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

Lysophosphatidylcholine (lysoPC) transferred from oxidatively modified low density lipoprotein (Ox-LDL) to the endothelial surface membrane has been shown to produce a selective unresponsiveness to cell surface receptor-regulated endothelium-dependent relaxation (EDR) in the rabbit aorta. To determine its mechanism we examined the effects of lysoPC on endothelial surface receptor-mediated transmembrane signals. Incubation for 1 minute with palmitoyl lysoPC (5-10 microM) decreased thrombin (Th, 2 units/ml)- or histamine (His, 0.1 mM)-stimulated inositol 1,4,5-trisphosphate (IP3) production in primary cultures of human umbilical vein endothelial cells (HUVECs). LysoPC also decreased Th- or His-induced intracellular calcium ([Ca2+]i, fura 2) elevation. Pretreatment with protein kinase C (PKC) inhibitors staurosporine (100 nM) or H-7 (50 microM) prevented the inhibitory actions of lysoPC, but HA-1004 had no effect. Incubation for 5 minutes with phorbol 12-myristate 13-acetate (PMA, 100 nM) produced the inhibitory actions on the Th- or His-induced intracellular signals, which closely mimic those exhibited by lysoPC. However, the inhibitory effect of lysoPC was lost in cells that were depleted of PKC by pretreatment for 24 hours with 100 nM PMA. Furthermore, incubation of the cells for 1 minute with lysoPC stimulated PKC activity in the membrane fraction. In organ chamber experiments with porcine coronary artery rings, pretreatment with staurosporine (20 nM) attenuated lysoPC-induced impairment of EDR in response to Th. These results indicate that lysoPC, which accumulates in Ox-LDL and atherosclerotic arterial walls, inhibits the early transmembrane signaling pathway in endothelial cells, and PKC activation could at least partially be involved in the negative regulation by lysoPC.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lysophosphatidylcholine inhibits surface receptor-mediated intracellular signals in endothelial cells by a pathway involving protein kinase C activation. 142 37

The zinc-binding properties of an endogenous protein inhibitor of protein kinase C was studied. Equilibrium gel penetration revealed that 1 mol of this protein binds 0.97 mol of zinc with a dissociation constant of 4.3 microM. The site of zinc-binding, MVVNEGSDGGQSVYHVHLHVLGGR, was identified by a multi-step process consisting of tryptic digestion, fragment isolation, transfer to nitrocellulose, and hybridization with 65ZnCl2. Binding of 65ZnCl2 to selected synthetic fragments further localized the site of interaction to the sequence QSVYHVHLHVL. This region contains 3 closely positioned histidine residues and represents a novel zinc-binding site.
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PMID:Characterization of a novel zinc binding site of protein kinase C inhibitor-1. 189 36

In the presence of extracellular Ca2+, epinephrine induces a rise in cytoplasmic Ca2+ ([Ca2+]i) that is associated with fibrinogen binding to the platelet surface, platelet aggregation, and enhancement of the thrombin-stimulated [Ca2+]i rise and protein phosphorylation. Whether the [Ca2+]i rise induced by epinephrine results from Ca2+ entry associated with fibrinogen binding to its receptor on the platelet surface, the glycoprotein (gp) IIb-IIIa complex, is unknown. To determine the importance of the occupancy of the gp IIb-IIIa receptor on platelet function after epinephrine administration, we studied the effects of two monoclonal antibodies (M-148 and 7E3) and two synthetic peptide analogues to fibrinogen (synthetic tetrapeptides Arg-Gly-Asp-Ser (RGDS) and dodecapeptide His-His-Leu-Gly-Gly-Ala-Lys-Gln-Ala-Gly-Asp-Val [gamma-(400-411)]), all of which bind to gp IIb-IIIa and inhibit fibrinogen binding and platelet aggregation on the epinephrine-induced rise in [Ca2+]i and enhancement of thrombin's phosphorylation of the 47-kDa substrate of protein kinase C (p47). None of the gp IIb-IIIa ligands significantly enhanced or inhibited the epinephrine-induced [Ca2+]i rise or its augmentation of p47 phosphorylation after thrombin administration; however, the synergistic [Ca2+]i rise that follows addition of both epinephrine and thrombin was reduced by both antibodies and both peptides. Thus ligand binding of gp IIb-IIIa does not influence the epinephrine-induced [Ca2+]i rise or its promotion of protein kinase C activation by thrombin; these events can be dissociated from the synergistic [Ca2+]i rise.
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PMID:Calcium mobilization and glycoprotein IIb-IIIa complex ligands in epinephrine-stimulated platelets. 203 81

vav is a human locus that appears to be specifically expressed in cells of hematopoietic origin regardless of their differentiation lineage. This gene was first identified as a result of its malignant activation during the course of gene transfer assays (Katzav, S., Martin-Zanca, D., and Barbacid, M. EMBO J., 8: 2283-2290, 1989). In this study, we report the isolation of complementary DNA clones containing the entire coding sequence of the mouse vav protooncogene. Antisera raised against a peptide corresponding to a predicted hydrophilic domain have allowed us to identify the product of the vav gene as a 95,000 Da protein. Analysis of the deduced amino acid sequence of p95vav revealed an amino-terminal leucine-rich region not present in the activated vav oncogene. This region consists of an amphipathic helix-loop-helix followed by a leucine zipper, a structure reminiscent of the carboxy-terminal region of myc proteins and the steroid binding domain of nuclear receptors. In vitro mutagenicity studies have indicated that removal of the amphipathic helix-loop-helix is sufficient to activate the transforming potential of human and mouse vav protooncogenes. vav proteins also possess a cysteine-rich domain whose sequence predicts the formation of two putative metal binding-like domains, Cys-X2-Cys-X13-Cys-X2-Cys and His-X2-Cys-X6-Cys-X2-His. Replacement of some of these cysteine and histidine residues completely abolished the transforming activity of vav genes. Further examination of the alignment of cysteine residues in this region revealed an alternative structure, Cys-X2-Cys-X13-Cys-X2-Cys-X7-Cys-X6-Cys, which is reminiscent of the phorbol ester binding domain of protein kinase C. A similar domain has been recently identified in a second enzyme, diacylglycerol kinase. These structural similarities, along with its expression pattern, suggest that the vav protooncogene codes for a new type of signal-transducing molecule that may play an important role in controlling hematopoiesis.
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PMID:Mechanism of activation of the vav protooncogene. 206 73

The human leukemic cell line KU-812-F is known to differentiate into mature basophil-like cells under serum-free culture conditions. In the present study, the activity of histidine decarboxylase (HDC), a histamine-forming enzyme, in KU-812-F cells was found to be high, ranging from 10 to 57 pmol/min/mg protein. The great variation in HDC activity appeared to be due to different percentages and degrees of maturity of basophil-like cells during differentiation of this cell line. The enzyme was inhibited by alpha-fluoromethylhistidine but not by carbidopa, was unable to form dopamine from L-3,4-dihydroxyphenylalanine, and had a Km value for histidine of 0.27 mM, indicating that it was HDC and not aromatic amino acid decarboxylase. The HDC activity increased 1.8-fold when the cells were stimulated by phorbol myristate acetate, which is known to activate protein kinase C, and this increase was blocked by staurosporine, a potent inhibitor of protein kinase C.
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PMID:Histidine decarboxylase in human basophilic leukemia (KU-812-F) cells. Characterization and induction by phorbol myristate acetate. 211 26

ARPP-21 (cAMP-regulated phosphoprotein, Mr = 21,000 as determined by SDS/PAGE) is a major cytosolic substrate for cAMP-stimulated protein phosphorylation in dopamine-innervated regions of rat CNS (Walaas et al., 1983c). This acidic phosphoprotein has now been identified in bovine caudate nucleus cytosol and purified to homogeneity from this source. The purification procedure involved diethylaminoethyl-cellulose chromatography, ammonium sulfate fractionation, phenyl-Sepharose CL-4B chromatography, and fast protein liquid chromatography using Mono Q anion-exchange resin. Two isoforms of ARPP-21 (ARPP-21A and ARPP-21B) were obtained, which were present in approximately equal amounts in the starting material. ARPP-21A was purified 2610-fold with a final yield of 20% and ARPP-21B was purified 2940-fold with a final yield of 21%. The purified preparations of both isoforms were judged to be homogenous by SDS/PAGE. ARPP-21A and ARPP-21B yielded identical 2-dimensional thin-layer tryptic phosphopeptide maps, identical amino acid compositions and closely related, but distinct, reverse-phase high-pressure liquid chromatograms of tryptic digests. The amino acid composition of ARPP-21 showed a high content of glutamic acid/glutamine, and no methionine, tryptophan, tyrosine, phenylalanine, or histidine. ARPP-21 was stable to heat denaturation and to 50% (vol/vol) ethanol treatment and was partially soluble at pH 2. The Mr determined for ARPP-21 by SDS/PAGE was 21,000. The Stokes radius of ARPP-21 was 26.3 A, and the sedimentation coefficient of ARPP-21 was 1.3 S; these values yield a calculated molecular mass of 13,700 Da and a frictional ratio of 1.7, indicative of an elongated tertiary structure. ARPP-21 was an excellent substrate for cAMP-dependent protein kinase and was either not phosphorylated or only poorly phosphorylated by cGMP-dependent protein kinase, calcium/calmodulin-dependent protein kinase I, calcium/calmodulin-dependent protein kinase II, casein kinase II, or protein kinase C. The purified catalytic subunit of cAMP-dependent protein kinase catalyzed the incorporation of 1.2 mol phosphate/mol purified ARPP-21. Phosphorylation occurred exclusively on seryl residues. Phospho-ARPP-21 was dephosphorylated effectively by protein phosphatase-1 or -2A, but not by protein phosphatase-2B or -2C. Rabbit polyclonal and mouse monoclonal antibodies were prepared to purified ARPP-21. These antibodies specifically immunoprecipitated ARPP-21, which was found to be highly enriched in the caudate nucleus and putamen of monkey brain.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:ARPP-21, a cyclic AMP-regulated phosphoprotein enriched in dopamine-innervated brain regions. I. Purification and characterization of the protein from bovine caudate nucleus. 253 84

A 29-residue synthetic peptide, Leu530-Leu-Tyr-Glu-Met-Leu-Ala-Gly-Gln-Ala-Pro-Phe-Glu-Gly-Glu-Asp -Glu-Asp- Glu-Leu-Phe-Gln-Ser-Ile-Met-Glu-His-Asn-Val-NH2(558), corresponding to part of the catalytic domain of protein kinase C, is a potent activator of the enzyme, with a Ka of approx. 10 microM. Activation was 59 +/- 4% of that observed with phosphatidylserine, predominantly due to an increased Vmax, partially calcium-dependent, observed with all three isoenzymes (alpha, beta, gamma), and resulted in autophosphorylation. It is proposed that the region between Gly528 and Arg583 is part of the protein substrate binding region of protein kinase C and synthetic peptide analogs of this region activate the enzyme by blocking the action of the enzyme's basic pseudosubstrate autoregulatory region.
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PMID:A synthetic peptide analog of the putative substrate-binding motif activates protein kinase C. 273 83

The activity of protein kinase C is dependent on communication between a catalytic domain and a Ca2+- and lipid-binding regulatory domain in the kinase molecule. It is shown here that acidic reaction conditions can bypass the calcium and lipid requirement in the autophosphorylation of protein kinase C. Acidic pH does not entirely deregulate the kinase, though, since only autophosphorylation is favored between pH 4 and 6 and not the phosphorylation of alternative substrate proteins. Interestingly, low pH stably activated protein kinase C: when restored to neutral pH, the autophosphorylation reaction remained independent of Ca2+ and lipid. These observations suggest that protonation of functional groups in the protein kinase C molecule, with their pKa suggestive of histidine imidazole, can produce a stable conformation where regulatory constraints on enzyme activity have been removed.
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PMID:Calcium- and lipid-independent protein kinase C autophosphorylation. Activation by low pH. 275 84

When rat basophilic leukemia (2H3) cells were stimulated by higher oligomer, the chemically cross-linked oligomers of IgE, in the presence of calcium the activity of histidine decarboxylase (HDC, L-histidine carboxylase, E.C.4.1.1.22), a histamine-forming enzyme, was increased by 1 hr, reaching maximum activity by 2 hr, and returning to the original level by 8 hr. A similar increase in enzyme activity was observed in cells treated with phorbol myristate acetate (PMA) or oleoyl-acetylglycerol (OAG), which are known activators of protein kinase C. Removal of calcium from medium abolished the increase in HDC activity in response to higher oligomer but not that induced by PMA or OAG, suggesting that the increase in HDC activity may be mediated by protein kinase C. The increase in the HDC activity probably required induction of enzyme synthesis, because it was prevented by cycloheximide.
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PMID:Induction of histidine decarboxylase of rat basophilic leukemia (2H3) cells stimulated by higher oligomeric IgE or phorbol myristate acetate. 335 61

The regulatory domain of protein kinase C contains an amino acid sequence between residues 19 and 36 that resembles a substrate phosphorylation site in its distribution of basic residue recognition determinants. The corresponding synthetic peptide (Arg19-Phe-Ala-Arg-Lys-Gly-Ala25-Leu-Arg-Gln-Lys-Asn-Val-His -Glu-Val-Lys-Asn36) acts as a potent substrate antagonist with an inhibitory constant of 147 +/- 9 nM. It is a specific inhibitor of protein kinase C and inhibits both autophosphorylation and protein substrate phosphorylation. Substitution of Ala25 with serine transforms the pseudosubstrate into a potent substrate. These results demonstrate that the conserved region of the regulatory domain (residues 19 to 36) of protein kinase C has the secondary structural features of a pseudosubstrate and may be responsible for maintaining the enzyme in the inactive form in the absence of allosteric activators such as phospholipids.
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PMID:Protein kinase C contains a pseudosubstrate prototope in its regulatory domain. 368 12


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