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 proteolytic processing of the beta-amyloid precursor protein (APP) is regulated by neurotransmitters. Stimulation of metabotropic glutamate receptors (mGluRs) has been shown to increase the release of soluble amyloid precursor protein derivatives (APPs) from cultured cells. We examined the effects of mGluR agonists on APP processing in cortical and hippocampal slices from rat brain. Incubation of the slices in the presence of L-glutamic acid (500 microM), trans-(1S,3R)-1-amino-1,3-cyclopentane dicarboxylic acid (1-100 microM) or quisqualic acid (1-100 microM) increased APP release into the medium, relative to the amount of APPs released during incubation in normal Krebs-Ringer buffer under basal conditions. N-Methyl-D-aspartate (1-320 microM), (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (1-100 microM) or kainic acid (5-500 microM) did not alter APP release. The increases in APP release induced by L-glutamic acid (500 microM), trans-(1S,3R)-1-amino-1,3-cyclopentane dicarboxylic acid (10 microM) or quisqualic acid (10 microM) were blocked by 100 microM (+/-)-alpha-methyl-4-carboxyphenylglycine, a selective antagonist of mGluRs. Incubation of the slices in the presence of 1 microM phorbol-12-myrisate-13-acetate, an activator of protein kinase C (PKC), also increased APP release, and an inhibitor of PKC, GF-109203X (1 microM), blocked this response as well as the release evoked by mGluR agonists. These data show that activation of mGluR increases APP release from brain slices via PKC-dependent mechanisms.
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PMID:Metabotropic glutamate receptor agonists increase release of soluble amyloid precursor protein derivatives from rat brain cortical and hippocampal slices. 910 92

Expression of the beta-amyloid precursor protein (beta-APP), a proteoglycan whose proteolytically derived fragments have been implicated in the neuropathology observed in Alzheimer's disease, is regulated by a variety of stimuli including cytokines, phorbol esters, and growth factors. In this study we report the effects of basic fibroblast growth factor (bFGF) and the protein kinase C activator, phorbol 12-myristate 13-acetate (PMA), on beta-APP expression and secretion in SKNMC human neuroblastoma cells. Treatment of the cells with bFGF for 24 h increased APP promoter activity 200%, cell-associated full-length protein 189%, and secreted amino-terminal fragments 192% compared to basal levels. Treatment of the cells with PMA for 24 h also up-regulated APP expression and secretion with increases of 170, 112, and 161% being observed for promoter activity, cell-associated full-length protein, and secreted amino-terminal fragments, respectively. The effects of bFGF and PMA on the expression and secretion of beta-APP were additive and distinct in that: (a) co-treatment of the cells with maximally stimulating doses of bFGF and PMA had an additive effect on both induced full-length protein expression (242%) and secretion of amino-terminal fragments (311%) compared to basal levels; (b) net levels of full-length protein expression and secretion induced by bFGF and PMA differed significantly from each other; and (c) down-regulation of phorbol ester-stimulated protein kinase C by pre-treatment of the cells for 24 h with 1 microM PMA failed to attenuate bFGF-induced transcription or induced secretion of beta-APP.
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PMID:Additive effects of basic fibroblast growth factor and phorbol ester on beta-amyloid precursor protein expression and secretion. 910 63

Neurotransmitter receptors that increase phosphatidylinositol hydrolysis generate second messengers that activate protein kinase C. Here, we used metabotropic glutamate receptor agonists to increase both phosphatidylinositol hydrolysis and secretion of the soluble extracellular fragment of amyloid precursor protein (APPs) from cortical astrocyte cultures. The increase in APPs secretion was mimicked by direct activation of protein kinase C with phorbol ester and was suppressed by the metabotropic glutamate receptor antagonist L-(+)-2-amino-3-phosphonopropionic acid or by the protein kinase C inhibitor GF109203X. Ionotropic glutamate agonists did not increase APPs secretion. Forskolin or dibutyryl cyclic AMP inhibited the increase in APPs secretion caused by metabotropic glutamate receptor agonists or by phorbol ester treatment but did not affect basal APPs levels. Therefore, glutamatergic agonists that increase protein kinase C activation or decrease cyclic AMP formation may enhance the conversion of full-length APP to nonamyloidogenic APPs in Alzheimer's disease.
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PMID:Metabotropic glutamate receptors increase amyloid precursor protein processing in astrocytes: inhibition by cyclic AMP. 910 7

Amyloid precursor-like proteins (APLPs), APLP1 and APLP2, are members of a gene family which include the Alzheimer beta-amyloid precursor protein (APP). APLP1, APLP2, and APP contain highly homologous amino acid sequences, especially in their cytoplasmic domains, although APLPs lack the beta-amyloid domain derived by proteolytic processing from APP. APP is phosphorylated at three sites in the cytoplasmic domain in cultured cells and adult rat brain [Suzuki et al. (1994) EMBO J. 13, 1114-1122; Oishi, et al. (1997) Mol. Med. 3, 109-121] and at sites in the extracellular domain in cultured cells [Knops et al. (1993) Biochem. Biophys. Res. Commun. 197, 380-385; Hung & Selkoe (1994) EMBO J. 13, 534-542; Walter et al. (1997) J. Biol. Chem. 272, 1896-1903]. We report here that a cytoplasmic domain peptide from APLP1 is phosphorylated in vitro by protein kinase C and that a cytoplasmic domain peptide from APLP2 is phosphorylated in vitro by protein kinase C and cdc2 kinase. APLP2 is phosphorylated by cdc2 kinase at a site homologous to the cdc2 kinase site phosphorylated in APP. Furthermore, phosphorylation of this site occurs in a cell cycle-dependent manner in cultured cells. These findings indicate that in intact cells the phosphorylation of APLP2 appears to be regulated in a similar fashion to that of APP.
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PMID:Phosphorylation of Alzheimer beta-amyloid precursor-like proteins. 910 75

Amyloid plaques in Alzheimer disease are primarily aggregates of Abeta peptides that are derived from the amyloid precursor protein (APP). Neurotransmitter agonists that activate phosphatidylinositol hydrolysis and protein kinase C stimulate APP processing and generate soluble, non-amyloidogenic APP (APPs). Elevations in cAMP oppose this stimulatory effect and lead to the accumulation of cell-associated APP holoprotein containing amyloidogenic Abeta peptides. We now report that cAMP signaling can also increase cellular levels of APP holoprotein by stimulating APP gene expression in astrocytes. Treatment of astrocytes with norepinephrine or isoproterenol for 24 h increased both APP mRNA and holoprotein levels, and these increases were blocked by the beta-adrenergic antagonist propranolol. Treatment with 8-bromo-adenosine 3',5'-cyclic monophosphate or forskolin for 24 h similarly increased APP holoprotein levels; astrocytes were also transformed into process-bearing cells expressing increased amounts of glial fibrillary acidic protein, suggesting that these cells resemble reactive astrocytes. The increases in APP mRNA and holoprotein in astrocytes caused by cAMP stimulation were inhibited by the immunosuppressant cyclosporin A. Our study suggests that APP overexpression by reactive astrocytes during neuronal injury may contribute to Alzheimer disease neuropathology, and that immunosuppressants can inhibit cAMP activation of APP gene transcription.
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PMID:Stimulation of amyloid precursor protein synthesis by adrenergic receptors coupled to cAMP formation. 914 53

Although regulated ectodomain shedding is a well known process that affects a large group of transmembrane molecules, it is not clear how the shedding system selects its substrates. Here we investigate the structural requirements for the regulated shedding of two substrates of the general shedding system, the transforming growth factor-alpha precursor, pro-TGF-alpha, and the beta-amyloid precursor protein, beta-APP. The ability of different regions of pro-TGF-alpha or beta-APP to confer susceptibility to the shedding system was tested using as a reporter a transmembrane molecule that is not a substrate of this shedding system. For this purpose we chose the TGF-beta accessory receptor, betaglycan, since genetic and biochemical evidence showed that betaglycan is not a substrate of the shedding system. We determined that replacement of the 14 extracellular amino acids adjacent to the transmembrane region of betaglycan with the corresponding regions of TGF-alpha or beta-APP rendered betaglycan susceptible to ectodomain shedding. These domain swap constructs were cleaved in response to protein kinase C stimulation, and cleavage was prevented by the metalloprotease inhibitor TAPI, both effects being characteristic of the general shedding system. Domain swap constructs containing the transmembrane and/or the cytoplasmic domains of pro-TGF-alpha did not undergo regulated ectodomain cleavage. We conclude that despite a lack of sequence similarity, the extracellular regions of pro-TGF-alpha and beta-APP immediately preceding their transmembrane domains are key determinants of ectodomain shedding.
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PMID:Role of the juxtamembrane domains of the transforming growth factor-alpha precursor and the beta-amyloid precursor protein in regulated ectodomain shedding. 920 36

Diverse membrane proteins are solubilized by a specific proteolytic cleavage in the stalk sequence adjacent to the membrane anchor, with release of the extracellular domain. Examples are the amyloid precursor protein, membrane-bound growth factors and angiotensin-converting enzyme (ACE). The identities and characteristics of the responsible proteases remain elusive. We have studied this process in Chinese hamster ovary (CHO) cells stably expressing wild-type ACE (WT-ACE) or juxtamembrane (stalk) deletion or chimaera mutants. Determination of the C termini (i.e. the cleavage sites) of released, soluble wild-type and mutant ACE by MALDI-TOF mass spectrometry indicated that the membrane-protein-solubilizing protease (MPSP) in CHO cells is not constrained by a particular cleavage site motif or by a specific distance from the membrane, but instead may position itself with respect to the putative proximal, folded extracellular domain adjacent to the stalk. Nevertheless, kinetic analyses of release rates indicated that a minimum distance from the membrane must be preserved. Interestingly, soluble full-length (anchor-plus) WT-ACE incubated with fractions of, or intact, CHO cells was not cleaved. In all cases, release was stimulated by a media change or by the addition of phorbol ester, with rate enhancements of 5- and 50-fold, respectively, for WT-ACE. The phorbol ester effect was abolished by staurosporine, a protein kinase C (PKC) inhibitor. We propose that the CHO cell MPSP that solubilizes ACE: (1) only cleaves proteins embedded in a membrane; (2) requires an accessible stalk and cleaves at a minimum distance from both the membrane and proximal extracellular domain; (3) positions itself primarily with respect to the proximal extracellular domain and (4) is regulated in part by a PKC-dependent mechanism.
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PMID:Proteolytic release of membrane proteins: studies on a membrane-protein-solubilizing activity in CHO cells. 922 57

There is mounting evidence indicating that overexpression or aberrant processing of amyloid precursor protein (betaAPP) is causally related to Alzheimer's disease. betaAPP is principally cleaved within the amyloid beta protein domain to release a large soluble ectodomain (betaAPPs) that has been known to have a wide range of trophic and protective functions. Activation of phospholipase C-coupled receptors has been shown to increase the release of betaAPPs through protein kinase C and calcium. Here we have examined whether nicotine can modulate the expression and processing of betaAPP in PC12 cells. Treatment of PC12 cells with nicotine increased the release of a carboxyl-terminally truncated, secreted form of betaAPP into the conditioned medium without affecting the expression level of betaAPP mRNA. The effect of nicotine on the secretion of betaAPPs is concentration (>50 microM)- and time (>2 hr)-dependent and attenuated by cotreatment with either mecamylamine, a specific nicotinic receptor antagonist, or EGTA, a calcium chelator, indicating calcium entry through the neuronal nicotinic acetylcholine receptor is essential in enhanced betaAPPs release by nicotine. However, nicotine did not significantly change the amyloid beta protein secretion from Swedish mutant betaAPP-transfected PC12 cells. These results imply that nicotinic receptor agonist might be beneficial in the treatment of Alzheimer's disease by not only supplementing the deficient cholinergic neurotransmission but also stimulating the release of betaAPPs.
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PMID:Enhanced release of secreted form of Alzheimer's amyloid precursor protein from PC12 cells by nicotine. 928 5

The amyloid precursor protein (APP) of Alzheimer's disease is a transmembrane protein that is cleaved by an uncharacterized enzyme known as alpha-secretase within its extracellular/intraluminal domain after the activation of guanine nucleotide-binding protein-coupled receptors linked to phosphoinositide hydrolysis. The secretory process results in the release of large soluble derivatives of APP (APPs), and, when elicited by muscarinic receptor activation, exhibits both protein kinase C (PKC)-dependent and tyrosine phosphorylation-dependent components [Slack, Breu, Petryniak, Srivastava and Wurtman (1995) J. Biol. Chem. 270, 8337-8344]. In this report we examine the regulation of the release of APPs by epidermal growth factor (EGF) receptors, which possess intrinsic tyrosine kinase activity, and are coupled to a variety of effectors including phosphoinositide-specific phospholipase Cgamma. In A431 cells, EGF caused time-dependent and dose-dependent increases in the formation of inositol phosphates in cultures prelabelled with myo--3H-inositol, and in the release of APPs into the culture medium; the two responses exhibited similar time courses and EC50 values for EGF. Concomitant with these effects, there were concentration-dependent (3-300 ng/ml) increases in the phosphorylation of tyrosine residues in several proteins, including the EGF receptor itself. The specific PKC antagonist GF 109203X decreased the effect of EGF by approx. 35% at a concentration that abolished the stimulation of the release of APPs by the PKC activator PMA. Tyrphostin AG 1478, an inhibitor of EGF receptor tyrosine kinase, abolished the EGF-induced release of APPs. These results demonstrate that in A431 cells, activation of the EGF receptor stimulates alpha-secretase activity by a mechanism that is partly dependent on PKC activity.
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PMID:Rapid stimulation of amyloid precursor protein release by epidermal growth factor: role of protein kinase C. 935 59

Alzheimer's beta-amyloid peptide (A beta) is normally present at nanomolar concentrations in body fluids and in the medium of cultured cells. In vitro experiments have shown that A beta has neurotrophic effects and can promote neuronal adhesion and elongation of axon-like processes. In an attempt to understand the molecular mechanisms underlying such effects, we have recently reported that nanomolar doses of A beta can stimulate protein tyrosine phosphorylation and activate phosphatidylinositol-3-kinase in neuronal cells. Here we show evidence that A beta can also activate protein kinase C, a serine/threonine kinase, in PC12 cells. First, using a serine-containing S6 peptide as an exogenous substrate, we found that nanomolar levels of A beta peptides 1-40 or 1-42 significantly stimulated an S6 phosphorylating kinase activity, whereas the A beta40-1 reverse sequence peptide had no effect. Down-regulation of PKC by prolonged (18 h) treatment with 1 microM PMA prevented the A beta-induced S6 phosphorylation. Using a more specific PKC substrate, N-terminal acetylated peptide (4-14) from myelin basic protein, we then demonstrated that A beta indeed increased PKC activity and that this activity could be blocked by the PKC inhibitor, staurosporine. Finally, immunoblotting experiments showed that A beta induced translocation of PKCgamma from cytosol to membrane and also significantly reduced cytosolic PKCalpha levels. Taken together, these data suggest that physiological levels of A beta can regulate PKC activity.
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PMID:Physiological levels of beta-amyloid peptide stimulate protein kinase C in PC12 cells. 937 97


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