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)

Phorbol esters, activators of protein kinase C (PKC), regulate the relative utilization of alternative processing pathways for the Alzheimer beta-amyloid precursor protein (beta-APP) in intact cells, increasing the production of nonamyloidogenic soluble beta-APP (s beta-APP) and decreasing that of neurotoxic beta-amyloid (A beta) peptide. The molecular and cellular bases of PKC-regulated beta-APP cleavage are poorly understood. Here we demonstrate in a reconstituted cell-free system that activation of endogenous PKC increases formation from the trans-Golgi network of secretory vesicles containing beta-APP and that this effect can be mimicked by purified PKC. The results demonstrate directly that PKC is involved in regulation of secretory vesicle formation and provide a mechanism by which PKC may reduce the formation of the A beta peptide characteristic of Alzheimer disease.
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PMID:Regulated formation of Golgi secretory vesicles containing Alzheimer beta-amyloid precursor protein. 755 74

The powerful regulatory machinery of protein phosphorylation operates in the extracellular environment of the brain. Enzymatic activity with the catalytic specificity of protein kinase C (PKC) was detected on the surface of brain neurons, where it can serve as a direct target for neurotrophic and neurotoxic substances that control neuronal development and cause neurodegeneration. This activity fulfilled all the criteria required of an ecto-protein kinase (ecto-PK). Detailed analysis of surface protein phosphorylation in cultured brain neurons using specific exogenous substrates (casein, histones, and myelin basic protein), inhibitors (PKC-pseudosubstrate 19-36; K252b) and antibodies (anti-PKC catalytic region M.Ab.1.9, antibodies to the carboxy-terminus of eight PKC isozymes) revealed several types of ecto-PK activity, among them ecto-PKs with catalytic specificity of the PKC isozymes zeta and delta. The activity of the neuronal ecto-PKC is constitutive and not stimulated by phorbol esters. the phosphorylation of a 12K/13K surface protein duplex by ecto-PKC-delta was found to be developmentally regulated, with peak activity occurring during the onset of neuritogenesis. Alzheimer's amyloid peptides beta 1-40 and beta 25-35 applied at neurotrophic concentrations stimulated the phosphorylation of endogenous substrates of ecto-PKC activity in brain neurons but inhibited specifically this surface phosphorylation activity with the same dose-response relationships that cause neurodegeneration. As may be expected from a relevant pathophysiological activity, beta-amyloid peptide 1-28 did not inhibit this surface phosphorylation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Surface phosphorylation by ecto-protein kinase C in brain neurons: a target for Alzheimer's beta-amyloid peptides. 759 86

Stimulation of muscarinic m1 or m3 receptors can, by generating diacylglycerol and activating protein kinase C, accelerate the breakdown of the amyloid precursor protein (APP) to form soluble, nonamyloidogenic derivatives (APPs), as previously shown. This relationship has been demonstrated in human glioma and neuroblastoma cells, as well as in transfected human embryonic kidney 293 cells and PC-12 cells. We now provide evidence that stimulation of metabotropic glutamate receptors (mGluRs), which also are coupled to phosphatidylinositol 4,5-bisphosphate hydrolysis, similarly accelerates processing of APP into nonamyloidogenic APPs. This process is demonstrated both in hippocampal neurons derived from fetal rats and in human embryonic kidney 293 cells transfected with cDNA expression constructs encoding the mGluR 1 alpha subtype. In hippocampal neurons, both an mGluR antagonist, L-(+)-2-amino-3-phosphonopropionic acid, and an inhibitor of protein kinase C, GF 109203X, blocked the APPs release evoked by glutamate receptor stimulation. Ionotropic glutamate agonists, N-methyl-D-aspartate or S(-)-5-fluorowillardiine, failed to affect APPs release. These data show that selective mGluR agonists that initiate signal-transduction events can regulate APP processing in bona fide primary neurons and transfected cells. As glutamatergic neurons in the cortex and hippocampus are damaged in Alzheimer disease, amyloid production in these regions may be enhanced by deficits in glutamatergic neurotransmission.
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PMID:Amyloid precursor protein processing is stimulated by metabotropic glutamate receptors. 764 42

The functionally selective M1 agonist xanomeline, which is currently undergoing clinical trials as a therapy for Alzheimer's disease, was compared to the muscarinic agonist carbachol for effects on secretion of soluble amyloid precursor protein (APPs) from Chinese hamster ovary cells transfected with the human m1 receptor (CHO-m1). Release of APPs from CHO-m1 cells was increased maximally (4-10 fold) by 100 microM carbachol (EC50 = 11 microM) and by 100 nM xanomeline (EC50 = 10 nM). Stimulation of APPs secretion by xanomeline and carbachol was blocked by preincubation with 1 microM atropine. Carbachol did not stimulate APPs secretion from non-transfected CHO cells. Pilocarpine at 1 mM also increased APPs release. The efficacy of carbachol, xanomeline and pilocarpine for stimulating APPs secretion did not differ significantly. Activation of protein kinase C (PKC) in m1 transfected cell lines by 1 microM phorbol dibutyrate (PDBu) increased APPs release, and this was inhibited 97% by the PKC inhibitor bisindolemalemide. The PKC inhibitor decreased xanomeline and carbachol-stimulated APPs secretion by only 25-30%. These results demonstrate that xanomeline increased APPs release by activation of m1 muscarinic receptors and support the possibility that cholinergic replacement therapy for Alzheimer's Disease may reduce amyloid deposition.
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PMID:The muscarinic M1 agonist xanomeline increases soluble amyloid precursor protein release from Chinese hamster ovary-m1 cells. 767 7

Stimulation of m1 and m3 muscarinic acetylcholine receptors, which are coupled to phosphoinositide hydrolysis and protein kinase C activation, has been shown to increase the release of soluble amyloid precursor protein derivatives (APPs). The effect is mimicked by phorbol esters, which directly activate protein kinase C. Using human embryonic kidney cells expressing individual muscarinic receptor subtypes, we found that stimulation of APPs release by the muscarinic agonist carbachol was only partially reduced by a specific inhibitor of protein kinase C (the bisindolylmaleimide GF 109203X), while the response to phorbol 12-myristate 13-acetate (PMA) was abolished. The increase in APPs release elicited by carbachol and PMA was accompanied by elevated tyrosine phosphorylation of several proteins and reduced by tyrosine kinase inhibitors; GF 109203X significantly reduced the stimulation of tyrosine phosphorylation by carbachol and PMA. Inhibition of protein tyrosine phosphatases by vanadyl hydroperoxide markedly increased cellular tyrosine phosphorylation and enhanced APPs release as effectively as PMA and carbachol. Direct phosphorylation of amyloid precursor protein on tyrosine residues following treatment with carbachol, PMA, or vanadyl hydroperoxide was not observed. The results implicate both tyrosine phosphorylation and protein kinase C-dependent mechanisms in the regulation of APPs release by G protein-coupled receptors, and suggest that carbachol and PMA increase APPs release from human embryonic kidney cells expressing m3 muscarinic receptors via partially divergent pathways that converge at a tyrosine phosphorylation-dependent step.
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PMID:Tyrosine phosphorylation-dependent stimulation of amyloid precursor protein secretion by the m3 muscarinic acetylcholine receptor. 771 42

A large soluble N-terminal fragment of Alzheimer's disease amyloid precursor protein (secreted form of APP: APPs) is produced by constitutive processing in the middle of the amyloid beta-protein portion of APP. Recent studies indicate that the activation of endogenous protein kinase C (PKC) with phorbol ester raises the rate of secretion of APPs. We constructed rat fibroblast 3Y1 cells that stably overexpress PKC isoenzymes alpha, delta, or epsilon, and analyzed the amount of APPs released from these PKC transfectants. The levels of APPs released from 3Y1 cells overexpressing PKC alpha and -epsilon were higher than those from PKC delta-transfected and control cells expressing vector only. These results suggest that specific isoforms of PKC regulate the secretion of APPs through a signaling pathway.
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PMID:Conventional protein kinase C (PKC)-alpha and novel PKC epsilon, but not -delta, increase the secretion of an N-terminal fragment of Alzheimer's disease amyloid precursor protein from PKC cDNA transfected 3Y1 fibroblasts. 775 May 71

We studied in vivo expression and in vitro secretion of the Alzheimer's disease amyloid precursor protein (APP). The results indicate that secretion of APP is mediated by PKC and the initial step of the processing may occur in the acidic secretory granules of the glial cells. Our results suggest that a metabolic switch of APP in neural cells is critical in amyloid deposition.
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PMID:Processing and secretion of Alzheimer's disease amyloid precursor protein. 776 86

The amyloid precursor protein (APP) undergoes abnormal metabolism in Alzheimer's disease, resulting in the accumulation of beta A4 amyloid in the brain. Normal APP metabolism includes the release of a truncated form (sAPP) which has been cleaved at the alpha-secretase site within the beta A4 amyloidogenic domain. However, intact forms of beta A4 protein may also be generated by the beta- and gamma-secretases. Soluble forms of beta A4 have been detected in various cell lines and in cerebrospinal fluid. Previous studies of protein kinase C activation have suggested a reciprocal relationship between sAPP secretion and beta A4 production and release. We find that phorbol ester activation of protein kinase C in untransfected SH-SY5Y neuroblastoma cells increases the release of sAPP without affecting beta A4 secretion. We provide further evidence for intracellular beta A4 production. Treatment of SY5Y cells with the protease inhibitor phosphoramidon results in a 2-fold increase in beta A4 secretion and an increase in the amount of beta A4 recovered from cell lysates, yet it does not affect sAPP secretion. The protease inhibitors thiorphan and N-[(RS)-2-carboxy-3-phenylpropanoyl]-L-leucine had no effect on beta A4 or sAPP secretion. The lysosomotropic agents chloroquine and NH4Cl decreased beta A4 secretion, providing additional evidence for the involvement of intracellular acidic compartments in the production of beta A4. Our results therefore demonstrate a double dissociation between the secretion of sAPP and beta A4 in the SH-SY5Y cell line. The effect of phosphoramidon supports previous studies which show that metalloproteases are involved in the biogenesis of beta A4.
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PMID:Intracellular production of beta A4 amyloid of Alzheimer's disease: modulation by phosphoramidon and lack of coupling to the secretion of the amyloid precursor protein. 779 22

Cleavage and release of membrane protein ectodomains, a regulated process that affects many cell surface proteins, remains largely uncharacterized. To investigate whether cell surface proteins are cleaved through a shared mechanism or through multiple independent mechanisms, we mutagenized Chinese hamster ovary (CHO) cells and selected clones that were unable to cleave membrane-anchored transforming growth factor alpha (TGF-alpha). The defect in TGF-alpha cleavage in these clones is most apparent upon cell treatment with the protein kinase C (PKC) activator PMA, which stimulates TGF-alpha cleavage in wild-type cells. The mutant clones do not have defects in TFG-alpha expression, transport to the cell surface or turnover. Concomitant with the loss of TGF-alpha cleavage, these clones have lost the ability to cleave many structurally unrelated membrane proteins in response to PMA. These proteins include beta-amyloid precursor protein (beta-APP), whose cleavage into a secreted form avoids conversion into the amyloidogenic peptide A beta, and a group of cell surface proteins whose release into the medium is stimulated by PMA in wild type CHO cells but not in mutants. The mutations prevent cleavage by PKC-dependent as well as PKC-independent mechanisms, and thus affect an essential component that functions downstream of these various signaling mechanisms. We propose that regulated cleavage and secretion of membrane protein ectodomains is mediated by a common system whose components respond to multiple activators and act on susceptible proteins of diverse structure and function.
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PMID:Transforming growth factor-alpha and beta-amyloid precursor protein share a secretory mechanism. 784 56

beta A4 is the principal component of Alzheimer's disease brain amyloid. It is derived from proteolytic processing of amyloid beta-protein precursors (APP), a family of transmembrane glycoproteins. Secretion of APPs, a secreted proteolytic derivative that is cleaved within the beta A4 domain of APP, is increased many-fold by the activation of cell-surface receptors, like the muscarinic m1 and m3 receptor subtypes, which are coupled to protein kinase C. Concomitantly, their activation decreases the formation of both secreted soluble beta A4 and of endosomal-lysosomal C-terminal APP derivatives. These data suggest that muscarinic m1 and m3 receptors accelerate non-amyloidogenic APP processing and depress the formation of potentially amyloidogenic derivatives. Other receptors that stimulate APPs secretion include those for bradykinin, vasopressin, and interleukin-1 receptors. A similar control mechanism is present in rat brain tissue slices, in which the release of both APPs and endogenous neurotransmitters is increased by electrical depolarization. This increase is tetrodotoxin-sensitive and frequency-dependent, suggesting that APPs release may normally depend on neuronal activity. Taken together, our findings suggest that specific receptor agonists might be effective in reducing the formation of potentially amyloidogenic APP derivatives in vivo.
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PMID:Regulation of proteolytic processing of the amyloid beta-protein precursor of Alzheimer's disease in transfected cell lines and in brain slices. 789 93


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