Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 14-3-3 proteins are a family of acidic proteins found mainly in the brain and are suggested to have a role in monoamine synthesis based on their ability to activate tyrosine and tryptophan hydroxylases in the presence of type II Ca2+/calmodulin-dependent protein kinase. Recently, however, it has been demonstrated that a member of the 14-3-3 family, termed Exo1, stimulates Ca(2+)-dependent exocytosis in permeabilized adrenal chromaffin cells, suggesting that this protein family may influence the protein kinase C-mediated control of Ca(2+)-dependent exocytosis. Here we show that the 14-3-3 proteins activate protein kinase C at about 2-fold more than the known level of the activated protein kinase, i.e. the activity of protein kinase C in the presence of Ca2+ and phospholipids. This raises the possibility that the cellular activity of protein kinase C is regulated by diverse members of the 14-3-3 family and that the reported ability of Exo1 to reactivate Ca(2+)-dependent exocytosis is based on its stimulatory effect on protein kinase C activity. The 14-3-3 family, therefore, appears to be a multifunctional regulator of cell signalling processes mediated by two types of Ca(2+)-dependent protein kinase, protein kinase C and type II calmodulin-dependent protein kinase.
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PMID:Activation of protein kinase C by the 14-3-3 proteins homologous with Exo1 protein that stimulates calcium-dependent exocytosis. 149 18

In many cell types an increase in cytosolic calcium is the main signal for the exocytotic release of stored secretory components such as hormones and neurotransmitters. The site of action of calcium in exocytosis is not known, neither are the participating molecules. In the case of the intracellular membrane fusions that occur during transport through early stages of the secretory pathway, several cytosolic and peripheral membrane proteins are necessary. Permeabilized cells have been useful in understanding the requirements for calcium and nucleotides in regulated exocytosis and under certain conditions there is leakage of soluble protein components and run-down of the exocytotic response. This system can be used to identify the soluble proteins involved in exocytosis, one candidate in chromaffin cells being annexin II (calpactin). Here we use this assay to identify two other cytosolic protein factors that regulate exocytosis in permeabilized adrenal chromaffin cells, which we term Exo1 and Exo2. Exo1 from brain cytosol resolves on electrophoresis in SDS-polyacrylamide gels as a group of polypeptides of relative molecular mass approximately 30,000 and shares sequence homology with the 14-3-3 family of proteins. The ability of Exo1 to reactivate exocytosis is potentiated by protein kinase C activation and therefore Exo1 may influence the protein kinase C-mediated control of Ca(2+)-dependent exocytosis.
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PMID:Exo1 and Exo2 proteins stimulate calcium-dependent exocytosis in permeabilized adrenal chromaffin cells. 153 62

We present the nucleotide sequence of a cDNA clone of mRNA encoding human 14-3-3 protein, a protein kinase-dependent activator of tyrosine and tryptophan hydroxylases and an endogenous inhibitor of protein kinase C. The 1,730-nucleotide sequence of the cloned cDNA contains 191 bp of a 5'-noncoding region, the complete 738 bp of coding region, and 801 bp of a 3'-noncoding region containing three canonical polyadenylation signals. The 14-3-3 protein eta chain cDNA encoded a polypeptide of 246 amino acids with a predicted molecular weight 28,196. The predicted amino acid sequence of human 14-3-3 protein eta was highly homologous to that of previously reported bovine and rat 14-3-3 proteins with only two amino acid differences. The sequence carries structural features as putative regions responsible for activation of tyrosine and tryptophan hydroxylases and for inhibition of Ca2+/phospholipid-dependent protein kinase C. Northern blot analysis demonstrated widespread expression of the 14-3-3 protein eta chain in cultured cell lines derived from various human tumors. These findings suggest the conservative functions of the 14-3-3 protein among species. Spot blot hybridization analysis with flow-sorted chromosomes showed that the human 14-3-3 protein eta chain gene is assigned to chromosome 22.
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PMID:cDNA cloning and chromosome assignment of the gene for human brain 14-3-3 protein eta chain. 157 11

Potent inhibitors of protein kinase C have been isolated from sheep brain by DEAE-cellulose, phenyl-Sepharose CL-4B and Mono Q anion-exchange chromatography. Analysis by one- and two-dimensional SDS/polyacrylamide gel electrophoresis showed the purified preparation to contain three bands ranging over 29-33 kDa in molecular mass, each consisting of several charge isomers with similar pI values (5.4-5.7). Peptide mapping, amino acid analysis and sequencing suggested that the proteins are related, with the possibility that some species are distinct gene products. The concentration of inhibitor proteins required for half-maximal inhibition of protein kinase C activity is 1.7 microM. Inhibitory activity could not be affected by increasing the substrate, cofactor or ATP concentration in the standard protein kinase C assay, but was abolished by heat treatment. The inhibitor preparation did not affect the binding of phorbol dibutyrate to protein kinase C and could inhibit phosphorylation over a wide range of calcium concentrations. Inhibitory activity could be removed by immunoprecipitation of the purified inhibitor proteins with polyclonal antibodies raised against synthetic peptides, the sequences corresponding to those of peptide fragments obtained from protein digests. Amino acid sequence analysis of the inhibitors confirms they are novel proteins although similarities exist with a neuronal specific protein termed 14-3-3 and the carboxy terminus of the calcium-lipid binding series (endonexin/calpactin/lipocortin).
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PMID:Protein kinase C inhibitor proteins. Purification from sheep brain and sequence similarity to lipocortins and 14-3-3 protein. 214 72

14-3-3 proteins are ubiquitous in eukaryotes associated with many fundamental functions in signal transduction pathways and cell cycle regulation. Protein kinase C comprises a large family of serine/threonine protein kinases that are involved in cell growth and differentiation. Different protein kinase C isozymes have distinct roles in signal transduction pathways; protein kinase C epsilon is of particular interest because its overexpression leads to oncogenic transformation. The 14-3-3 protein has been reported to regulate the activity of protein kinase C, although the nature of its effect is equivocal. In this study we report the differential activation of various protein kinase C isoforms by 14-3-3 zeta protein. The classical isozymes show approximately a twofold activation, protein kinase C delta shows no significant increase in activity, whereas protein kinase C epsilon, another novel isozyme, is highly activated. This activation shows strong positive cooperativity with a Hill coefficient of 6.1 +/- 0.2.
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PMID:Differential activation of PKC isozymes by 14-3-3 zeta protein. 748 74

A broad range of organisms and tissues contain 14-3-3 proteins, which have been associated with many diverse functions including critical roles in signal transduction pathways, exocytosis and cell cycle regulation. We report here the crystal structure of the human T-cell 14-3-3 isoform (tau) dimer at 2.6 A resolution. Each monomer (Mr 28K) is composed of an unusual arrangement of nine antiparallel alpha-helices organized as two structural domains. The dimer creates a large, negatively charged channel approximately 35 A broad, 35 A wide and 20 A deep. Overall, invariant residues line the interior of this channel whereas the more variable residues are distributed on the outer surface. At the base of this channel is a 16-residue segment of 14-3-3 which has been implicated in the binding of 14-3-3 to protein kinase C.
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PMID:Structure of a 14-3-3 protein and implications for coordination of multiple signalling pathways. 760 73

The 14-3-3 proteins comprise a family of highly conserved acidic proteins. Several activities have been ascribed to these proteins, including activation of tyrosine and tryptophan hydroxylases in the presence of calcium/calmodulin-dependent protein kinase II, regulation of protein kinase C, phospholipase A2 activity, stimulation of exocytosis and activation of bacterial exoenzyme S (ExoS) during ADP-ribosylation of host proteins. In addition, a plant 14-3-3 protein is present in a G-box DNA/protein-binding complex. Previously, we isolated the BMH1 gene from Saccharomyces cerevisiae encoding a putative 14-3-3 protein. Using the polymerase chain reaction method, we have isolated a second yeast gene encoding a 14-3-3 protein (BMH2). While disruption of either BMH1 or BMH2 alone had little effect, it was impossible to obtain viable cells with both genes disrupted. The cDNA encoding a plant 14-3-3 protein under the control of the inducible GAL1 promoter complemented the double disruption. Transfer of the complemented double disruptant to a medium with glucose resulted in the appearance of a high percentage of large budded cells. After prolonged incubation, these cells became enlarged with irregular buds and chains of cells defective in cell-cell separation became visible. These results suggest an essential role of the 14-3-3 proteins, possibly at a later stage of the yeast cell cycle.
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PMID:The 14-3-3 proteins encoded by the BMH1 and BMH2 genes are essential in the yeast Saccharomyces cerevisiae and can be replaced by a plant homologue. 774 48

Kidney development is a complex, little understood process based on inductive interactions and intricate epithelial and mesenchymal morphogenesis. Here, we report the use of subtractive hybridization to clone cDNAs expressed in early nephrogenesis. cDNA made from E14.5 mouse kidney was hybridized with adult mouse liver mRNA employing a technique based on labeling the driver mRNA with photoactivatable biotin and using streptavidin to remove RNA:cDNA complexes. An aliquot of the unhybridized cDNA identified several clones including three isolates that proved to be the epsilon isoform of the 14-3-3 gene family that is, among other functions, implicated in protein kinase C regulation. Northern blot analysis showed a 2.0-kb transcript widely present in mouse embryos from E7.5 onward, but, as expected from the subtractive strategy, absent in adult liver. In situ hybridization was carried out on mouse embryos aged E8.5 to E15.5. These showed that, in the E8.5 embryo, the 14-3-3 epsilon gene was expressed throughout the embryo, but that, within a day, expression was more marked in mesenchyme than elsewhere (e.g., epithelial tissue, where it was generally low), although levels in neural tissue rose again by about E12.5. This difference was maintained until E15.5 when expression levels started to drop in most tissues, with those of the nervous system, tooth, and kidney being exceptions. Perhaps the most intriguing feature of the expression pattern, however, was that, while the gene was strongly expressed in early mesenchyme, the level of expression decreased as the mesenchyme differentiated. This change was particularly noted in mesenchymal condensations that would become cartilage, bone, and myotome-derived muscle, in the presumptive muscle layer of the gut, and in the kidney. In this last case, the gene was strongly expressed in stem cells and mesenchyme, but expression levels dropped markedly as early nephrogenic condensates epithelialized. The results as a whole thus argue for the 14-3-3 epsilon isoform playing roles in neural development and in early mesenchyme, with this latter function being lost or replaced as the tissue differentiates.
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PMID:The mouse 14-3-3 epsilon isoform, a kinase regulator whose expression pattern is modulated in mesenchyme and neuronal differentiation. 775 Jun 40

The fusicoccin binding protein (FCBP) is a highly conserved plasma membrane protein present in all higher plants tested thus far. It exhibits high- and low-affinity binding for the fungal toxin fusicoccin (FC). We purified the active FCBP from a fraction highly enriched in plasma membrane by selective precipitation and anion exchange chromatography. After SDS-PAGE, the two FCBP subunits of 30 and 31 kD were detected as major bands. Amino acid sequence analysis of the 31-kD polypeptide displayed a high degree of identity with so-called 14-3-3 proteins, a class of mammalian brain proteins initially described as regulators of neurotransmitter synthesis and protein kinase C inhibitors. Thereafter, we affinity purified the 30- and 31-kD FCBP subunits, using biotinylated FC in combination with a monomeric avidin column. Immunodecoration of these 30- and 31-kD FCBP subunits with polyclonal antibodies raised against a 14-3-3 homolog from yeast confirmed the identity of the FCBP as a 14-3-3 homolog. Similar to all 14-3-3 protein homologs, the FCBP seems to exist as a dimer in native form. Thus far, the FCBP is the only 14-3-3 homolog with a receptor-like function. The conserved structure of the 14-3-3 protein family is a further indication that the FCBP plays an important role in the physiology of higher plants.
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PMID:A fusicoccin binding protein belongs to the family of 14-3-3 brain protein homologs. 782 99

The 14-3-3 family of proteins plays a role in a wide variety of cellular functions including regulation of protein kinase C and exocytosis. Using antisera specific for the N termini of 14-3-3 isoforms described previously and an additional antiserum specific for the C terminus of epsilon isoform, protease digestion of intact 14-3-3 showed that the N-terminal half of 14-3-3 (a 16 kDa fragment) was an intact, dimeric domain of the protein. Two isoforms of 14-3-3, tau and epsilon, were expressed in E. coli and their secondary structure was shown by circular dichroism to be identical to wild-type protein, and expression of N-terminally-deleted epsilon 14-3-3 protein showed that the N-terminal 26 amino acids are important for dimerization. Intact 14-3-3 is a potent inhibitor of protein kinase C, but the N-terminal domain does not inhibit PKC activity. Site-specific mutagenesis of several regions in the tau isoform of 14-3-3, including the mutation of a putative pseudosubstrate site to a potential substrate sequence, did not alter its inhibitory activity. Intact 14-3-3 proteins are phosphorylated by protein kinase C with a low stoichiometry, but truncated isoforms are phosphorylated much more efficiently by this kinase. This may imply that the proteins may adopt a different structural conformation, possibly upon binding to the membrane, which could modulate their activity. 14-3-3 proteins are found at high concentration on synaptic plasma membranes and this binding is mediated through the N-terminal 12 kDa of 14-3-3.
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PMID:Expression and structural analysis of 14-3-3 proteins. 783 70


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