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)

Previous reports have shown that heparin is an inhibitor of casein kinase-2 (CK-2). It is unclear whether heparin is also an inhibitor of glycogen synthase (casein) kinase-1 (CK-1), a type 1 casein kinase. In this study it is shown that CK-1 is potently inhibited by heparin when phosvitin or calcineurin are used as substrates. With casein as a substrate, however, the kinase is insensitive to inhibition by heparin. Using phosvitin as a substrate half-maximal inhibition of CK-1 was observed with 0.14 microgram/ml heparin. Kinetic analyses indicate that at a constant concentration (0.10 mM) of ATP the Km of CK-1 for phosvitin is increased eightfold in the presence of 0.9 microgram/ml heparin; the Vmax is unchanged with or without heparin. At a constant concentration of phosvitin (4 mg/ml) heparin (0.9 microgram/ml) decreased the Vmax for ATP by 57%; the Km is unchanged with or without heparin. The inhibition of CK-1 by heparin can be reversed by KCl (greater than 100 mM). These results indicate that heparin is a potent inhibitor not only of CK-2 but also of CK-1. Hence heparin inhibition can no longer be arbitrarily used as a criterion to discriminate between these kinases.
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PMID:Inhibition of glycogen synthase (casein) kinase-1 by heparin. 282 38

The identities and quantities of calcium-binding proteins were determined in axoplasm isolated from the squid giant axon. 45Ca-binding assays on nitrocellulose filters containing axoplasm proteins separated by SDS-polyacrylamide electrophoresis revealed 4 major calcium-binding bands. These included the high-molecular-weight (Mr greater than 330 and 220 X 10(3] neurofilament proteins, an unidentified protein band that migrated around Mr 55,000, and a diverse group of proteins that migrated together around Mr 17,000. The low-molecular-weight (Mr 17,000) calcium-binding proteins could be resolved into calmodulin (ca. 120 mumol/kg axoplasm), 2 other Mr 17,000 calcium-binding proteins, and a small amount of calcineurin B. It is estimated that these calcium-binding proteins in squid axoplasm could theoretically bind about 1 mmol Ca2+/kg axoplasm. 125I-Calmodulin overlay and Western blot analyses disclosed a number of calmodulin-binding proteins in axoplasm. These included fodrin, calcineurin A, and Ca2+/CaM protein kinase II subunits.
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PMID:Identification and quantification of calcium-binding proteins in squid axoplasm. 283 94

The Ca2+/calmodulin (CaM)-dependent protein phosphatase calcineurin is rapidly phosphorylated (0.8 mol of 32PO4 per mol of 60-kDa subunit of calcineurin) by brain Ca2+/CaM-dependent protein kinase II (CaM-kinase II). This reaction requires the autophosphorylated, Ca2+-independent form of CaM-kinase II since Ca2+/CaM binding to calcineurin inhibits phosphorylation. However, the phosphorylation reaction does require Ca2+, presumably acting through the 19-kDa subunit of calcineurin. Calcineurin is a good substrate for CaM-kinase II, with a Km of 19 microM and Vmax of 2.4 mumol/min per mg. Phosphorylation of calcineurin changed its phosphatase activity with either a 2-fold increase in Km (32P-labeled myosin light chain as substrate) or a 50% decrease in Vmax (p-nitrophenyl phosphate as substrate). The phosphorylated calcineurin exhibited very slow autodephosphorylation (0.09 nmol/min per mg) but was effectively dephosphorylated by brain protein phosphatase IIA. Dephosphorylation, like phosphorylation, was blocked by high concentrations of Ca2+/CaM and stimulated by Ca2+ alone. Thus calcineurin has a regulatory phosphorylation site that is phosphorylated by the Ca2+-independent form of CaM-kinase II and blocked by high concentrations of Ca2+/CaM.
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PMID:Regulatory interactions of calmodulin-binding proteins: phosphorylation of calcineurin by autophosphorylated Ca2+/calmodulin-dependent protein kinase II. 284

The extensive enzymic dephosphorylation of neurofilaments determined the progressive loss of their capacity to interconnect in vitro into a reticulated network, measured by the formation of highly viscous gels in purified preparations of neurofilaments [Leterrier & Eyer (1987) Biochem. J. 245, 93-101]. Conversely, a cyclic AMP-dependent activation of the gelation process was obtained by phosphorylation of the neurofilament proteins by the cyclic-nucleotide-dependent protein kinase added to the preparation. These findings argue for a direct relationship between the high phosphorylation level of the neurofilament subunits and the cross-bridging of the polymers in vitro. However, a transient stimulation of the neurofilament viscosity kinetics was also observed during the early steps of dephosphorylation with acid phosphatase, which, moreover, disappeared with longer incubation times before the net inhibition was obtained. In the same way, the calmodulin-dependent brain phosphatase, calcineurin, induced a permanent activation of the phenomenon, correlated with a low dephosphorylation capacity of the neurofilament molecules. Taken together, these results suggest a functional heterogeneity of the numerous phosphate groups of the neurofilament subunits and raise the hypothesis of a highly controlled regulation of the neurofilament cross-bridging by selective phosphorylation-dephosphorylation mechanisms.
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PMID:Influence of the phosphorylation state of neurofilament proteins on the interactions between purified filaments in vitro. 284 52

Previous studies have established that casein kinase-2 (CK-2) is stimulated by polyamines. In this study it is shown that glycogen synthase (casein) kinase-1 (CK-1) can be activated similarly. Using casein as the substrate, bovine kidney CK-1 was stimulated 7-, 2-, and 0.5-fold by spermine, spermidine, and putrescine, respectively. Half-maximal activation of CK-1 by these polyamines was observed at 0.25, 0.70, and 0.50 mM, respectively. CK-1 was optimally activated by spermine at low ionic strength and low Mg2+ concentrations (1-3 mM). Using phosvitin as the substrate, CK-1 was stimulated at low concentrations (0-0.8 mM) and inhibited at higher concentrations of spermine. By contrast CK-2 was inhibited at all concentrations of spermine when phosvitin was used as substrate. Using calcineurin (not a substrate for CK-2) as a substrate, CK-1 from bovine kidney or from three rat tissues (liver, kidney, and testis) was stimulated greater than 2-fold by spermine. It is further shown that heparin inhibits CK-1 and this inhibition can be reversed by spermine. The Vmax of CK-1 for both casein and ATP is increased by spermine while the Km remains unchanged by the polyamine. These studies indicate that CK-1, like CK-2, is a heparin-inhibited and polyamine-activated protein kinase. The results also suggest that CK-1 may be activated by spermine in vivo.
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PMID:Polyamines stimulate the activity of glycogen synthase (casein) kinase-1 from bovine kidney and different rat tissues. 284 47

Nanomolar concentrations of synthetic peptides corresponding to the calmodulin-binding domain of skeletal muscle myosin light chain kinase were found to inhibit calmodulin activation of seven well-characterized calmodulin-dependent enzymes: brain 61 kDa cyclic nucleotide phosphodiesterase, brain adenylate cyclase, Bordetella pertussis adenylate cyclase, red blood cell membrane Ca++-pump ATPase, brain calmodulin-dependent protein phosphatase (calcineurin), skeletal muscle phosphorylase b kinase, and brain multifunctional Ca++ (calmodulin)-dependent protein kinase. Inhibition could be entirely overcome by the addition of excess calmodulin. Thus, the myosin light chain kinase peptides used in this study may be useful antagonists for studying calmodulin-dependent enzymes and processes.
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PMID:Synthetic peptides based on the calmodulin-binding domain of myosin light chain kinase inhibit activation of other calmodulin-dependent enzymes. 290 35

Calcineurin dephosphorylated microtubule-associated protein 2 (MAP2) and tau factor phosphorylated by cyclic AMP-dependent and Ca2+, calmodulin-dependent protein kinases from the brain. Tubulin, only phosphorylated by the Ca2+, calmodulin-dependent protein kinase, served as substrate for calcineurin. The concentrations of calmodulin required to give half-maximal activation of calcineurin were 21 and 16 nM with MAP2 and tau factor as substrates, respectively. The Km and Vmax values were in ranges of 1-3 microM and 0.4-1.7 mumol/mg/min, respectively, for MAP2 and tau factor. The Km value for tubulin was in a similar range, but the Vmax value was lower. The peptide map analysis revealed that calcineurin dephosphorylated MAP2 and tau factor universally, but not in a site-specific manner. The autophosphorylated Ca2+, calmodulin-dependent protein kinase was not dephosphorylated by calcineurin. These results suggest that calcineurin plays an important role in the functions of microtubules via dephosphorylation.
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PMID:Dephosphorylation of microtubule-associated protein 2, tau factor, and tubulin by calcineurin. 298 15

Occupancy of one of the two phenothiazine-binding sites on calmodulin does not significantly decrease the affinity of calmodulin for its target proteins; however, it does affect the ability of calmodulin to activate some enzymes. Previously we demonstrated that a covalent adduct of calmodulin with one molecule of phenothiazine (CAPP1-calmodulin) is an antagonist for the calmodulin-dependent enzymes, cAMP phosphodiesterase and myosin kinase, and a partial agonist for calcineurin. We now show that CAPP1-calmodulin is a full agonist for glycogen synthase kinase and phosphorylase kinase. Unlike phenothiazines, CAPP1-calmodulin is specific for calmodulin-regulated proteins; it has no effect on protein kinase C. With the exception of phosphorylase kinase, occupancy of two phenothiazine-binding sites completely eliminates the ability of calmodulin to activate these proteins. Thus, the study of the interaction of CAPP1-calmodulin with calmodulin target proteins demonstrates that calmodulin interacts differently with different proteins. This is confirmed by studies of the effect of calmodulin fragments, 1-77 and 78-148, on calmodulin-regulated enzymes.
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PMID:Selective effects of CAPP1-calmodulin on its target proteins. 298 45

The deinhibitor protein, responsible for the decreased sensitivity of the ATP,Mg-dependent protein phosphatase to inhibitor-1 and the modulator protein, is inactivated by cyclic AMP-dependent protein kinase and reactivated by dephosphorylation. The specificity of this reaction was tested with the ATP,Mg-dependent phosphatase in its activated or spontaneously active form, four different forms of polycation-stimulated phosphatases (PCSH, PCSM, PCSL and PCSC) and calcineurin. Only the high -Mr polycation-stimulated protein phosphatase (PCSH), but not its catalytic subunit (PCSC), shows a high degree of specificity for the deinhibitor protein. Deinhibitor phosphatase activity of PCSH is affected neither by polycations nor by Mn ions.
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PMID:Dephosphorylation of the deinhibitor protein by the PCSH protein phosphatase. 299 24

High-affinity antibodies against calmodulin (CaM)-dependent cyclic nucleotide phosphodiesterase and protein phosphatase (calcineurin) were purified and characterized. Rabbit anti-phosphodiesterase antibody did not react with other phosphodiesterases or with the regulatory subunits of cAMP-dependent protein kinase. Affinity-purified goat anti-calcineurin antibody recognized both the 61-kDa catalytic subunit and the 18-kDa Ca2+-binding subunit of the phosphatase. Neither antibody reacted with CaM, several CaM-binding proteins (calmodulin-dependent protein kinase, myosin light chain kinase, fodrin), or other cytosolic proteins from brain. The antibodies were used to compare the cellular localization of these two CaM-dependent enzymes in rat brain. Both calcineurin and phosphodiesterase were found predominantly in nerve cells; however, phosphodiesterase was restricted to very specific neuronal populations. Phosphodiesterase was prominent in the somatic cytoplasm and dendrites of regional output neurons--e.g., cerebellar Purkinje cells and hippocampal and cortical pyramidal cells. The extensive and uniform staining in the dendrites was consistent with postsynaptic localization and suggested an important function for this enzyme in neurons that integrate multiple convergent inputs. Calcineurin was present in virtually all classes of neurons, with immunoreactivity confined primarily to cell bodies. Both diffuse cytoplasmic staining and characteristic punctate staining of cell bodies were observed; the latter suggested compartmentalization of calcineurin at or near the plasma membrane. The results of this study demonstrate that calcineurin and phosphodiesterase are differentially localized in the central nervous system. Thus, the expression and compartmentalization of CaM-binding proteins may be highly regulated and specific for particular differentiated nerve cell types.
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PMID:Differential localization of calmodulin-dependent enzymes in rat brain: evidence for selective expression of cyclic nucleotide phosphodiesterase in specific neurons. 302 62


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