Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The interaction of high density lipoproteins (HDL) with the HDL receptor stimulates the translocation of cholesterol from intracellular pools to the plasma membrane where the cholesterol becomes available for removal by appropriate acceptors. The role of signal transduction through protein kinase C in HDL receptor-dependent cholesterol translocation and efflux was examined using cholesterol-loaded cultured human skin fibroblasts. Treatment of cells with HDL3 activated protein kinase C, demonstrated by a transient increase in membrane associated kinase activity. Kinase activation appeared to be dependent on binding of HDL3 to the HDL receptor, since tetranitromethane-modified HDL3, which does not bind to the receptor, was without effect. Translocation of intracellular sterol to the plasma membrane was stimulated by treatment of cells with the protein kinase C activators, dioctanoylglycerol and phorbol myristic acetate, and the calcium ionophore A23187. Conversely, treatment of cells with sphingosine, a protein kinase C inhibitor, reduced HDL3-mediated translocation and efflux of intracellular sterols. However, sphingosine had no effect on efflux of labeled cholesterol derived from the plasma membrane. Down-regulation of cellular protein kinase C activity by long term incubation with phorbol esters also inhibited HDL3-mediated efflux of intracellular sterols and abolished the ability of sphingosine to further inhibit HDL3-mediated efflux. These studies support the conclusion that HDL receptor-mediated translocation and efflux of intracellular cholesterol occurs through activation of protein kinase C.
 ...
PMID:Protein kinase C as a mediator of high density lipoprotein receptor-dependent efflux of intracellular cholesterol. 164 39

The excess risk of atherosclerosis that is associated with diabetes mellitus cannot be completely accounted for by other known risk factors. Recent studies have suggested that increased glycation of high density lipoproteins (HDL) at high glucose concentrations causes functional abnormalities that might contribute to accelerated atherosclerosis. Other investigators also have shown that elevated glucose concentrations can stimulate the activity of protein kinase C in cultured cells. Because protein kinase C appears to be involved in HDL receptor-mediated efflux, the hypothesis that a high glucose concentration in vitro might modulate HDL-mediated efflux of cholesterol from human fibroblasts was tested. These studies indicate that a high glucose level alone does not affect the interaction of normal HDL3 with cultured human skin fibroblasts.
 ...
PMID:High glucose levels do not directly impair cellular binding of HDL3 or HDL-mediated efflux of cholesterol from human skin fibroblasts. 166 7

These studies provide evidence that binding of HDL3 to the HDL receptor stimulates translocation and efflux of intracellular cholesterol through mechanisms involving the activation of protein kinase C. This conclusion is supported by data demonstrating that HDL is able to increase cell diacylglycerol levels and activate protein kinase C. Sphingosine, a protein kinase C inhibitor, was able to inhibit HDL3-mediated cholesterol translocation and efflux, further suggesting a role for protein kinase C in HDL receptor-dependent cholesterol efflux. Inhibition of HDL-mediated diacylglycerol formation by pertussis toxin suggests the possible involvement of a G protein-activated phospholipase. Further studies are needed to understand how activation of protein kinase C promotes cholesterol translocation and to identify the target proteins for protein kinase C phosphorylation.
 ...
PMID:Role of the protein kinase C signaling pathway in high-density lipoprotein receptor-mediated efflux of intracellular cholesterol. 166 90

Low concentrations of HDL3 stimulate a transient biphasic increase in 1,2-diacylglycerol (DAG), with an early phase peaking at 30 seconds and a late phase at 60 seconds in (3H)-phosphatidylcholine prelabelled platelets. DAG generation is coupled to apolipoprotein AII or AI binding to specific surface receptors. Coincubations with HDL3 and 0.2 microM phorbol ester induced a significant rise in the second phase DAG indicating the involvement of protein kinase C in this late phase. The HDL3 induced production of DAG in platelets pretreated with 6 microM R 59022 is enhanced, while phosphatidic acid (PA) content was reduced, suggesting that DAG attenuation is derived at least in part from a pathway involving DAG-Kinase.
 ...
PMID:Phosphatidylcholine breakdown in HDL3 stimulated platelets. 217 55

Apolipoprotein A-I (apo A-I)*/DMPC complexes have been previously shown to promote cholesterol efflux from cholesterol-preloaded adipose cells whereas apo A-II/DMPC complexes, which bind to the same cell surface binding sites, were ineffective. Addition of apo A-I/DMPC complexes led to a rapid and transient formation of diacylglycerol. However, in contrast to PGF2 alpha (Doglio et al., Proc. Natl. Acad. Sci. USA, 1989, 86, 1148), no accumulation of inositol phosphates was observed. Apo A-II/DMPC complexes had no effect on diacylglycerol formation. Stimulation by apo A-I/DMPC complexes or native HDL3 of cells prelabelled with (2-palmitoyl 9,10[3H])phosphatidylcholine induced also the formation of labelled diacylglycerol whereas apo A-II/DMPC complexes and HDL3 treated with tetranitromethane showed no effect. Direct activation of protein kinase C(s) by PMA promoted cholesterol efflux providing that DMPC liposomes were present as cholesterol acceptor. It is proposed that lipoprotein particles have two separate effects, i.e. a ligand-induced effect leading to cholesterol translocation from intracellular stores to the cell surface and a bilayer-induced effect allowing cholesterol efflux from the cell surface to the acceptor.
 ...
PMID:Cholesterol efflux from adipose cells is coupled to diacylglycerol production and protein kinase C activation. 226 37

Monokine-induced hepatic secretion of serum amyloid A protein (apo-SAA), an acute-phase reactant, is followed by rapid association with high-density lipoprotein (HDL) in plasma. Plasma clearance of apo-SAA is more rapid than any of the other HDL apolipoproteins. It has been shown that, of the acute-phase HDL3 apolipoproteins, apo-SAA preferentially associates with neutrophil membranes. HDL apolipoproteins have been shown to activate protein kinase C in endothelial cells. We therefore investigated potential phosphorylation of HDL3 apolipoproteins by protein kinase C. Apo-SAA was the only apolipoprotein phosphorylated (Km = 12 mM). Phosphorylation of the apo-SAA-containing HDL3 particle was selective for the more basic isoforms of apo-SAA (pI 7.0, 7.4, 7.5 and 8.0), with more acidic isoforms being phosphorylated when delipidated acute-phase apolipoproteins were used as substrate. However, phosphorylation was not in itself responsible for the establishment of the apo-SAA isoforms.
 ...
PMID:Phosphorylation of human serum amyloid A protein by protein kinase C. 319 20

The influence of HDL3 on phospholipid breakdown was examined in human skin fibroblasts. HDL3 elicited phosphatidylcholine (PC) and phosphatidylinositol (PI) turnover and activated multiple phospholipases. In [14C]lyso-PC-labeled or [14C]choline (Cho)-labeled cells, a biphasic activation of PC-specific phospholipase D (PLD) with peak maxima 30 to 60 seconds and 5 to 7 minutes after stimulation with 20 micrograms/mL HDL3 was shown by (1) a 1.5- to 3-fold increase in Cho release, and (3) transphosphatidylation of PC to phosphatidylbutanol in the presence of 0.3% butanol. Activation of PC-specific PLD was paralleled by an activation of PC-specific phospholipase C (PLC). A significant increase in [14C]diacylglycerol (DG) was seen from 2 minutes after stimulation onward and remained for at least 2 hours. By means of butanol, the PA-phosphohydrolase (PPH) inhibitor propranolol, and the PC-PLC inhibitor D609, we demonstrated that the initial PC-derived DG formation occurred primarily by a coupled PLD/PPH pathway and that a major part of the sustained DG formation was derived directly from PC by PC-PLC. By down-regulating protein kinase C (PKC) we demonstrated that PKC activates PC-PLC and desensitizes PC-PLD at no longer incubation times. The sustained PC hydrolysis as well as HDL3-mediated PI turnover and PC resynthesis was observed on stimulation with 5 to 75 micrograms/mL HDL3, whereas the rapid activation of PC-PLD/PPH was detected only on stimulation with HDL3 at concentrations of between 10 and 75 micrograms/mL. Only the latter response could be mimicked by apolipoprotein A-I and apolipoprotein A-II proteoliposomes, and only this response was inducible by cholesterol loading. The HDL3-mediated second-messenger responses were inhibited by modification of HDL3 by tetranitromethane and could not be mimicked by protein-free liposomes. These data suggest that HDL3-induced cell signaling in human skin fibroblasts is mediated by specific protein-receptor interaction and that more than one agonist activity may be involved.
 ...
PMID:HDL3 stimulates multiple signaling pathways in human skin fibroblasts. 758 79

We compared HDL3- and LDL-induced signal transduction in normal and Tangier fibroblasts to elucidate whether impaired signal transduction responses to lipoproteins might contribute to disturbed cellular lipid and lipoprotein metabolism in Tangier disease, a rare autosomal disorder of cellular lipid and lipoprotein metabolism. In several cell types HDL and LDL activate a currently unknown isoform of phosphatidylinositol-specific phospholipase C (PI-PLC) that results in the generation of 1,2-diacylglycerol and inositol 1,4,5-trisphosphate. Compared with normal fibroblasts, Tangier fibroblasts stimulated with HDL3 or LDL resulted in a significantly reduced accumulation of inositol phosphates and 1,2-diacylglycerol formation. Furthermore, in Tangier fibroblasts both lipoproteins failed to mobilize calcium from internal pools, and the cytosol-to-membrane redistribution of protein kinase C (in both the alpha and epsilon isoforms) was markedly reduced. Thus, the data indicate an impaired PI-PLC activation in response to lipoproteins in Tangier fibroblasts.
 ...
PMID:Activation of phosphatidylinositol-specific phospholipase C in response to HDL3 and LDL is markedly reduced in cultured fibroblasts from Tangier patients. 767 Sep 51

Previous studies from our laboratory demonstrated that high-density lipoproteins (subclass 3; HDL3) bind to sites specific for apolipoprotein AI on the human adenocarcinoma cell line A549 and that HDL3 binding promotes a mitogenic effect [Favre, Tazi, Le Gaillard, Bennis, Hachem and Soula (1993) J. Lipid Res. 34, 1093-1106]. In the present study, we have examined the cell proteins that showed modified phosphorylation after binding of HDL3 to specific sites, and the roles of Ca2+ and protein kinase C. Native HDL3 (but not tetranitromethane-modified HDL3) and Ca2+ ionophore A23187 strongly enhanced the phosphorylation of a 20 kDa protein (x 3.6) and, to a lower extent, the phosphorylation of 24 and 28 kDa proteins (x 2.2 and 2.6 respectively). The two effectors were equally able to stimulate cell growth. Down-regulation of protein kinase C by a 24 h incubation of cells with phorbol myristate acetate prevented the effects of HDL3 on the phosphorylation of 24 and 28 kDa proteins. However, the extent of phosphorylation of the 20 kDa protein was not affected. In contrast, activation of protein kinase C by a short incubation with phorbol myristate acetate resulted in inhibition of proliferation and an increase in 24 and 28 kDa (but not 20 kDa) protein phosphorylation. These results suggest that HDL3 putative receptors exert their proliferative effect on A549 cells through activation of a Ca(2+)-dependent protein kinase. This kinase activity is not modulated by phorbol ester and thus may be a calmodulin kinase or an isoenzyme of protein kinase C that is independent of phorbol ester. It allows a subsequent 20 kDa protein to be phosphorylated.
 ...
PMID:Involvement of the Ca(2+)-dependent phosphorylation of a 20 kDa protein in the proliferative effect of high-density lipoproteins (subclass 3) on the adenocarcinoma cell line A549. 773 97

It has been found that blood lipoproteins are capable of inducing rapid and reversible elevations of [Ca2+]i in human blood platelets and vascular smooth muscle cells (VSMC) loaded with Ca(2+)-sensitive fluorescent probes. The effects of LDL and HDL3 were dose-dependent and reached saturation at physiological concentrations of these lipoproteins. Both lipoproteins activated the phosphoinositide turnover, producing elevated levels of diacylglycerol and inositol mono-, bis- and triphosphates. Analysis of isomers of inositol phosphates in lipoprotein-treated VSMC by anion-exchange HPLC supported the view that LDL and HDL3 activate polyphosphoinositide-specific phospholipase C. These data demonstrate that lipoproteins, similarly to aggregation inducers and vasoactive hormones, stimulate second messenger systems in platelets and VSMC. It was shown that pretreatment of cells with protein kinase C activators, cAMP- and cGMP-dependent protein kinases, significantly decreased the hormone-like effects of the lipoproteins. Preincubation of VSMC with pertussis toxin also attenuated the effects of LDL and HDL3. In contrast, adrenaline potentiated the 2-3-fold LDL-induced elevation of [Ca2+]i in platelets. Considering that increase in the intracellular cAMP and cGMP and the activation of protein kinase C are known to inhibit the effects of Ca(2+)-mobilizing hormones, the results obtained demonstrate a similarity between the mechanisms of activation of cell-signalling systems by hormones and lipoproteins, suggesting also that lipoprotein-induced activation may be transduced by G-proteins.
 ...
PMID:[Hormone-like action of blood plasma lipoproteins on human platelets and smooth vascular muscle cells]. 794 21


1 2 Next >>