for at least 10 min. Bradykinin also caused a significant (twofold, p less than 0.02) increase in keratinocyte growth. These data demonstrate that bradykinin is a potent agonist of the phospholipase C/protein kinase C signal transduction system in cultured adult human keratinocytes and that activation of this pathway by bradykinin is associated with increased keratinocyte growth.
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PMID:Bradykinin induces phosphoinositide turnover, 1,2-diglyceride formation, and growth in cultured adult human keratinocytes. 217 49

A protein of Mr approximately 120,000, related to the human erythrocyte membrane skeletal protein alpha-adducin, has been identified by immunological criteria in human fibroblasts. Using similar methods, beta-adducin (an Mr approximately 110,000 protein that forms a dimeric complex with alpha-adducin in the erythrocyte) is not present in fibroblasts. Subcellular distribution studies reveal that fibroblast alpha-adducin is largely associated with the particulate fraction and is most effectively solubilized from that fraction by a combination of nonionic detergent and high salt. Immunocytochemistry of quiescent fibroblasts shows that alpha-adducin is clustered in large perinuclear arrays that may correspond to vesicular structures; weak staining was also found in the sub-plasma membrane region. As in erythrocytes, the phosphorylation of fibroblast alpha-adducin is elevated on exposure of cells to phorbol esters that activate protein kinase C (PK-C). In addition, various mitogens such as serum, bradykinin and vasopressin also stimulate alpha-adducin phosphorylation by a PK-C-dependent pathway. The elevation in alpha-adducin phosphorylation is maintained for up to 30 min after mitogen addition. Peptide maps of phospho-alpha-adducin from both fibroblasts and erythrocytes after PK-C-mediated phosphorylation showed multiple phosphorylated peptides but with dissimilar migration patterns, suggesting divergence of structure around the phosphorylation sites. Adducin appears to play an important role in the regulation of spectrin-actin interactions in the red cell and may play a role in cytoskeletal function in the fibroblasts.
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PMID:Identification and protein kinase C-dependent phosphorylation of alpha-adducin in human fibroblasts. 219 89

Hormonal activation of the phosphatidylinositol (PI) signaling system initiates a biochemical pathway that bifurcates to increase cellular levels of diacylglycerol and of inositol trisphosphate/Ca2+. Both Diacylglycerol and Ca2+ are known to activate protein kinase C, a primary mediator of the PI signaling system. We now find that the two limbs of the PI pathway utilize distinct multifunctional protein kinases to mediate their cellular effects. An important consequence of Ca2+ elevated by the PI signaling system, when PC12 cells are treated with bradykinin, is the activation of multifunctional Ca2+/calmodulin-dependent protein kinase. This activation stimulates autophosphorylation of CaM kinase at its regulatory domain and converts it to an active, Ca2(+)-independent species that may be a basis for potentiation of Ca2+ transients.
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PMID:Ca2+/calmodulin kinase is activated by the phosphatidylinositol signaling pathway and becomes Ca2(+)-independent in PC12 cells. 221 81

Calcitonin is a well known inhibitor of osteoclastic bone resorption, both in vivo and in vitro. However, it is also known that calcitonin has only a transient inhibitory effect on bone resorption. The mechanism for this so-called "escape from inhibition" phenomenon is not clear. In the present study, the inhibitory effect of calcitonin on phorbol ester-induced bone resorption was examined in cultured neonatal mouse calvaria. Bone resorption was assessed as the release of radioactivity from bones prelabelled in vivo with 45Ca. Two protein kinase C-activating phorbol esters, phorbol-12-myristate-13-acetate and phorbol-12,13-dibutyrate, both stimulated 45Ca release in 120-h cultures at a concentration of 10 nmol/l. Calcitonin (30 nmol/l) inhibited phorbol ester-stimulated bone resorption without any "escape from inhibition". This was in contrast to the transient inhibitory effect of calcitonin on bone resorption stimulated by parathyroid hormone (10 nmol/l), prostaglandin E2 (2 mumol/l), and bradykinin (1 mumol/l). Our results suggest that activation of protein kinase C produces a sustained inhibitory effect of calcitonin on bone resorption.
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PMID:Calcitonin causes a sustained inhibition of protein kinase c-stimulated bone resorption in contrast to the transient inhibition of parathyroid hormone-induced bone resorption. 222 Feb 63

Calcium signaling systems in nonexcitable cells involve activation of Ca2+ entry across the plasma membrane and release from intracellular stores as well as activation of Ca2+ pumps and inhibition of passive Ca2+ pathways to ensure exact regulation of free cytosolic Ca2+ concentration [( Ca2+]i). A431 cells loaded with fura-2 cells were used as a model system to examine regulation of Ca2+ entry and intracellular release. Epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha) both stimulated Ca2+ entry and release while bradykinin appeared only to release Ca2+ from intracellular stores. The possible role of protein kinase C (PKC) in modulating the [Ca2+]i response to these agonists was examined by four methods. Low concentrations of TPA (2 x 10(-10) M) had no effect on Ca2+ release due to EGF, TGR-alpha or bradykinin but resulted in a rapid return of [Ca2+]i to baseline levels for EGF or TGF-alpha. Addition of the PKC inhibitor staurosporine (1 and 10 nM) completely inhibited the action of TPA on EGF-induced [Ca2+]i changes. An inhibitor of diglyceride kinase (R59022) mimicked the action of TPA. Down-regulation of PKC by overnight incubation with 0.1 or 1 microM TPA produced the converse effect, namely prolonged Ca2+ entry following stimulation with EGF or TGF-alpha. To show that one effect of TPA was on Ca2+ entry, fura-2 loaded cells were suspended in Mn2+ rather than Ca2+ buffers. Addition of EGF or TGF-alpha resulted in Ca2+ release and Mn2+ entry. TPA but not the inactive phorbol ester, 4-alpha-phorbol-12,13-didecanoate, inhibited the Mn2+ influx. Thus, PKC is able to regulate Ca2+ entry due to EGF or TGF-alpha in this cell type. A431 cells treated with higher concentrations of TPA (5 x 10(-8) M) inhibited not only Ca2+ entry but also Ca2+ release due to EGF/TGF-alpha but had no effect on bradykinin-mediated Ca2+ release, suggesting differences in the regulation of the intracellular stores responsive to these two classes of agonists. Furthermore, sequential addition of EGF or TGF-alpha gave a single transient of [Ca2+]i, showing a common pool of Ca2+ for these agonists. In contrast, sequential addition of EGF (or TGF-alpha) and bradykinin resulted in two [Ca2+]i transients equal in size to those obtained with a single agonist.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Role of protein kinase C in the regulation of cytosolic Ca2+ in A431 cells: separation of growth factor and bradykinin pathways. 228 81


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