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)

Phosphorylation of membrane components is thought to be an important process in membrane function. Phosphorylated proteins and a special class of phospholipids, the (poly)phosphoinositides (poly PI), are implicated in the regulation of membrane permeability and synaptic transmission in neurones. For many years, protein phosphorylation and poly PI metabolism have been studied in parallel without knowledge of their possible interaction. We report here that the ACTH-sensitive protein kinase/B-50 protein complex which we recently isolated in soluble form from rat brain synaptosomal plasma membranes has lipid phosphorylating activity. Exogenously added phosphatidylinositol 4-phosphate (DPI) is phosphorylated to phosphatidylinositol 4,5-diphosphate (TPI), and this DPI-kinase activity is dependent on the state of phosphorylation of the protein kinase/B-50 protein complex. The results imply that phosphorylation of protein may affect the metabolism of (poly) PI in brain cell membranes.
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PMID:Modulation of brain polyphosphoinositide metabolism by ACTH-sensitive protein phosphorylation. 625 80

Brain membranes contain several protein kinases, all of which appear to play a role in the regulation of neuronal functioning. These membranes also contain numerous (phospho) proteins. It has been proposed that the degree of phosphorylation of some of these proteins may affect neuronal membrane properties. In a series of previous reports we showed that ACTH1--24 inhibits the endogenous phosphorylation of several synaptosomal plasma membrane (SPM) proteins including the B-50 protein. Although we have speculated that the degree of phosphorylation of B-50 may be important in regulating the turnover of membrane (poly)-phosphoinositides, the exact nature of the interaction between ACTH1--24 and B-50/B-50 protein kinase is unknown. The purpose of the present study was to determine whether treatment of SPM with ACTH1--24 will lead to a specific release of proteins from SPM. We found that ACTH1--24 specifically releases a 41,000 Mr protein from rat brain SPM. Although we are not certain about the biological significance of the release of this polypeptide, it is of sufficient interest for further research in view of the lack of success of finding binding of labeled ACTh to brain membranes.
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PMID:ACTH1--24 releases a protein from synaptosomal plasma membranes. 627 86

It has been hypothesized that changes in the phosphorylation of synaptic membrane constituents (proteins and lipids) may affect transmission in certain types of synapses. In this paper some of the recent evidence that neuropeptides like ACTH may bring about their behavioral activity by influencing brain protein and lipid phosphorylation is reviewed. An ACTH-sensitive, cAMP-independent protein kinase was isolated from rat brain synaptosomal plasma membranes. This enzyme was partially characterized and it was observed that its activity greatly depended on the presence of calcium ions. One of its substrate proteins B-50 (MW 48,000; IEP 4.5) may play a key role in the turnover of a special class of membrane phospholipids i.e. the (poly)phosphoinositides. Evidence was obtained to suggest that the degree of phosphorylation of the B-50 protein determines the conversion of diphosphoinositol to triphosphoinositol. A model which links the protein phosphorylation to lipid phosphorylation and which points to a functional role for peptides in the regulation of the permeability of brain membranes for calcium ions will be discussed. As the structure-activity relationship for the peptide effects on grooming behavior closely resembles that on phosphorylation, it is assumed that this neurochemical event may indeed be of relevance to the biological activity of the peptide. As the ion permeability may be altered by the peptide it can be suggested that this may lead to modulation of transynaptic information processing in the brain.
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PMID:ACTH and brain membrane phosphorylation: a model for modulation by neuropeptides. 628 75

Affinity-purified anti-B-50 protein antibodies were used to study the previously proposed relationship of the phosphorylation state of B-50 protein and polyphosphoinositide metabolism in synaptic plasma membranes. Antibodies were raised against a membrane extract enriched in the B-50 protein and its adrenocorticotropin-sensitive protein kinase, obtained from rat brain. Anti-B-50 protein immunoglobulins were purified by affinity chromatography on a solid immunosorbent prepared from B-50 protein isolated by an improved procedure. The purified antibodies reacted only with the B-50 and B-60 protein, a proteolysis derivative (of B-50), as assessed by the sodium dodecyl sulfate-gel immunoperoxidase method. These antibodies inhibited specifically the endogenous phosphorylation of B-50 protein in synaptic plasma membranes, without affecting notably the phosphorylation of other membrane proteins. This inhibition was accompanied by changes of the formation of phosphatidylinositol 4,5-diphosphate and phosphatidic acid in synaptic plasma membranes, whereas formation of phosphatidylinositol 4-phosphate was not altered. Inhibition by ACTH 1-24 of the endogenous phosphorylation of B-50 protein in membranes was associated only with an enhancement of the phosphorylation of phosphatidyl-inositol 4-phosphate to phosphatidylinositol 4,5-diphosphate. These data support our hypothesis on the functional interaction of B-50 protein and phosphatidylinositol 4-phosphate kinase in rat brain membranes. The evidence shows that purified anti-B-50 protein antibodies can be used to probe specifically the function of B-50 protein in membranes.
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PMID:Affinity-purified anti-B-50 protein antibody: interference with the function of the phosphoprotein B-50 in synaptic plasma membranes. 630 57

B-50 is a brain-specific phosphoprotein, the phosphorylation state of which may play a role in the regulation of (poly)phosphoinositide metabolism. Several kinases were tested for their ability to phosphorylate purified B-50 protein. Only calcium-activated, phospholipid-dependent protein kinase (kinase C) and B-50 protein kinase were able to use B-50 protein as a substrate. Furthermore, kinase C specifically phosphorylates B-50 when added to synaptic plasma membranes. We further characterized the sensitivity of kinase C and B-50 kinase to ACTH (and various fragments), phospholipids, chlorpromazine, and proteolytic activation. Since the sensitivities of both kinases were similar, we conclude that B-50 protein kinase is a calcium-dependent, phospholipid-stimulated protein kinase of the same type as kinase C.
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PMID:Phosphorylation of B-50 protein by calcium-activated, phospholipid-dependent protein kinase and B-50 protein kinase. 630 67

Insulin action on [32P]-phosphate incorporation into brain membranes was determined. Hippocampal homogenate tissue was phosphorylated with [32P]-ATP, and insulin was introduced at various times before or after ATP addition. With 50 microM Mg++ in the medium, insulin selectively stimulated the phosphorylation of a 47kD phosphoprotein, Protein F1. This effect required the prior presence of ATP. No effect of insulin on other phosphoproteins, or on [32P]-phosphate incorporation into TCA-precipitated material, was observed under these conditions. At 1 mM Mg++, insulin selectively decreased the phosphorylation of the alpha-subunit of pyruvate dehydrogenase. Insulin had no effect on other phosphoproteins, or on [32P]-phosphate incorporation into TCA-precipitated material under these conditions. The present study suggests a role for insulin in the modulation of brain protein phosphorylation. Since Protein F1 is phosphorylated by exogenous C kinase, and is likely the CNS-specific B-50 protein, these data also indicate a brain-specific function for insulin, possibly by action on a Ca++/phospholipid protein kinase.
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PMID:Brain protein phosphorylation in vitro: selective substrate action of insulin. 638 12

Protein phosphorylation represents a key process by which neuronal function is regulated by first messengers interacting with extracellular membrane receptors. Protein kinases transfer the phosphate group from ATP to neuron specific proteins and phosphatases, catalyzing the removal of the phosphate group, shut off the signal by restoring the reactive form of the protein. These phosphorylation processes seem to be particularly important in long-term changes which follow sustained activation of neurons. Particular importance has been given to the Calcium/phospholipid-dependent protein kinase (PKC) as the molecular mechanism in synaptic plasticity associated with learning and memory. We have studied the changes of PKC activity in an animal model of impaired cognitive functions as a consequence of an exposure during embryonic life to an antimitotic agent, methylazoxy-methanol acetate (MAM). Treatment at gestational day (GD) 15 results in offspring showing a dose-dependent reduction in the size of cortex and hippocampus. When adult, these animals show impairments in several tests for learning and memory. In hippocampal slice preparations from MAM-treated rats, Long-Term Potentiation could not be induced in the CA1 region, the area affected by the treatment. However, in the hippocampal dentate gyrus, an area not affected by the treatment, LTP could be induced. Moreover, these animals show area-specific changes in the phosphorylation state of the protein B-50/GAP-43, a well characterized neuron specific substrate for PKC. By changing the time of MAM exposure, i.e. at GD19, a different pattern of brain damage occurs and this results both in a different pattern in behavior and B-50 phosphorylation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Synaptic protein phosphorylation changes in animals exposed to neurotoxicants during development. 785 86

The aim of the present study was to characterize the second messenger activated protein kinase and phosphatase systems in chick ciliary ganglion using biochemical and immunochemical techniques. Using synthetic peptide substrates cyclic-AMP-, cyclic-GMP-, Ca2+/calmodulin- and Ca2+/phospholipid-dependent protein kinase activities were detected in homogenates of ciliary ganglion dissected from 15-16-day-old embryos. Autophosphorylation of the alpha and beta subunits of Ca2+/calmodulin-dependent protein kinase II in the presence of Ca2+/calmodulin or 5 mM ZnSO4 was detected by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and autoradiography. Protein kinase C was shown to be present using a monoclonal antibody. Two cyclic-AMP binding proteins whose molecular weights corresponded to the regulatory subunits of cyclic AMP-dependent protein kinase (RI and RII) were detected in ciliary ganglia using 8-azido-cyclic-AMP. The most heavily labelled band following incubation with [gamma-32P]ATP under most conditions had an apparent molecular weight of 65,000 which corresponds to the chicken form of myristoylated alanine-rich C kinase substrate, a known substrate of protein kinase C. Another substrate for protein kinase C was a 45,000 molecular weight protein which was tentatively identified as neuromodulin (B-50/GAP-43). Although no endogenous substrate proteins for cyclic-GMP-dependent protein kinase were detected, protein kinase A strongly labelled a 40,000 molecular weight protein. Using 32P(i)-labelled glycogen phosphorylase, protein phosphatases 1 and 2A were identified in ciliary ganglia homogenates at levels which were indistinguishable from forebrain at the same age. The major endogenous protein substrates in ciliary ganglion homogenates from 15-16-day-old embryos were also labelled to a similar extent in homogenates of ciliary ganglia from newly hatched chickens. Intact ciliary ganglia remained viable for several hours after dissection and, after incubation with 32P(i), responded to phorbol ester stimulation by an increased endogenous phosphorylation of several proteins, but especially myristoylated alanine-rich C kinase substrate. These results represent the first systematic characterization of the protein phosphorylation systems in chicken ciliary ganglion and provide a basis for future studies on the biochemical mechanisms responsible for regulating synaptic transmission in this tissue.
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PMID:Characterization of protein kinase and phosphatase systems in chick ciliary ganglion. 884 61

B-50/GAP-43 is a growth-associated phosphoprotein enriched in growth cones and in the presynaptic terminal. The expression of the protein is restricted to the nervous system and is highest in the first week after birth. In adult brain, B-50 is enriched in areas with high plasticity. The regulation of expression of the B-50 gene occurs both at the transcriptional and post-transcriptional level by unknown mechanisms. The gene contains 2 regions displaying promoter activity, the most 3' of which (P2) is the active on in vivo. Expression of B-50 in non-neuronal cells results in filopodial extensions whereas antibodies or antisense oligo's to B-50 prevent neurite outgrowth. The protein is important for neuronal pathfinding. Several post-translational modifications have been described, ADP-ribosylation and palmitoylation in the membrane binding domain, phosphorylation by PKC, casein kinase II and phosphorylase kinase, and dephosphorylation by several phosphatases, among which is calcineurin. Interactions of B-50 have been described with calmodulin, PIP kinase, F-actin, and phospholipids. Recent studies indicate that the phosphorylation state and amount of calmodulin bound to B-50 regulate the rate of transmitter release. Induction of long-term potentiation by high frequency stimulation of hippocampal slices results in an increased state of B-50 phosphorylation. This will increase the amount of free calmodulin in the presynaptic terminal and increase the amount of transmitter released. Although B-50 is involved in seemingly unrelated forms of neuronal plasticity, neurite outgrowth and transmitter release, our unifying hypothesis is that the protein plays an (unknown) essential, modulatory role in membrane expansion.
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PMID:Presynaptic phosphoprotein B-50/GAP-43 in neuronal and synaptic plasticity. 886 78

Growth-associated phosphoprotein B-50 is a neural protein kinase C (PKC) substrate enriched in nerve growth cones that has been implicated in growth cone plasticity. Here we investigated whether B-50 is a physiological substrate for casein kinase II (CKII) in purified rat cortical growth cone preparations. Using site-specific proteolysis and known modulators of PKC, in combination with immunoprecipitation, mass spectrometry, and phosphoamino acid analysis, we demonstrate that endogenous growth cone B-50 is phosphorylated at multiple sites, on both serine and threonine residues. Consistent with previous reports, stimulation of PKC activity increased the phosphorylation of only those proteolytic fragments containing Ser41. Under basal conditions, however, phosphorylation was predominantly associated with fragments not containing Ser41. Mass spectrometry of tryptic digests of B-50, which had been immunoprecipitated from untreated growth cones, revealed that in situ phosphorylation occurs within peptides B-50(181-198) and B-50(82-98). These peptides contain the major and minor in vitro CKII phosphosites, respectively. In addition, cyanogen bromide digestion of immunoprecipitated chick B-50 generated a 4-kDa C-terminal B-50 phosphopeptide, confirming that phosphorylation of the CKII domain occurs across evolutionary diverse species. We conclude that B-50 in growth cones is not only a substrate for PKC, but also for CKII.
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PMID:Phosphorylation of the casein kinase II domain of B-50 (GAP-43) in rat cortical growth cones. 934 68


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