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 mechanism of immunosuppressant activity of phosphatidylserine has been studied in peripheral blood mononuclear cells depleted or not of monocytes. After the addition of phosphatidylserine, mass determinations and uptake of labeled compound demonstrate its transfer into the cells. Phosphatidylserine incorporation causes a 2.5-fold increase of membrane-bound protein kinase C activity. The activation of translocated enzyme is indicated by the inhibition of phosphoinositide hydrolysis, and early feedback effect induced by activated protein kinase C. This action of phosphatidylserine is reproduced by tetradecanoylphorbolacetate and is prevented by the protein kinase C inhibitor, staurosporine. Consistently, phosphatidylserine (8 nmol/10(6) cells) decreases by 46% the production of inositol phosphates in cells responding to phytohemagglutinin. The decrease of phosphoinositide signal pathway as well as the inhibition of mitogen-induced DNA synthesis are produced at the same phosphatidylserine concentration and are equally manifest in total mononuclear cells or in preparations depleted of monocytes. However, only in the presence of monocytes does tetradecanoylphorbolacetate enhance the action of phospholipid, decreasing its IC50 from 13-15 microM to 7 microM. Thus, the data suggest that a reaction driven by protein kinase-C and a factor released by activated monocytes are involved in the phosphatidylserine-induced inhibition of lymphocyte DNA synthesis.
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PMID:Role of protein kinase C in the phosphatidylserine-induced inhibition of DNA synthesis in blood mononuclear cells. 133 10

Cytosol (C) (100,000 x g/60 min, supernatant) from liver, brain and testis (Wistar male rats) are shown to contain insulin degrading activity (C-IDA). The regulation of C-IDA in these fractions by ligands that activate G protein and PKC were examined C-IDA from liver, brain and testis was inhibited 76%; 64% and 50% by 50 mM F- respectively. Chromatography of C fraction from liver on Sephadex G-50 in presence of 1 M (NH4)2SO4 and 20% (v/v) glycerol (experimental condition to remove guanine nucleotides from G proteins) decreased in about 3-fold aluminum fluoride effect on C-IDA. Mg++ (from 5mM to 10 mM) enhanced fluoride effects by inhibiting fully C-IDA. Phosphatidylserine in presence of ATP completely inhibited C-IDA; this inhibition was 31.3% mediated by a phosphorylation reaction. It is concluded that cytosol from different tissues contain proteins capable to associate ligands as aluminum fluoride and PS to regulate C-IDA. It is proposed a mechanism of protein-protein interaction to modulate C-IDA.
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PMID:Fluoride and phosphatidylserine induced inhibition of cytosolic insulin-degrading activity. 134 87

The effect of hypoxia on the incorporation of [14C]serine into serine glycerophospholipids was investigated in rat brain cortex. Brain slices were incubated, in the presence of the labeled precursor, in Krebs-Henseleit Ringer bicarbonate or Krebs Ringer phosphate, and hypoxia was induced by bubbling nitrogen in the medium. The lowering of oxygen caused an increase of the incorporation of the base into phosphatidylserine in slices incubated in both media, although the effect was greater in Krebs Ringer phosphate. Such an effect was also observed in the homogenate subjected to N2-treatment, with an increase in the incorporation similar to that obtained in slices incubated in Krebs-Henseleit Ringer bicarbonate. Phosphatidylserine is synthesized in mammalian tissues by a "base-exchange" enzyme, strictly Ca2+ dependent, and, moreover, is necessary for protein kinase C activity. We postulate that the increased synthesis of phosphatidylserine might affect signal transduction mechanisms and participate in the modification of lipid metabolism observed in hypoxia and/or ischemia.
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PMID:Serine incorporation into phosphatidylserine in hypoxic rat brain cortex. 149 81

Maximal protein kinase C activity with vesicles of phosphatidic acid and 1,2-dioleoyl-sn-glycerol is observed in the absence of added Ca2+. Addition of phosphatidylcholine to these vesicles restores some calcium dependence of enzyme activity. 1,2-Dioleoyl-sn-glycerol eliminates the Ca(2+)-dependence of protein kinase C activity found with phosphatidic acid alone. Phorbol esters do not mimic the action of 1,2-dioleoyl-sn-glycerol in this respect. This suggests that the 1,2-dioleoyl-sn-glycerol effect is a result of changes it causes in the physical properties of the membrane rather than to specific binding to the enzyme. The effect of 1,2-dioleoyl-sn-glycerol on the phosphatidic-acid-stimulated protein kinase C activity is dependent on the molar fraction of 1,2-dioleoyl-sn-glycerol used and results in a gradual shift from Ca2+ stimulation at low 1,2-dioleoyl-sn-glycerol concentrations to calcium inhibition at higher concentrations of 1,2-dioleoyl-sn-glycerol. Phosphatidylserine-stimulated activity is also shown to be largely independent of the calcium concentration at higher molar fractions of 1,2-dioleoyl-sn-glycerol. Thus, with certain lipid compositions, protein kinase C activity becomes independent of the calcium concentration or requires only very low, stoichiometric binding of Ca2+ to high affinity sites on the enzyme. Protein kinase C can bind to phosphatidic acid vesicles more readily than it can bind to phosphatidylserine vesicles in the absence of calcium. Addition of 1,2-dioleoyl-sn-glycerol to phosphatidylserine vesicles promotes the partitioning of protein kinase C into the membrane in the absence of added Ca2+. There is no isozyme specificity in this binding. These results suggest that a less-tightly packed headgroup region of the bilayer causes increased insertion of protein kinase C into the membrane. This is a necessary but not sufficient condition for activation of the enzyme in the presence of EGTA.
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PMID:Lipid vesicles which can bind to protein kinase C and activate the enzyme in the presence of EGTA. 152 29

Biological membranes exhibit an asymmetric distribution of phospholipids. Phosphatidylserine (PS) is an acidic phospholipid that is found almost entirely on the interior of the cell where it is important for interaction with many cellular components. A less well understood phenomenon is the asymmetry of the neutral phospholipids, where phosphatidylcholine (PC) is located primarily on exterior membranes while phosphatidylethanolamine (PE) is located primarily on interior membranes. The effect of these neutral phospholipids on protein-phospholipid associations was examined using four cytoplasmic proteins that bind to membranes in a calcium-dependent manner. With membranes containing PS at a charge density characteristic of cytosolic membranes, protein kinase C and three other proteins with molecular masses of 64, 32, and 22 kDa all showed great selectively for membranes containing PE rather than PC as the neutral phospholipid; the calcium requirements for membrane-protein association of the 64- and 32-kDa proteins were about 10-fold lower with membranes containing PE; binding of the 22-kDa protein to membranes required the presence of PE and could not even be detected with membranes containing PC. Variation of the PS/PE ratio showed that membranes containing about 20% PS/60% PE provided optimum conditions for binding and were as effective as membranes composed of 100% PS. Thus, PE, as a phospholipid matrix, eliminated the need for membranes with high charge density and/or reduced the calcium concentrations needed for protein-membrane association. A surprising result was that PKC and the 64- and 32-kDa proteins were capable of binding to neutral membranes composed entirely of PE/PC or PC only. The different phospholipid headgroups altered only the calcium required for membrane-protein association. For example, calcium concentrations at the midpoint for association of the 64-kDa protein with membranes containing PS, PE/PC, or PC occurred at 6, 100, and 20,000 microM, respectively. Thus, biological probes detected major differences in the surface properties of membranes containing PE versus PC, despite the fact that both of these neutral phospholipids are often thought to provide "inert" matrices for the acidic phospholipids. The selectivity for membranes containing PE could be a general phenomenon that is applicable to many cytoplasmic proteins. The present study suggested that the strategic location of PE on the interior of the membranes may be necessary to allow some membrane-protein associations to occur at physiological levels of calcium and PS.
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PMID:Importance of phosphatidylethanolamine for association of protein kinase C and other cytoplasmic proteins with membranes. 173 60

Phosphatidylserine has been implicated both in the regulation of protein kinase C activity and in the regulation of T lymphocyte activation. Taking into account the fact that some serine analogues modify the activity of the base exchange enzyme system responsible for the synthesis of phosphatidylserine and to a lesser extent the synthesis of phosphatidylcholine and phosphatidylethanolamine, in vitro, we have tested the ability of both isoserine and serinol to modify phospholipid synthesis in the T cell line Jurkat. It was found that serinol was able to decrease by 75% the amount of phosphatidylserine synthesized by the cells and also to decrease the synthesis of phosphatidylcholine and phosphatidylethanolamine, while phosphatidylinositol synthesis was not affected. Concomitantly, in serinol-treated Jurkat cells, interleukin-2 production was markedly inhibited. Monitoring the production of second messengers generated by T cell activators showed that in serinol-treated cells the production of diacylglycerol was impaired while Ca2+ mobilization remained unaffected. Serinol thus appeared to be a potential immunoregulatory molecule active at the level of protein kinase C regulation either through its interaction with phosphatidylserine or through diacylglycerol production.
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PMID:Effects of the serine analogues isoserine and serinol on interleukin-2 synthesis and phospholipid metabolism in a human T cell line Jurkat. 176 42

Phosphatidylserine has been implicated both in the regulation of protein kinase C activity and in the regulation of T lymphocyte activation in vitro and in vivo. Treatment of Jurkat T cells with PS, results in a strong decrease of Interleukin-2 synthesis. Arachidonoyl-diacylglycerol production and Ca++ mobilization due to the increase of the phosphatidylinositide turnover appeared not affected by PS. On the contrary, oleoyl-diacylglycerol production arising from phosphatidylcholine breakdown was impaired. Studies on phospholipid synthesis in PS-treated cells suggest 1) that the phospholipid methylation pathway that lead to the conversion of phosphatidylethanolamine into phosphatidylcholine is the major site of action of exogenous added PS and 2) confirm that this pathway is a major source of oleoyl-diacylglycerol in Jurkat T cells.
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PMID:Mechanism of phosphatidylserine-induced inhibition of interleukin 2 synthesis in the human T cell line Jurkat. 209 43

Phosphatidylserine (PS) is a necessary cofactor for protein kinase C (PKC) activation, and changes in the synthesis of PS have been shown to participate in the mechanism(s) involved in the transmembrane signaling of interleukin 1 (IL-1). In view of the age-associated defects in T-cell functions, in the present study we have addressed the question of whether an in vivo treatment with PS might interfere with such processes. Furthermore, the effect of an in vitro treatment with PS in human peripheral blood monocytes (PBMC) or splenocytes activated with a lectin mitogen, on the expression of IL-2 receptor, was assessed. While the process of ageing was accompanied by a marked decline of humoral response monitored by anti-BSA antibodies (of the IgG class) production, following immunization with BSA in complete Freund adjuvant, chronic treatment with PS (50 mg/kg, in drinking water), reversed this effect, raising specific antibody titers to levels practically indistinguishable from those measured in young animals. Pharmacological depression of humoral immune response induced by a treatment of adult animals with dexamethasone was similarly reversed by a chronic treatment with PS. While only a pharmacological concentration (10(-5) M) of PS significantly increased IL-2 receptor expression in activated human PBMC, simultaneous treatment of PBMC with inactive doses of PS and the pharmacological activator of PKC (phorbol myristate acetate, PMA, 10(-8) M) resulted in a synergistic stimulation of Tac+ cells. Furthermore, in cultures of rat splenocytes PS (10(-6) M) significantly stimulated the expression of IL-2 receptor, and concomitant addition of PS (10(-7) M) to Con A-stimulated splenocytes produced a significant potentiation of IL-2 receptor induction. The present results indicate that in vivo treatment of ageing animals with the specific phospholipid PS is able to reverse the physiological decline of the humoral immune response induced by the ageing process. Moreover, treatment of young rats with PS reversed the pharmacological associated depression of specific antibody production. The in vitro effects of the phospholipid on human PBMC and rat splenocytes might suggest that PS is implicated in T-cell activation through its action on IL-2 receptor.
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PMID:Phosphatidylserine counteracts physiological and pharmacological suppression of humoral immune response. 239 81

Protein kinase C plays a crucial role in signal transduction for activating cellular function. Phosphatidylserine and Ca2+ are essential for the activation of protein kinase C, and diacylglycerol which is produced in the receptor-mediated hydrolysis of inositol phospholipids, increases the affinity of this enzyme for phosphatidylserine and Ca2+. In brain tissues, protein kinase C has been shown to be separated into three fractions, Type I, II, and III by hydroxyapatite column chromatography, and cDNA analysis has revealed that they correspond to gamma-, beta I-, beta II-, and alpha-cDNA, respectively. Phospholipase D has been known to catalyze the transphosphatidyl reaction between various membrane phospholipids and alcohols. In fact, phosphatidylethanol has been found in many tissues including brain of ethanol-treated rats. This report describes the different responses of three distinct forms of protein kinase C to phosphatidylethanol. Phosphatidylethanol can replace phosphatidylserine at high Ca2+ concentrations for the activation of Type I, II, and III protein kinase C. However, phosphatidylethanol can activate only Type I enzyme at physiological Ca2+ concentrations, which is expressed exclusively in the central nervous tissue. Consideration of these results suggests the possibility that ethanol may exert some effect on the signal transduction in neuronal tissue, via changes in protein phosphorylation.
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PMID:Distinct effects of phosphatidylethanol on three types of rat brain protein kinase C. 263 87

Phosphatidylserine/calcium-dependent protein kinase C (PKC) from rat brain is activated fifty times more efficiently by phosphatidylinositol-4,5-bisphosphate (PIP2) (Kapp = 0.04 mole% in Triton-lipid micelles) than by diacylglycerol (DG) (Kapp = 2 mole%). Both effector lipids appear to bind to the same site but PIP2 may confer a narrower substrate specificity on the kinase. DG, which together with inositol trisphosphate (IP3) is generated by hydrolysis from PIP2 after cell stimulation, has been considered the natural activator of the kinase but it is likely to be anteceded in this function by PIP2; DG may perhaps retain the function of a back-up activator. The lack of PKC-activation by phosphatidylinositol (PI) or phosphatidylinositol-4-phosphate (PIP) opens the possibility that the Inositide Shuttle, PI reversible PIP reversible PIP2, has a role in controlling the activity of the kinase.
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PMID:Phosphatidylinositol-4,5-bisphosphate may antecede diacylglycerol as activator of protein kinase C. 284 76


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