EC:2.7.11.13 - FACTA Search

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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)

At least two signalling systems have the potential to contribute to the activation of protein kinase C (PKC) family members such as PKCepsilon. One of these is phosphoinositide 3-kinase (PI 3-kinase), whose lipid products activate PKCepsilon in vitro and in living cells. The recent observation that there are multiple waves of PI 3-kinase and PKCepsilon activity within the G(0)-to-S phase interval provides a new opportunity to investigate the relationship between these two signalling enzymes in vivo. We have assessed the relative importance of the early and late waves of PI 3-kinase activity for the corresponding waves of PKCepsilon activity. Blocking the first phase of PI 3-kinase activity inhibited both early and late activation of PKCepsilon. In contrast, the second wave of PI 3-kinase activity was dispensable for late activation of PKCepsilon. These findings suggested that early PI 3-kinase activation induced a stable change in PKCepsilon, which predisposed it to subsequent activation by lipid cofactors. Indeed, partial proteolysis of PKCepsilon indicated that early activation of PI 3-kinase led to a conformation change in PKCepsilon that persisted as the activity of PKCepsilon cycled. We propose a two-step hypothesis for the activation of PKCepsilon in vivo. One step is stable and depends on PI 3-kinase, whereas the other is transient and may depend on the availability of lipid cofactors. Finally, these studies reveal that PI 3-kinase and PKCepsilon are capable of communicating over a relatively long time interval and begin to elucidate the mechanism.
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PMID:Early phosphoinositide 3-kinase activity is required for late activation of protein kinase Cepsilon in platelet-derived-growth-factor-stimulated cells: evidence for signalling across a large temporal gap. 1151 25

As with the neutrophil NADPH oxidase, the B lymphocyte NADPH oxidase consists of a membrane-bound flavocytochrome b and regulatory factors including Rac and the cytosolic phox protein triad p67phox, p47phox, and p40phox. Here we demonstrate by phosphoamino acid analysis and the use of the potent PKC inhibitor GFX that, in response to stimulation of B lymphocytes with sodium orthovanadate and H(2)O(2), the p40phox component of the cytosolic phox triad is selectively phosphorylated on serine and threonine residues by a PKC-type protein kinase. The pattern of p40phox phosphorylation was closely related to the kinetics of tyrosine phosphorylation of PKC-delta, the main PKC isotype of B lymphocytes. Blocking H(2)O(2)-dependent tyrosine phosphorylation of PKC by genistein resulted in inhibition of p40phox phosphorylation. The correlation between the tyrosine phosphorylation of PKC-delta and the serine/threonine phosphorylation of p40phox, together with the inhibition of p40phox phosphorylation by rottlerin, a selective inhibitor of PKC-delta, makes the activated PKC-delta a likely candidate in the process of the oxidant-dependent phosphorylation of p40phox in B cells.
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PMID:Oxidant-dependent phosphorylation of p40phox in B lymphocytes. 1157 65

Short-lasting application (10 min) of tachykinin neuropeptides evokes long-lasting (>24 h) modulation of N-methyl-D-aspartate (NMDA)-evoked locomotor network activity in the lamprey spinal cord. In this study, the net effects of the tachykinin substance P on the isolated spinal cord have been examined by recording from motor neurons in the absence of NMDA and ongoing network activity. Brief bath application of substance P (30 s to 2 min) induced irregular membrane potential oscillations in motor neurons. These oscillations consisted of depolarizing and hyperpolarizing phases and were associated with phasic ventral-root activity. The oscillations were blocked by the tachykinin antagonist spantide II. They were also blocked by tetrodotoxin (TTX), suggesting that they were not dependent on intrinsic membrane properties of the motor neurons but were synaptically mediated. Substance P could also have a direct effect, however, because a membrane potential depolarization persisted in the presence of TTX. Protein kinase agonists and antagonists were used to investigate the intracellular pathways through which substance P acted. The oscillations were blocked by the selective protein kinase C (PKC) antagonist chelerythrine. However, the TTX-resistant membrane potential depolarization was not significantly affected by blocking PKC. The protein kinase A and G antagonist H8 did not affect either the oscillations or the direct TTX-resistant membrane potential depolarization. The glutamate receptor antagonist kynurenic acid abolished the substance-P-evoked oscillations, suggesting that they were dependent on glutamate release. The oscillations were abolished or reduced by the AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxalene-2,3-dione but were only reduced by the NMDA receptor antagonist D-AP5. The oscillations were thus mediated by glutamatergic inputs with a greater dependence on non-NMDA receptors. Blocking glycinergic inputs with strychnine resulted in large depolarizing plateaus and bursts of spikes. The glutamatergic and glycinergic inputs underlying the oscillations are apparently evoked through direct and indirect excitatory effects on inhibitory and excitatory premotor interneurons. Substance P thus has a distributed excitatory effect in the spinal cord. While it can activate premotor networks, this activation alone is not able to evoke a coordinated behaviorally relevant motor output.
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PMID:Synaptically evoked membrane potential oscillations induced by substance P in lamprey motor neurons. 1178 34

The present study demonstrates a novel stimulatory effect of a cannabinoid agonist on calcium channels. DALN (1 nM) potentiated 45Ca(2+)-uptake by N18TG2 neuroblastoma cells, an effect that was abolished by the specific CB1 receptor antagonist SR141716A. The stimulation of 45Ca(2+)-uptake by DALN was resistant to pertussis toxin (PTX), suggesting that Gi/Go GTP-binding proteins did not mediate this effect. Furthermore, PTX unmasked a stimulatory effect of a high concentration of DALN (1 microM), which by itself failed to stimulate calcium uptake in naive cells. The stimulatory effect of DALN on calcium entry to the cells was blocked by nicardipine but not by omega-conotoxin GVIA, indicating the entry of calcium through L-type voltage-dependent calcium channels. Blocking cAMP-dependent protein kinase (PKA) by H-89 completely eliminated the elevation in calcium uptake, while blocking protein kinase C (PKC) by chelerythrine and calphostine-C only partially attenuated the stimulation. Blocking calmodulin by W-7 revealed a similar partial inhibition of the stimulatory effect of DALN. Hence, we suggest a cannabinoid-specific, PTX-insensitive, stimulatory effect on L-type voltage-dependent calcium channels, which is mediated by PKA and modulated by PKC and calmodulin.
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PMID:The cannabinoid agonist DALN positively modulates L-type voltage-dependent calcium-channels in N18TG2 neuroblastoma cells. 1200 36

Sphingosine 1-phosphate (S1P), a potent bioactive sphingolipid, has been implicated in many critical cellular events, including a regulatory role in the pathogenesis of airway inflammation. We investigated the participation of S1P as an inflammatory mediator by assessing interleukin-8 (IL-8) secretion and phospholipase D (PLD) activation in human bronchial epithelial cells (Beas-2B). S1P(1), S1P(3), S1P(4), S1P(5), and weak S1P(2) receptors were detected in Beas-2B and primary human bronchial epithelial cells. S1P stimulated a rapid activation of PLD, which was nearly abolished by pertussis toxin (PTX) treatment, consistent with S1P receptor/G(i) protein coupling. S1P also markedly induced Beas-2B secretion of IL-8, a powerful neutrophil chemoattractant and activator, in a PTX-sensitive manner. This S1P-mediated response was dependent on transcription as indicated by a strong induction of IL-8 promoter-mediated luciferase activity in transfected Beas-2B cells and a complete inhibition by actinomycin D. Beas-2B exposure to 1-butanol, which converts the PLD-generated phosphatidic acid (PA) to phosphatidylbutanol by a transphosphatidylation reaction, significantly attenuated the S1P-induced IL-8 secretion, indicating the involvement of PLD-derived PA in the signaling pathway. Inhibition of 12-O-tetradecanoyl-phorbol-13-acetate-stimulated IL-8 production by 1-butanol further strengthened this observation. Blocking protein kinase C and Rho kinase also attenuated S1P-induced IL-8 secretion. Our data suggest that PLD-derived PA, protein kinase C, and Rho are important signaling components in S1P-mediated IL-8 secretion by human bronchial epithelial cells.
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PMID:Phospholipase D activation by sphingosine 1-phosphate regulates interleukin-8 secretion in human bronchial epithelial cells. 1203 47

A possible role for signalling through phospholipase C in histamine-induced catecholamine secretion from bovine adrenal chromaffin cells has been investigated. Secretion evoked by histamine over 10 min was not prevented by inhibiting inositol-1,4,5-trisphosphate receptors with 2-APB, by blocking ryanodine receptors with a combination of ryanodine and caffeine, or by depleting intracellular Ca(2+) stores by pretreatment with thapsigargin. Inhibition of protein kinase C with Ro31-8220 also failed to reduce secretion. Inhibition of phospholipase C with ET-18-OCH(3) reduced both histamine- and K(+) -induced inositol phosphate responses by 70-80% without reducing their secretory responses. Stimulating phospholipase C with Pasteurella multocida toxin did not evoke secretion or enhance the secretory response to histamine. The secretory response to histamine was little affected by tetrodotoxin or by substituting extracellular Na(+) with N -methyl-d-glucamine(+) or choline(+), or by substituting external Cl(-) with nitrate(-). Blocking various K(+) channels with apamin, charybdotoxin, Ba(2+), tetraethylammonium, 4-aminopyridine, tertiapin or glibenclamide failed to reduce the ability of histamine to evoke secretion. These results indicate that histamine evokes secretion by a mechanism that does not require inositol-1,4,5-trisphosphate-mediated mobilization of stored Ca(2+), diacylglycerol-mediated activation of protein kinase C, or activation of phospholipase C. The results are consistent with histamine acting by depolarizing chromaffin cells through a phospholipase C-independent mechanism.
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PMID:Phospholipase C-mediated signalling is not required for histamine-induced catecholamine secretion from bovine chromaffin cells. 1206 24

Vascular endothelial growth factor (VEGF) promotes angiogenesis by a variety of mechanisms including stimulation of endothelial cell proliferation and migration and increasing vascular permeability. Although its mitogenic activity is mediated primarily by the beta(2)-isoforms of protein kinase C (PKC), little is known about the signaling pathways transducing its other physiological properties. Accordingly, we used a novel inhibitor molecule to examine the role of PKC isoforms alpha and beta in mediating VEGF-induced angiogenesis and vascular permeability. Because conventional inhibitors of PKC, such as staurosporine or calphostin C, also inhibit a variety of other protein kinases, we used a novel compound to specifically inhibit PKC. A myristoylated peptide, which mimics the pseudosubstrate motif of PKC-alpha and -beta subtypes, has been shown to be a highly selective and cell-permeable inhibitor of PKC. Blocking led, as expected, to abrogation of VEGF-induced endothelial cell proliferation in vitro. In vivo, VEGF-induced angiogenesis was impaired by myristoylated peptide. Surprisingly, selective inhibition of PKC induced vascular permeability in vivo via a NO-dependent mechanism. Moreover, PKC inhibition led to a 6.4-fold induction of NO synthase (NOS) activity in endothelial cells. Our findings demonstrate that activation of PKC is a major signaling pathway required for VEGF-induced proliferation and angiogenesis, whereas vascular permeability was enhanced by blocking PKC. Inhibition of calcium-dependent PKC by itself led to induction of NOS. Although NOS is a downstream target for VEGF-induced angiogenesis, its induction by PKC inhibition was not sufficient to promote neovascularization. These results reveal that angiogenesis and vascular permeability induced by VEGF are mediated by mechanisms which ultimately diverge.
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PMID:Divergence of angiogenic and vascular permeability signaling by VEGF: inhibition of protein kinase C suppresses VEGF-induced angiogenesis, but promotes VEGF-induced, NO-dependent vascular permeability. 1206 96

Gene expression profiling identified human melanoma cells demonstrating increased cell motility and invasiveness. The gene WNT5A best determined in vitro invasive behavior. Melanoma cells were transfected with vectors constitutively overexpressing Wnt5a. Consistent changes included actin reorganization and increased cell adhesion. No increase in beta-catenin expression or nuclear translocation was observed. There was, however, a dramatic increase in activated PKC. In direct correlation with Wnt5a expression and PKC activation, there was an increase in melanoma cell invasion. Blocking this pathway using antibodies to Frizzled-5, the receptor for Wnt5a, inhibited PKC activity and cellular invasion. Furthermore, Wnt5a expression in human melanoma biopsies directly correlated to increasing tumor grade. These observations support a role for Wnt5a in human melanoma progression.
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PMID:Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma. 1208 64

Listeriolysin O (LLO) and a phosphatidylinositol-specific phospholipase C (PI-PLC) are known virulence factors of Listeria monocytogenes in both tissue cultures and the murine model of infection. LLO is a member of a family of pore-forming cholesterol-dependent cytotoxins and is known to play an essential role in escape from the primary phagocytic vacuole of macrophages. PI-PLC plays an accessory role, in that PI-PLC mutants are partially defective in escape. We have shown that both of these molecules are essential for initiating rapid increases in the calcium level in the J774 murine macrophage cell line (S. J. Wadsworth and H. Goldfine, Infect. Immun. 67:1770-1778, 1999). Here we show that both LLO and PI-PLC are required for translocation of protein kinase C delta (PKC delta) to the periphery of J774 cells and for translocation of PKC beta II to early endosomes beginning within the first minute after addition of bacteria to the culture medium. Treatment with the calcium channel blocker SK&F 96365 inhibited translocation of PKC beta II but not PKC delta. Our findings lead us to propose a host signaling pathway requiring LLO and the formation of diacylglycerol by PI-PLC in which calcium-independent PKC delta is responsible for the initial calcium signal and the subsequent PKC beta II translocation. LLO-dependent translocation of PKC beta I to early endosomes also occurs between 1 and 4 min after infection, but this occurs in the absence of PI-PLC. All of these signals were observed in cells that had not internalized bacteria. Blocking PKC beta translocation with hispidin resulted in more rapid uptake of wild-type bacteria and greatly reduced escape from the primary phagocytic vacuoles of J774 cells.
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PMID:Mobilization of protein kinase C in macrophages induced by Listeria monocytogenes affects its internalization and escape from the phagosome. 1211 79

Fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling induces the expression of Runx2, a key transcription factor in osteoblast differentiation, but little is known about the molecular signaling mechanisms that mediate this. Here we examined the role of the protein kinase C (PKC) pathway in regulating Runx2 gene expression and its transactivation function. Treatment with FGF2 or FGF4, or transfection with a vector expressing a mutant FGFR2 that is constitutively activated in the absence of ligand, strongly stimulates Runx2 expression. Electrophoretic mobility shift assays also showed that FGF2 treatment increases the specific binding of Runx2 to the cognate response element in the osteocalcin gene promoter. Blocking PKC completely inhibited FGF2-induced Runx2 expression, whereas mitogen-activate protein kinase inhibitors had no effect. The FGF/FGFR-stimulated 6xOSE2 promoter activity was also blocked by inhibiting PKC, as was the FGF2 stimulation of the DNA-binding activity of Runx2. Experiments with PKC isoform-specific inhibitors and dominant negative isoforms of PKC indicate that PKCdelta is one of key isoforms involved in the FGF2-stimulated Runx2 expression. In addition, experiments with Runx2-knockout cells showed that, although the PKC pathway largely regulates FGF2-stimulated Runx2 activity by up-regulating Runx2 expression, it also modifies Runx2 protein post-translationally and thereby increases its transcriptional activity. Thus, we show for the first time that FGF/FGFR signaling stimulates the DNA-binding and transcriptional activities of Runx2 as well as its expression, and these are largely regulated by the PKC pathway.
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PMID:The protein kinase C pathway plays a central role in the fibroblast growth factor-stimulated expression and transactivation activity of Runx2. 1240 80

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