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)

Treatment of BC3H1 myocytes or 3T3-L1 fibroblasts with fluoroaluminate (AlF4-), a direct activator of G proteins, increased the tyrosine phosphorylation of a 42-kDa cytosolic protein. AlF4- induced a parallel increase in protein kinase activity toward myelin basic protein (MBP) in partially purified cell extracts. To test whether AlF4- was activating the 42-kDa MAP (mitogen-activated protein) kinase, extracts from AlF4--treated cells were taken through the chromatographic steps routinely used to purify MAP kinase from growth factor-stimulated cells. Following phenyl-Superose chromatography, a peak of MBP kinase activity eluted at a position characteristic of MAP kinase. Immunoblotting of the active fractions with anti-phosphotyrosine antibodies revealed a single reactive protein band of Mr 42,000. Stimulation of MAP kinase by AlF4- was rapid, peaking within 15 min and persisting for at least 1 h. In contrast, the activation of MAP kinase by insulin was transient, characteristic of its activation by growth factors in other cell types. Although concentrations of sodium fluoride greater than 1 mM also activated MAP kinase, this effect was shown to be dependent upon the simultaneous presence of aluminum ions in the medium. Activation of MAP kinase by AlF4- was not affected by either cellular depletion of protein kinase C or pretreatment of cells with pertussis toxin. Potential sites of action of AlF4- are discussed. These findings suggest that activation of a G protein(s) in intact cells can initiate events that result in tyrosine phosphorylation and activation of MAP kinase.
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PMID:Activation of mitogen-activated protein kinase in BC3H1 myocytes by fluoroaluminate. 170 25

Chronic, oral administration of aluminum to rats increases the in vivo concentration of cyclic AMP and the phosphorylation of microtubule-associated protein-2 (MAP-2) and the 200 kD neurofilament subunit (15,16). In the present study, the effect of this treatment on endogenous protein phosphorylation in soluble and particulate fractions prepared from cerebral cortices was examined. Chronic aluminum treatment significantly elevated the basal and cyclic AMP-dependent phosphorylation of 11-12 endogenous proteins in the soluble fraction prepared from cerebral cortices. Endogenous protein phosphorylation in the soluble fraction occurring in the presence of Ca++ alone or Ca++, phorbol 12-myristate 13-acetate and phosphatidylserine was not significantly altered by aluminum treatment. In the particulate fraction the phosphorylation of several proteins was significantly decreased by aluminum administration; however, the phosphorylation of the majority of protein substrates remained unaltered. Aluminum treatment did not alter the activities of cyclic AMP-dependent protein kinase or protein tyrosine kinase in the soluble and particulate fractions. The activity of Ca++/phospholipid-dependent protein kinase (protein kinase C) was increased in the particulate fraction of aluminum-fed rats. These results clearly demonstrate that specific effects on protein phosphorylation and protein kinase activities result from in vivo aluminum administration.
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PMID:Oral aluminum alters in vitro protein phosphorylation and kinase activities in rat brain. 216 94

When the synaptosomal cytosol fraction from rat brain was chromatographed on a DEAE-cellulose column and assayed for protein phosphatases for tau factor and histone H1, two peaks of activities, termed peak 1 (major) and peak 2 (minor), were separated. Each peak was in a single form 2 (minor), were separated. Each peak was in a single form on Sephacryl S-300 column chromatography. Both peaks 1 and 2 dephosphorylated tau factor phosphorylated by Ca2+/calmodulin-dependent protein kinase II and the catalytic subunit of cyclic AMP-dependent protein kinase. The Km values were in the range of 0.42-0.84 microM for tau factor. There were no differences in kinetic properties of dephosphorylation between the substrates phosphorylated by the two kinases. The phosphatase activities did not depend on Ca2+, Mn2+ and Mg2+. Immunoprecipitation and immunoblotting analysis using polyclonal antibodies to the catalytic subunit of brain protein phosphatase 2A revealed that both protein phosphatases are the holoenzymic forms of protein phosphatase 2A. Aluminum chloride inhibited the activities of both peaks 1 and 2 with IC50 values of 40-60 microM. These results suggest that dephosphorylation of tau factor in presynaptic nerve terminals is controlled mainly by protein phosphatase 2A and that the neurotoxic effect of aluminum seems to be related mostly to inhibition of dephosphorylation of tau factor.
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PMID:Dephosphorylation of tau factor by protein phosphatase 2A in synaptosomal cytosol fractions, and inhibition by aluminum. 216 75

The regulation of Cl- conductance by cytoplasmic nucleotides was investigated in pancreatic and parotid zymogen granules. Cl- conductance was assayed by measuring the rate of cation-ionophore-induced osmotic lysis of granules suspended in iso-osmotic salt solutions. Both inhibition and stimulation were observed, depending on the type and concentration of nucleotide. Under optimal conditions, the average inhibition measured in different preparations was 1.6-fold, whereas the average stimulation was 4.4-fold. ATP was inhibitory at 1-10 microM but stimulated Cl- conductance above 50 microM. Stimulation by ATP was more pronounced in granules with low endogenous Cl- conductance. The potency of nucleotides in terms of inhibition was ATP greater than adenosine 5'-[gamma-thio]triphosphate (ATP[S]) greater than UTP much greater than or equal to CTP much greater than or equal to GTP much greater than or equal to guanosine 5'-[gamma-thio]triphosphate (GTP[S]) much greater than or equal to ITP. The potency with respect to stimulation had the following order: adenosine 5'-[beta gamma-methylene]triphosphate (App[CH2]p) greater than ATP greater than guanosine 5'-[beta-thio]diphosphate (GDP[S]). Adenosine 5'-[beta gamma-imido]triphosphate (App[NH]p) was also stimulatory, and was more potent than ATP in the parotid granules, but less potent in the pancreatic granules. Aluminium fluoride stimulated Cl- conductance maximally at 15-30 microM-Al3+ and 10-15 mM-F. F was less effective at higher concentrations. Protein phosphorylation by kinases was apparently not involved, since the nucleotide effects (1) could be mimicked by non-hydrolysable analogues of ATP and GTP, (2) showed reversibility, and (3) were not abolished by the protein kinase inhibitors 1-(5-isoquinolinesulphonyl)-2-methylpiperazine (H-7) or staurosporine. The data suggest the presence of at least two binding sites for nucleotides, whereby occupancy of one induces inhibition and occupancy of the other induces stimulation.
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PMID:Dual modulation of chloride conductance by nucleotides in pancreatic and parotid zymogen granules. 226 15

The antigen receptors on B lymphocytes, membrane forms of immunoglobulins, transduce signals regulating B cell growth and differentiation by activating a phosphoinositide-specific phospholipase C. In this report, we describe our recent work aimed at understanding this process in greater detail. We have shown that a GTP-binding component is a necessary cofactor in the stimulation of phospholipase C by mIgM. This component has a number of properties in common with the G protein family of receptor-effector coupling components seen in the adenylate cyclase and other signaling systems. For example, analogues of GTP that cannot be hydrolyzed stimulated mIgM-triggered phosphoinositide breakdown, and an analogue of GDP that cannot be converted to GTP inhibited the reactions. Furthermore, aluminum fluoride, which activates known G proteins, also stimulates phosphoinositide breakdown. The G protein that appears to link mIgM to phospholipase C is not one of the well characterized G proteins involved in the regulation of adenylate cyclase or cGMP phosphodiesterase (GS, Gi, and transducin), as judged by its insensitivity to two bacterial toxins that modify these G proteins, cholera toxin and pertussis toxin. Interestingly, analysis of pertussis toxin sensitivity indicates that there are at least 2 distinct G proteins that couple receptors to phospholipase C. For example, the G protein required for chemotactic peptide receptor signaling in neutrophils is sensitive to pertussis toxin, in contrast to the phosphoinositide signaling G protein in B cells. We have also begun to explore the mechanisms by which mIgM signal transduction can be modulated. Stimulation of protein kinase C with phorbol esters or synthetic DG was found to inhibit mIgM-triggered phosphoinositide breakdown. This regulation probably represents a feedback inhibition that would occur with DG produced by phosphoinositide breakdown. Alternatively, there appear to be other signaling pathways that generate DG33, and they could possibly inhibit phosphoinositide breakdown via protein kinase C. This could be an important locus of regulation during B cell activation. For example, other signals could increase or decrease the potency of this feedback inhibition, and thereby adjust the sensitivity of the B cell to antigen. Alternatively, other agents could stimulate protein kinase C directly, or could stimulate another protein kinase which can do the same thing in this regard, and thereby make the B cell insensitive to antigen by preventing antigen receptor signaling.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Signal transduction via the B cell antigen receptor: involvement of a G protein and regulation of signaling. 255 95

Cyclic nucleotide-dependent protein phosphorylation in albino rabbit ciliary processes was studied in particulate and soluble fractions of the tissue by the technique of SDS-polyacrylamide gel electrophoresis and autoradiography. In the presence of gamma-32P-ATP, the soluble fraction showed increased phosphorylation of proteins of 200, 32 and 16 kDa molecular weight when 10 microM cAMP was added. Protein phosphorylation increased with time up to 5 min. No significant augmentation of phosphorylation was observed in the presence of 10 microM cGMP compared to control. In the particulate fraction, proteins with molecular weights of 200, 160, 105, 72, 58, 32 and 16 kDa showed increased phosphorylation in the presence of 10 microM cAMP. Phosphorylation caused by the addition of cAMP was maximal between 30 sec and 1 min for the particulate membrane fraction, but with longer incubation times the incorporation of phosphate residues decreased. The same molecular weight proteins of the membrane fraction that were phosphorylated in a cAMP-dependent manner were phosphorylated in the absence of exogenous cAMP by addition of either the catalytic subunit of cAMP-dependent protein kinase or activators of membrane-bound adenylate cyclase such as l-isoproterenol, vasoactive intestinal peptide, aluminum fluoride or forskolin. A cAMP-dependent dephosphorylation of a 56 kDa protein was observed in the membrane fraction. Cyclic GMP did not cause observable changes in the pattern of protein phosphorylation in the particulate fraction of rabbit ciliary processes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cyclic nucleotide-dependent phosphorylation of proteins in rabbit ciliary processes. 272 44

Phosphorus-31 (31P) NMR is proving to be a powerful analytical method for investigating molecular/metabolic issues in neural tissues. Recent studies have demonstrated high levels of phosphomonoesters and phosphodiesters in mammalian brain, and revealed the influence of brain maturation, development, and aging on these levels. Preliminary studies in Alzheimer's disease have demonstrated elevated levels of phosphomonoesters and phosphodiesters in the areas of Alzheimer's brain which exhibit neuropathological changes. Moreover, phosphomonoester levels were also elevated in areas of Alzheimer's brain that were devoid of neuropathological changes. These findings suggest that the phosphomonoester elevations in Alzheimer's brain antedate changes in cellular morphology and structure. Abnormalities in protein kinase function could potentially explain these findings, as well as the reported hyperphosphorylation of tau protein in Alzheimer's brain. Recent studies from this laboratory suggest that aluminum could also be involved in the changes in phosphomonoesters and phosphodiesters.
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PMID:31P nuclear magnetic resonance (NMR) spectroscopy of brain in aging and Alzheimer's disease. 331 99

Protein kinase C was identified as a major protein kinase enzyme activity in rabbit ciliary processes. Phorbol myristate acetate (4 beta-PMA) in the presence of Ca2+ activated protein kinase C but did not directly affect the cyclic AMP-dependent protein kinase enzyme isolated from ciliary processes. To elucidate possible roles of protein kinase C, PMA was injected intravitreally into rabbit eyes. Fifty pmoles of PMA produced approximately a 40% decrease of the intraocular pressure relative to the control eye lasting for more than 72 hr. A reduction of intraocular pressure was still elicited by this dose of PMA in animals pretreated with systemic indomethacin given to suppress a possible inflammatory response. The biologically inactive analogue, 4 alpha-phorbol didecanoate (100 pmoles/eye) had no significant effect on intraocular pressure. In vivo and in vitro treatment with PMA had no significant effect on adenylate cyclase in ciliary process membranes assayed in vitro. However, protein kinase C isolated from rat brain, when added together with cofactors to membranes in vitro, augmented adenylate cyclase activation by isoproterenol, vasoactive intestinal peptide and aluminum fluoride. A slight increase in the basal activity and in the forskolin response was not statistically significant. The effect of protein kinase C to increase responsiveness of ciliary process adenylate cyclase was totally dependent on the presence of Ca2+ and was augmented by addition of PMA. These findings indicate modulation of adenylate cyclase activity by protein kinase C acting at the level of the G-proteins and suggest a possible role for this enzyme in water and electrolyte transport in the ciliary processes.
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PMID:Phorbol ester: effect on intraocular pressure, adenylate cyclase, and protein kinase in the rabbit eye. 367 53

Effects of morphine and aluminum fluoride on field potentials evoked in hippocampal pyramidal cells were investigated revealing the physiological significance of adenylate cyclase in morphine action. Dibutyryl-cyclic AMP (db-cAMP) reduces the amplitude of potentials, while morphine enhances it. Morphine was without effects on db-cAMP induced reduction of potentials. Aluminum fluoride, known to activate GTP binding proteins, also reduced potentials and this was antagonized by morphine. Furthermore, N-[2-(methylamino)ethyl]-5-isoquinolinesulphonamide dihydrochloride (H-8), a protein kinase A inhibitor, enhanced potentials. When GABA synthesis was inhibited by 3-mercaptopropinoic acid, both morphine and db-cAMP was without effect. These results suggested the inhibition of adenylate cyclase by morphine which might be related with the reduction of GABA release in hippocampal slices.
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PMID:Effect of morphine on aluminium fluoride and dibutyryl-cyclic AMP induced reduction of field potentials in hippocampal slices. 759 56

Dose- and time-dependent killing of cultured rat hepatocytes was produced by aluminum maltolate (AlM), a neutral, water-soluble complex of aluminum 3-hydroxy-2-methyl-4H-pyran-4-one. Treatment with 10 mM AlM for 1 h killed 50% or more of the cells within 3 h. Removal of calcium from the culture medium or treatment with calcium channel blockers (verapamil, nifedipine, diltiazem) potentiated the cell killing. By contrast, inhibition by thapsigargin of the sequestration of intracellular calcium by the endoplasmic reticulum reduced the toxicity of AlM. In turn, activation of protein kinase C with 12-O-tetradecanoylphorbol 13-acetate or activation of protein kinase A with 8-[4-chlorophenyl-thio]adenosine 3',5'-cyclic monophosphate also reduced the toxicity of AlM. By contrast, inhibition of protein kinase activity by staurosporine potentiated the cell killing. Staurosporine, however, did not reverse the protection afforded by thapsigargin. Hepatocytes treated with AlM for 1 h were rescued by adding deferoxamine as late as 90 min following the removal of AlM, whereas pretreatment for 1 h with deferoxamine did not prevent the toxicity of AlM. ATP depletion did not precede loss of viability. Pharmacologic probes excluded oxidative stress as a mechanism of lethal injury by AlM, and inhibition of protein synthesis by cycloheximide did not protect the hepatocytes, thereby excluding activation of a cell death program. These data define a new model in which aluminum kills liver cells by a mechanisms distinct from previously recognized pathways of lethal cell injury. It is hypothesized that aluminum binds to cytoskeletal proteins intimately associated with the plasma membrane. This interaction eventually disrupts the permeability barrier function of the cell membrane, an event that heralds the death of the hepatocyte. The intracellular calcium ion concentration and protein phosphorylation may modify the interaction of aluminum with its critical targets. Alternatively, aluminum may inhibit the phosphorylation of cytoskeletal elements, thereby interfering with their function.
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PMID:The absence of extracellular calcium potentiates the killing of cultured hepatocytes by aluminum maltolate. 784 Jun 48


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