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)

Cholera toxin activated beef thyroid cyclic AMP-dependent protein kinase in a dose (0.2 to 8 microgram/ml)-related fashion. Thus, when beef thyroid slices were incubated with toxin (8 microgram/ml) for 90 minutes and then assayed for protein kinase, the activity ratio (i.e. -cyclic AMP/+cyclic AMP) increased from 0.32 +/- 0.02 to 0.77 +/- 0.06. The toxin (5 microgram/ml)-induced increase was abolished by inclusion of ganglioside GM1 in the incubation medium (I50, 0.7 microgram/ml), whereas, gangliosides GD1a and GT1 were without effect. In contrast, TSH-activated protein kinase was unaffected by ganglioside addition. Cholera toxin increased rat thyroid ornithine decarboxylase (ODC) activity in-vitro in a dose (0.1 to 10 microgram/ml)-related fashion [basal, 100 cf cholera toxin (10 microgram/ml), 1500 pmol 14CO2/g tissue/30 min]. The toxin (1 microgram/ml)- (but not TSH-) induced increase in ODC was abolished by inclusion of ganglioside Ga and GT1 were without effect. Cholera toxin stimulation of ODC was inhibited by indomethacin or iodide as are the stimulatory effects of TSH or dibutyryl cyclic AMP. These results demonstrate that although there are differences in the TSH and cholera toxin responses with respect to receptor (ganglioside) interaction, they nevertheless elicit similar intracellular responses in thyroid.
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PMID:Effects of cholera toxin on thyroid cyclic AMP-dependent protein kinase and ornithine decarboxylase activities. 22 45

Preincubation of rat brain synaptosomes with GM1, GD1a or GT1b (10(-10)-10(-6) M), as well as with phorbol 12-myristate, 13-acetate (10(-10)-10(-6) M) was found to have dose dependent inhibitory effect on Fe(2+)-ascorbate induced lipid peroxidation, while penetrating analogue of c-AMP markedly decreased the inhibitory effect of these compounds. In liposomes made of lipids isolated from synaptosomal membranes the degree of inhibition of induced LPO by gangliosides was practically absent. The inhibitory effect of GM1 on lipid peroxidation could not be revealed after thermal denaturation of synaptosomes or after treatment with polymyxin B (inhibitor of lipid-dependent protein kinases). These results and some other data provide evidence for the existence of ganglioside-dependent factor inhibiting lipid peroxidation in brain tissue. It may be suggested to be a protein kinase modulated by gangliosides.
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PMID:Ganglioside-dependent factor, inhibiting lipid peroxidation in rat brain synaptosomes. 130 35

The effect of cholera toxin (CT) on the growth of 12 small cell lung carcinoma (SCLC) and 15 non-small cell lung carcinoma (NSCLC) cell lines is presented. CT inhibited the growth of nine SCLC cell lines (concentration for 50% inhibition of growth, 27-700 ng/ml), all of which had abundant expression of GM1 ganglioside, the surface receptor for CT. CT-resistant SCLC all had greatly decreased GM1 expression. In contrast, CT inhibited the growth of only four of 15 NSCLC cell lines. Seven of the 11 CT-resistant NSCLC had levels of GM1 comparable to CT-sensitive NSCLC or SCLC. In a limited panel of cell lines, cyclic AMP (cAMP) agonists including forskolin, 8Br[cAMP], and dibutyryl[cAMP] did not consistently reproduce CT-mediated inhibition of cell growth, nor did these compounds overcome resistance of cells to the growth inhibitory effects of CT. Expression of the RI and RII regulatory subunits of cAMP-dependent protein kinase was similar in CT-resistant and CT-sensitive SCLC or NSCLC cell lines. In the presence of isobutylmethylxanthine, intracellular cAMP levels induced by CT in a CT-resistant, GM1(+) NSCLC cell line were comparable to those achieved in a CT-sensitive NSCLC cell line. We conclude that inhibition of lung carcinoma cell growth by CT in all cases requires expression of GM1, and in the case of SCLC cell lines the presence of GM1 is sufficient. In NSCLC cell lines, expression of GM1 is not sufficient for growth inhibition by CT. These findings imply refractoriness to growth inhibition by cAMP in GM1(+), CT-resistant NSCLC cell lines and the possibility of non-cAMP-related mechanisms for growth inhibition in CT-sensitive cell lines.
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PMID:Growth inhibition by cholera toxin of human lung carcinoma cell lines: correlation with GM1 ganglioside expression. 137 68

The effects of exogenous GM1 ganglioside on depolarization and ligand-induced Ca2+ signaling were investigated in PC12 cells. Cellular responses to K+ depolarization and bradykinin application in control and GM1-treated cells were examined with respect to: 1) changes in the intracellular Ca2+ concentration ([Ca2+]i) measured using fura-2 fluorescence in single cells, and 2) changes in Ca(2+)-dependent protein kinase activity as assayed by two-dimensional phosphopeptide analysis of the site-specific phosphorylation of tyrosine hydroxylase. Pretreatment of cells with GM1 (10 or 100 microM) enhanced K+ depolarization-stimulated increases in [Ca2+]i and in 32PO4 incorporation into tyrosine hydroxylase phosphopeptide T2, a Ca2+/calmodulin-dependent protein kinase II substrate. In contrast, GM1 treatment had no effect on the transient increases in [Ca2+]i evoked by bradykinin or on bradykinin-induced increases in the site-specific phosphorylation of tyrosine hydroxylase. The depolarization-induced and GM1-enhanced increases in [Ca2+]i and T2 phosphorylation were prevented by removal of external Ca2+ or pretreatment with 1 microM nitrendipine, suggesting that these increases result from Ca2+ entry through dihydropyridine-sensitive Ca2+ channels. The ability of exogenous gangliosides to potentiate increases in [Ca2+]i may underlie their diverse neuritogenic and neurotrophic actions in the nervous system.
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PMID:Modulation of a Ca2+ signaling pathway by GM1 ganglioside in PC12 cells. 144 16

We have investigated the ability of exogenous gangliosides to modulate nerve growth factor (NGF) signal transduction in PC12 cells. The effects of exogenous ganglioside GM1 on multiple protein kinase activities were assayed by analyzing site-specific serine phosphorylation of tyrosine hydroxylase (TyrOHase) by two-dimensional phosphopeptide mapping. In the presence of NGF, exogenous GM1 (1-10 microM) increased 32P incorporation into TyrOHase phosphopeptide T2, a Ca2+/calmodulin-dependent protein kinase substrate whose phosphorylation is not normally affected by NGF treatment. In the absence of NGF, GM1 treatment had no significant effects on TyrOHase phosphorylation. The removal of extracellular Ca2+ or blockade of dihydropyridine-sensitive Ca2+ channels prevented the GM1-induced increases in 32P incorporation into phosphopeptide T2. Exogenous GM1 also potentiated K+ depolarization-induced increases in the phosphorylation of TryOHase. These results suggest that the stimulatory effects of exogenous GM1 ganglioside on NGF actions may be due to its ability to potentiate a Ca(2+)-dependent signaling pathway.
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PMID:Stimulation of a Ca(2+)-dependent protein kinase by GM1 ganglioside in nerve growth factor-treated PC12 cells. 167 13

Complete obstruction of the maternal blood flow to fetal rats at 20 days of gestation for a period of 10 min causes a significant shift of approximately 22% in protein kinase C (PKC) activity from a cytosolic to a membrane-bound form in the fetal brain. This translocation can be entirely reversed without losses in activity by a single intraperitoneal injection into the gravid rat of either a mixture of disialo- and trisialoganglioside [polysialoganglioside (PSG)] or by GM1 (50 mg/kg of body weight) given 3 h before onset of the ischemic episode. Cessation of blood flow for 15 min followed by a reperfusion period of 24 h results in a 47% loss in total PKC activity. This down-regulation can be almost entirely prevented upon intraperitoneal administration of GM1 3 h before, but also during and even 90 min after the onset of ischemia. The PSG mixture is also effective, particularly when given 3 h before the insult. Down-regulation of PKC is accompanied by an increase in a Ca2(+)-phosphatidylserine-independent kinase [protein kinase M (PKM)] activity, which rises from 30 pmol/min/mg of protein in control animals to a maximal value of 83.1 pmol/min/mg of protein after 15 min of ischemia and 6 h of reperfusion. By 24 h, PKM activity is 46.8 pmol/min/mg of protein. Administration of GM1 blocks completely the appearance of PKM, a result suggesting that PKC down-regulation and PKM activity elevation are intimately associated events and that both are regulated by GM1 ganglioside.
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PMID:Gangliosides prevent ischemia-induced down-regulation of protein kinase C in fetal rat brain. 223 Aug 13

Gangliosides inhibit the phosphorylation of both small and large rat myelin basic proteins (SMBP, LMBP) by an endogenous phospholipid-sensitive Ca2+-dependent protein kinase (C-kinase). Using a rat brain myelin preparation in an in vitro phosphorylation assay system, we determined the inhibition constants (IC50's) of the gangliosides GM1, GD1a, GD1b, and GT1b to be approximately 160 microM, 65 microM, 65 microM, and 40 microM, respectively. Asialoganglioside GA1, ceramide, and N-acetylneuraminic acid (NANA, sialic acid) failed to produce similar inhibition, suggesting that both the lipid and the sialic acid moieties are necessary, but neither alone is sufficient to produce inhibition. The results indicate that gangliosides may regulate protein kinase C activities in the nervous system.
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PMID:Gangliosides inhibit phospholipid-sensitive Ca2+-dependent kinase phosphorylation of rat myelin basic proteins. 242 Oct 6

Gangliosides have profound effects on the phosphorylation of several proteins in myelin. Addition of polysialogangliosides to purified guinea pig brain myelin enhanced the endogenous phosphorylation of a 62-kDa phosphoprotein, but completely inhibited the phosphorylation of myelin basic protein (MBP) (18.5 kDa). The ganglioside-stimulated phosphorylation of the 62-kDa protein was dose-dependent and -specific. Asialo-GM1, ceramide trihexosides, N-acetylneuraminic acid, or colominic acid alone could not mimic this effect, suggesting that the activation process requires both the hydrophobic head group and the anionic character of the gangliosides. Studies on the time course of this reaction revealed that it was a rapid and reversible process and was affected only very slightly by Ca2+. Thus, the stimulatory effect of gangliosides may not involve Ca2+-gangliosides complexes or proteolysis, but may be mediated through an activation of a ganglioside-dependent protein kinase or due to substrate protein-glycolipid interaction. Modulation of the phosphorylation of MBP by gangliosides varies with the states of phosphorylation of this protein. Prior addition of ganglioside to myelin inhibited the phosphorylation of MBP. However, addition of gangliosides to myelin subsequent to maximal phosphorylation of MBP retarded the dephosphorylation of this protein. Phosphorylation of isolated MBP by protein kinase C was stimulated by gangliosides, provided phosphatidylserine was present. In contrast, the glycolipid inhibited the phosphorylation of a unique site catalyzed by cAMP-dependent protein kinase. This site was distinct from those phosphorylated by protein kinase C and was also sensitive to chymotryptic cleavage. Although the exact physiological significance of protein phosphorylation in myelin has yet to be established, gangliosides may play an important role in the modulation of this reversible post-translational modification mechanism.
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PMID:Ganglioside-modulated protein phosphorylation in myelin. 243 83

Purified cyclic AMP-dependent protein kinase (cAK) catalytic subunit phosphorylated 180-, 49-, 31-, 19-, and 14-kilodalton (kDa) proteins of rabbit sciatic nerve membranes. The ability of cAK to phosphorylate these membrane substrate proteins was inhibited by gangliosides GM1, GD1a, and GT1b with half-maximal inhibitory concentration (I50) = 7-25 microM. Neutral glycolipids and lysophosphatidylcholine were much less effective. Cyclic AMP (cAMP) kinase phosphorylation of histone IIA was inhibited by GM1, GD1a, and GT1b (I50 = 115 microM, 75 microM, and 75 microM, respectively). Inhibition by GM1 was competitive with respect to histone (Ki = 108 microM). Autophosphorylation of cAMP kinase was inhibited by GM1 (I50 = 15 microM). GT1b, GD1a, and GM1 half-maximally stimulated calmodulin-dependent cyclic nucleotide phosphodiesterase at 0.1 microM, 0.2 microM, and 0.3 microM, respectively. Although GT1b stimulated phosphodiesterase by increasing Vmax and decreasing Km (similar to calmodulin), GD1a and GM1 produced only an increase in Vmax. These results suggest that ganglioside can modulate the activity of cAMP kinase by both direct inhibition of the enzyme and indirect reduction of cAMP levels through activation of phosphodiesterase. Through these mechanisms, gangliosides may alter cAMP-dependent protein phosphorylation and cell function within the nervous system.
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PMID:Ganglioside modulation of cyclic AMP-dependent protein kinase and cyclic nucleotide phosphodiesterase in vitro. 272 53

Gangliosides have profound modulatory effects on protein phosphorylation in brain. A protein kinase activated directly by gangliosides has been partially purified from the particulate fractions of guinea pig brain through extraction with nonionic detergent, ion-exchange chromatography, hydrophobic chromatography, and gel filtration. This novel ganglioside-stimulated protein kinase is distinct from cAMP-dependent, Ca2+/calmodulin-dependent, and Ca2+/phospholipid-dependent protein kinases. The partially purified kinase preparation could undergo ganglioside-stimulated autophosphorylation of a major phosphoprotein with Mr corresponding to 68,000. It also could phosphorylate exogenous substrates such as the synthetic peptide Leu-Arg-Arg-Ala Ser-Leu-Gly. The requirement of gangliosides for the activation of kinase activity is dose-dependent and specific. Among the various gangliosides tested, GT1b and GD1a were found to be the most potent activators, whereas GD1b and GM1 were slightly less effective. The activation process is rapid and does not require the presence of Ca2+, suggesting that the stimulatory effect of gangliosides is not mediated through limited proteolysis or Ca2+-glycolipid complexes. Although the exact physiological significance of the ganglioside-stimulated protein kinase is not known at present, it is possible that certain functions related to gangliosides in the nervous system are mediated through the activation of this novel enzyme.
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PMID:Ganglioside-modulated protein phosphorylation. Partial purification and characterization of a ganglioside-stimulated protein kinase in brain. 303 Oct 46


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