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)

Calcium- and calmodulin-regulated ATPase and protein kinase activities are shown to be strongly associated with brain actomyosin. Similar enzymatic activities and an invariable polypeptide profile on sodium dodecyl sulfate-polyacrylamide gel electrophoresis were obtained for brain actomyosin taken through a solubilization-precipitation cycle (1.0-0.1 M KCl), or precipitated from buffers containing 1% Triton X-100 or 10 mM EDTA and 10 mM EGTA. These data suggest a specific complex of brain actomyosin with a protein kinase similar to calmodulin-dependent kinase II, a 190-kDa calmodulin-binding protein (P190), and a calmodulin-like polypeptide. P190 was the major substrate for endogenous calcium-dependent phosphorylation. 125I-Calmodulin overlay technique revealed four major calmodulin-binding polypeptides associated with brain actomyosin: 50- and 60-kDa subunits of the calmodulin-dependent kinase II, P190, and a high molecular weight polypeptide which is probably fodrin. A fraction enriched in P190 had Ca2(+)- and calmodulin-stimulated MgATPase activity, but not myosin-like K-EDTA ATPase activity. The lack of immunological cross-reactivity between brain myosin heavy chain and P190 confirmed that they are distinct molecules.
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PMID:Calmodulin-binding proteins and calcium/calmodulin-regulated enzyme activities associated with brain actomyosin. 213 13

Studies in animal models have suggested that alterations affecting phospholamban-mediated stimulation of Ca2+ uptake by sarcoplasmic reticulum are involved in the pathophysiology of heart disease. A monoclonal antibody that binds to phospholamban and stimulates Ca2+ uptake was used to characterize phospholamban-mediated effects in human cardiac sarcoplasmic reticulum and to compare these effects in tissue from normal and failing hearts. Stimulation of Ca2+ uptake by anti-phospholamban monoclonal antibody simulated the effect of phosphorylation of phospholamban by cAMP-dependent protein kinase. Binding of anti-phospholamban antibody reduced the K0.5 of the Ca2(+)-transporting ATPase from 0.53 microM [( Ca2+]) to 0.29 microM [( Ca2+]), without affecting Vmax or nHill. At 0.2 microM Ca2+, stimulation was 1.93-fold in sarcoplasmic reticulum prepared from normal human left ventricular myocardium and 1.94-fold in sarcoplasmic reticulum prepared from the left ventricular myocardium of patients with heart failure resulting from idiopathic dilated cardiomyopathy. Stimulation of Ca2+ uptake in canine cardiac sarcoplasmic reticulum under identical conditions was 1.89-fold. Phospholamban-mediated stimulation of Ca2+ uptake in human cardiac sarcoplasmic reticulum is thus comparable in magnitude to that observed in other species and results from an increase in the apparent affinity of the Ca2(+)-transporting ATPase for Ca2+. The pathogenesis of heart failure in idiopathic dilated cardiomyopathy does not, however, appear to involve intrinsic alterations of this mechanism.
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PMID:Phospholamban-mediated stimulation of Ca2+ uptake in sarcoplasmic reticulum from normal and failing hearts. 213 70

Studies involving 32P labeling and wet ashing of isolated dynein reveal that isolated dynein contains approximately 6 mol of phosphate predominantly distributed over four polypeptides of molecular masses of 78, 76, 47, and 23 kDa. Dynein must, therefore, be phosphorylated to at least this extent in vivo. The catalytic subunit of cAMP-dependent protein kinase and an axonemal cAMP-dependent protein kinase contaminating the dynein preparation can further phosphorylate dynein in vitro. Each kinase can place up to 0.5 mol of phosphate on native dynein polypeptides of molecular masses of 78 and 34 kDa. Removal of two of the phosphates on isolated dynein by either acid or alkaline phosphatase results in a 28% decrease in the specific activity of dynein in the presence or absence of microtubules. Selective attenuation of the microtubule-activated ATPase, but not the uncoupled free dynein ATPase, would be indicative of a regulatory function of the phosphates. The in vivo regulation of the dynein ATPase by the two phosphates accessible to acid or alkaline phosphatase is therefore subject to question. Other phosphates on dynein must be examined for their effect on the microtubule-dynein cross-bridge cycle and motility before phosphorylation can definitively be established as a mode of dynein regulation.
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PMID:Phosphorylation of Tetrahymena 22 S dynein. 214 71

High affinity Ca2(+)-activated, Mg2(+)-dependent ATP-ase [Ca2+ + Mg2+)-ATPase) activities were characterized in the membrane fractions of the porcine aorta. The (Ca2+ + Mg2+)-ATPase activity, similar to those found in the plasma membranes of the erythrocyte and the heart, ie, Ca2(+)-pumping ATPase activity, was not found in the membrane fractions isolated by the conventional method. The activity, however, became apparent in a plasma membrane-enriched fraction obtained from the microsomes treated with digitonin. The enzyme activity was stimulated by a purified C-kinase and by cyclic GMP or a purified cyclic GMP-dependent protein kinase (G-kinase). In addition to the Ca2(+)-pumping ATPase which requires millimolar concentration of Mg2+ for its activity, another high affinity (Ca2+ + Mg2+)-ATPase was detected that required micromolar concentration of Mg2+ for its full activation. Cell fractionation studies suggested its localization to plasma membranes, but the biochemical characteristics of the enzyme indicated that the enzyme could not be a biochemical expression of the plasma membrane Ca2+ pump.
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PMID:Two high affinity (Ca2+ + Mg2+)-ATPases of vascular smooth muscle plasma membrane preparation. Their relation to the Ca2(+)-pumping ATPase. 214 70

The regulation of cellular growth and proliferation is perhaps the most investigated and elusive problem in cell biology and seems to be possible to solve from almost any angle of study chosen. Among the non-systemic factors that have been discussed are genetic damage, genomic control, regulation by stimulatory and inhibitory peptide factors such as EGF, chalones, and fibronectin, protein kinase activation with tyrosine phosphorylation, adenylylcyclase and cAMP, cGMP, membrane perturbations and specifically in tumours the failure of the Pasteur effect in control of glycolysis, excessive membrane ATPase activity, and excessive hydrolytic and proteolytic activities at the cell surface. This article focuses on the central role of fluxes within the plasma membrane and re-examines the possibility that changes of flux of metabolites, ions, and reducing equivalents may be the common denominator regulating cellular proliferation.
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PMID:A unifying model of the cell proliferation emphasizing plasma membrane fluxes. 214 43

Phosphorylation of the Ca2(+)-pump ATPase of cardiac sarcolemmal vesicles by exogenously added protein kinases was examined to elucidate the molecular basis for its regulation. The Ca2(+)-pump ATPase was isolated from protein kinase-treated sarcolemmal vesicles using a monoclonal antibody raised against the erythrocyte Ca2(+)-ATPase. Protein kinase C (C-kinase) was found to phosphorylate the Ca2(+)-ATPase. The stoichiometry of this phosphorylation was about 1 mol per mol of the ATPase molecule. The C-kinase activation resulted in up to twofold acceleration of Ca2+ uptake by sarcolemmal vesicles due to its effect on the affinity of the Ca2+ pump for Ca2+ in both the presence and absence of calmodulin. Both the phosphorylation and stimulation of ATPase activity by C kinase were also observed with a highly-purified Ca2(+)-ATPase preparation isolated from cardiac sarcolemma with calmodulin-Sepharose and a high salt-washing procedure. Thus, C-kinase appears to stimulate the activity of the sarcolemmal Ca2(+)-pump through its direct phosphorylation. In contrast to these results, neither cAMP-dependent protein kinase, cGMP-dependent protein kinase nor Ca2+/calmodulin-dependent protein kinase II phosphorylated the Ca2(+)-ATPase in the sarcolemmal membrane or the purified enzyme preparation, and also they exerted virtually no effect on Ca2+ uptake by sarcolemmal vesicles.
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PMID:Protein kinase-dependent phosphorylation of cardiac sarcolemmal Ca2(+)-ATPase, as studied with a specific monoclonal antibody. 214 59

Most of the currently available calmodulin (CaM) antagonists inhibit the actions of CaM by binding directly to it. These CaM-binding drugs tend to be relatively nonselective, because they inhibit the interaction of CaM with most, if not all, of its target enzymes. In order to develop more selective CaM antagonists, we synthesized covalent adducts of CaM and several drugs, including chlorpromazine (CPZ), fluphenazine-N-mustard (FNM), and phenoxybenzamine (PBZ), and examined the effects of these adducts on various CaM and Ca2(+)-dependent enzymes. One of the adducts (CPZ-CaM) selectively inhibited the CaM-induced activation of phosphodiesterase and myosin light chain kinase, without affecting the basal activity of either enzyme. The inhibition of these enzymes by CPZ-CaM was competitive with respect to CaM. CPZ-CaM did not inhibit CaM-sensitive Ca2(+)-ATPase or CaM-dependent protein kinase or the CaM-insensitive enzyme protein kinase C. The FNM-CaM and PBZ-CaM adducts did not inhibit the effects of CaM on any of the enzymes, but they selectively activated two of the enzymes; FNM-CaM slightly activated the CaM-dependent protein kinase, and PBZ-CaM slightly activated phosphodiesterase. These results show that certain covalently linked drug-CaM adducts can differentially inhibit or activate various CaM-sensitive enzymes, and they provide further evidence that it may be possible to develop new classes of CaM antagonists that are directed against the CaM recognition sites on CaM-sensitive enzymes.
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PMID:Differential inhibition of calcium-dependent and calmodulin-dependent enzymes by drug-calmodulin adducts. 214 88

ATPase activity in rat heart sarcoplasmic reticulum was stimulated in a concentration-dependent manner by both Ca2+ and Mg2+ in the complete absence of the other cation. Increasing concentrations of Mg2+ produced an apparent inhibition of the Ca2(+)-dependent ATP hydrolysis. CDTA (trans-1,2-diaminocyclo-hexane-N,N,N',N'-tetraacetate) had no effect on these responses. The results indicate the presence of a low affinity non-specific divalent cation-stimulated ATPase in rat heart sarcoplasmic reticulum. However, sarcoplasmic reticulum vesicles transported Ca2+ with a high affinity (K0.5 Ca2+ = 0.41 microM) suggesting the presence of a high affinity Ca2(+)-transporting ATPase. Calmodulin did not stimulate rat heart sarcoplasmic reticulum ATPase activity over a range of Ca2+ and Mg2+ concentrations and failed to stimulate membrane phosphorylation and Ca2+ transport into sarcoplasmic reticulum vesicles. Calmodulin antagonists trifluoperazine and compound 48/80 did not affect the ATPase activity. Catalytic subunit of cAMP-dependent protein kinase was also ineffective in stimulating the ATPase activity. These results suggest the presence of an ATPase activity in rat heart sarcoplasmic reticulum with different properties from the high affinity Ca2(+)-pumping ATPase previously characterized in dog heart and other species.
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PMID:A non-specific Ca2+ (or Mg2+)-stimulated ATPase in rat heart sarcoplasmic reticulum. 214 1

Phospholamban is the regulator of the Ca(2+)-ATPase in cardiac sarcoplasmic reticulum (SR). The mechanism of regulation appears to involve inhibition by dephosphorylated phospholamban, and phosphorylation may relieve this inhibition. Fast-twitch skeletal muscle SR does not contain phospholamban, and it is not known whether the Ca(2+)-ATPase isoform from this muscle may be also subject to regulation by phospholamban in a similar manner as the cardiac isoform. To determine this we reconstituted the skeletal isoform of the SR Ca(2+)-ATPase with phospholamban in phosphatidylcholine proteoliposomes. Inclusion of phospholamban was associated with significant inhibition of the initial rates of Ca2+ uptake at pCa 6.0, and phosphorylation of phospholamban by the catalytic subunit of cAMP-dependent protein kinase reversed the inhibitory effects on the Ca2+ pump. Similar effects of phospholamban were also observed using phosphatidylcholine:phosphatidylserine proteoliposomes, in which the Ca2+ pump was activated by the negatively charged phospholipids (24). Regulation of the Ca(2+)-ATPase appeared to involve binding with the hydrophilic portion of phospholamban, as evidenced by cross-linking experiments, using a synthetic peptide that corresponded to amino acids 1-25 of phospholamban. These findings suggest that the fast-twitch isoform of the SR Ca(2+)-ATPase may be also regulated by phospholamban, although this regulator is not expressed in fast-twitch skeletal muscles.
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PMID:Regulation of the skeletal sarcoplasmic reticulum Ca2+ pump by phospholamban in reconstituted phospholipid vesicles. 215 30

Protein kinase C (PKC) consists of a family of Ca2(+)- and phospholipid-dependent protein kinases that catalyze the transfer of the gamma-phosphate of ATP to phosphoacceptor serine or threonine residues of protein and peptide substrates. In this report, we demonstrate that purified, autophosphorylated rat brain PKC catalyzes a Ca2(+)- and phospholipid-dependent ATPase reaction, that appears to represent the bond-breaking step of its phosphotransferase reaction. The histone kinase and ATPase activities of PKC each had a Kmapp of 6 microM for ATP, and their metal ion cofactor requirements were similar. The rate of the Ca2(+)- and phospholipid-dependent PKC-catalyzed ATPase reaction was approximately 5 times slower than the rate of histone phosphorylation, but the basal rates of the PKC-catalyzed ATPase and histone kinase activities differed by less than a factor of 2. The mechanism of the ATPase reaction could entail either direct hydrolysis of ATP by water or formation of a stable phosphoenzyme (PKC-P) followed by its hydrolysis (PKC + Pi). The latter mechanism appears unlikely since [gamma-32P]ATP failed to label autophosphorylated PKC. Furthermore, the PKC preparation did not contain contaminating protein phosphatases, excluding the possibility that the ATPase activity represented dephosphorylation of contaminating PKC substrates. Therefore, our results suggest that water may effectively compete with protein substrates of PKC for the gamma-phosphate of ATP. Using PKC inhibitors and activators, we found that the ATPase and protein kinase activities of PKC were regulated analogously, providing evidence that allosteric activation of PKC involves facilitation of the bond-breaking step of the phosphotransferase reaction.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of a Ca2(+)- and phospholipid-dependent ATPase reaction catalyzed by rat brain protein kinase C. 216 79


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