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 39-43 residue polypeptide (amyloid beta protein, beta A4) deposited as amyloid in Alzheimer's disease (AD) is derived from a set of 695-770 residue precursors referred to as the amyloid beta A4 protein precursor (beta APP). In each of the 695, 751, and 770 residue precursors, the 43 residue beta A4 is an internal peptide that begins 99 residues from the COOH-terminus of the beta APP. Each holoform is normally cleaved within the beta A4 to produce a large secreted derivative as well as a small membrane associated fragment. Neither of these derivatives can produce amyloid because neither contains the entire beta A4 peptide. In this study, we employ cells stably transfected with full length beta APP695, beta APP751, or beta APP770 expression constructs to show that phorbol ester activation of protein kinase C substantially increases the production of secreted forms from each isoform. By increasing processing of beta APP in the secretory pathway, PKC phosphorylation may help to prevent amyloid deposition.
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PMID:Secretory processing of the Alzheimer amyloid beta/A4 protein precursor is increased by protein phosphorylation. 141 5

There is ample evidence for the involvement of aberrant protein phosphorylation reactions in aging and age-associated neurological disorders. Alzheimer's disease (AD) in particular. The exact nature of this involvement, however, is not yet elucidated. In the brain tissue of AD patients, there are numerous examples of altered protein phosphorylation pathways. Individual protein kinases and phosphorylation by these kinases in AD brain tissues have been found to be altered. Protein kinases studied include protein kinase C (PKC), protein tyrosine kinase (PTK), casein kinase II (CKII), Ca++/calmodulin-dependent kinase II and mitogen-activated protein (MAP) kinases, all of which are thought to be necessary for cell survival. Interestingly, different protein kinases are involved in different aspects of AD pathology. It is postulated that the perturbation of amyloid beta/A4-protein precursor (APP) metabolism triggers abnormal protein phosphorylation reactions responsible for dysfunction and eventual death of neurons in the brain. The association of APP mutation with certain familial types of AD strongly suggests that there might be a link between aberrant APP metabolism, protein phosphorylation cascades and the eventual expression of AD pathology (plaques and tangles) and neurodegeneration. In summary, recent studies emphasise the prime importance of protein phosphorylation in aging and AD. This raises the possibility that future pharmacological interventions might be devised to interfere with this kinase cascade for the prevention or treatment of age-associated neurological disorders.
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PMID:Changes in protein kinases in brain aging and Alzheimer's disease. Implications for drug therapy. 771 60

The beta-amyloid precursor protein (beta APP) is a widely expressed integral membrane protein that is proteolytically processed to yield several secreted derivatives, including soluble APP (APPs), the 4-kDa amyloid beta-peptide (A beta), and a related 3-kDa peptide (p3). To understand beta APP trafficking and processing, we analyzed the sorting of beta APP in Madin-Darby canine kidney (MDCK) cells, an epithelial cell known to possess physiologically distinct apical and basolateral plasma membranes. Processing of beta APP resulted in highly polarized secretion of APPs. More than 90% of APPs was detected in the basolateral compartment, and less than 10% was found in the apical compartment. This was associated with a preferential localization of beta APP on the basolateral cell surface. Activation of protein kinase C, which is known to enhance the secretion of APPs, did not change the polarity of APPs release but significantly increased the amount secreted. A beta and p3 peptides were also secreted predominantly basolaterally. In addition, MDCK cells secreted a truncated form of A beta beginning at Arg-5. These data show that the proteolytic processing products of beta APP undergo polarized secretion. Moreover, the results suggest that the amyloidogenic A beta peptide is generated following the polarized sorting of beta APP. The polarized basolateral secretion of A beta in these epithelial cells provides a potential mechanism for the accumulation of A beta in the abluminal basement membrane of brain microvessels during Alzheimer disease.
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PMID:Polarized secretion of beta-amyloid precursor protein and amyloid beta-peptide in MDCK cells. 810 45

In order to explore the effect of aberrant sprouting in the CNS, phorbol 12-myristate 13-acetate (PMA) was administered into the neocortex of adult rats. PMA is a growth-promoting agent that activates and eventually downregulates protein kinase C (PKC), and induces in the rat the expression of several genes, including amyloid precursor protein (APP). We found that multiple injections of 100 nM PMA into the rat neocortex promote, in the first week postinjection, a widespread vacuolization of the neuropil with a subsequent disruption of the synapses in the injection site, followed, at d 15, by the formation of abnormally distended clusters of neurites that resembled aberrant, sprouting axons. At d 30, fewer aberrant sprouts were observed, and many degenerating neurites were found. At the ultrastructural level, the PMA-induced abnormal neurites at d 7-15 resembled growth cones, whereas the dystrophic neurites at d 30 contained abundant dense and laminated bodies. Immunohistochemical analysis indicated that the abnormal neurites in the areas of denervation and PMA administration were positive with antisynaptophysin and antigrowth-associated protein 43 (GAP-43), with an increased APP immunoreactivity surrounding them. APP immunoreactivity around the injection site was mostly associated with pyramidal neurons and glial cells. Control experiments, where saline alone or 4 alpha-phorbol 12, 13-didecanoate (PDD, an inactive phorbol derivative) was injected, failed to show aberrant sprouting neurites. Further immunohistochemical analysis showed that the PMA-treated animals presented increased amyloid beta immunoreactivity in the pyramidal cells at the site of injection, when compared with control injections. These findings suggest that aberrant sprouting induced by overstimulation could be followed by neurodegeneration. Alternatively, PKC downregulation could directly induce the neurodegeneration, with a secondary sprouting response.
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PMID:Phorbol ester-induced neuritic alterations in the rat neocortex. Structural and immunocytochemical studies. 829 18

The beta-amyloid precursor protein (beta APP) is a highly conserved integral membrane protein expressed in most mammalian tissues and found at highest levels in the nervous system. Cerebral deposition of the amyloid beta-peptide (A beta), derived by proteolysis of beta APP, is an early and invariant feature of Alzheimer's disease. Protein phosphorylation by protein kinase C (PKC) has been found to regulate the metabolism of beta APP into nonamyloidogenic and amyloidogenic derivatives, but both the mechanism of these effects and the nature of beta APP phosphorylation are unknown. When labeled in vivo with [32P]orthophosphate, beta APP was phosphorylated only on serine residues in the N-terminal half of the extracellular domain, resulting in the secretion of phosphorylated soluble beta APP. PKC-mediated stimulation of beta APP secretion and concurrent inhibition of A beta release did not involve enhanced phosphorylation of beta APP and proceeded in the absence of cytoplasmic or extracellular phosphorylation of the precursor. The region of beta APP required for this indirect regulation by PKC was largely restricted to a 64 amino acid stretch around the secretory cleavage site. Moreover, in a truncated molecule designed to release soluble beta APP without the need for proteolytic cleavage, secretion was no longer regulated by PKC. Our data indicate that PKC-mediated pathways play a pivotal role in the control of beta APP metabolism and amyloid formation. However, in contrast to current postulates, this regulation is independent of beta APP phosphorylation and instead involves phosphorylation of other substrates that alter beta APP processing, such as beta APP-cleaving proteases.
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PMID:Selective ectodomain phosphorylation and regulated cleavage of beta-amyloid precursor protein. 831 98

Alzheimer's disease amyloid consists of amyloid beta-peptides (Abeta) derived from the larger precursor amyloid precursor protein (APP). Non-amyloidogenic APP processing involves regulated cleavage within the Abeta domain followed by secretion of the ectodomain (APPs). APPs secretion can be stimulated by muscarinic acetylcholine receptors coupled to phospholipases and kinases. To determine whether other receptor classes can regulate APP processing, we examined the relation between serotonin receptors and APPs secretion. Serotonin increased APPs release 3-4-fold in 3T3 cells stably overexpressing 5-HT2aR or 5-HT2cR. The increase was dose-dependent and was blocked by serotoninergic antagonists. Phorbol esters also increased APPs secretion, but neither kinase inhibitors nor down-regulation of PKC blocked the serotonin-induced increase in APPs secretion. Thus PKC is not necessary to stimulate APPs secretion. Phospholipase A2 (PLA2) inhibitors blocked the 5-HT2aR-mediated increase in APPs secretion, suggesting a role of PLA2 in coupling 5-HT2aR to APP processing. In contrast, coupling of 5-HT2cR to APPs secretion involved both PKC and PLA2. Serotonin also stimulated the release of the APLP2 ectodomain, suggesting that additional members of the APP multigene family are processed via similar regulated pathways. Inasmuch as generation of APPs precludes the formation of amyloidogenic derivatives, serotonin receptors provide a novel pharmacological target to reduce these derivatives in Alzheimer's disease.
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PMID:Serotonin 5-HT2a and 5-HT2c receptors stimulate amyloid precursor protein ectodomain secretion. 862 61

alpha-Secretase cleaves the full-length Alzheimer's amyloid precursor protein (APP) within the amyloid beta peptide sequence, thus precluding amyloid formation. The resultant soluble truncated APP is constitutively secreted. This nonamyloidogenic processing of APP is increased on stimulation of the phospholipase C/protein kinase C pathway by phorbol esters. Here we used C6 cells transfected with APP751 to examine whether the alpha-secretase cleavage is regulated by the adenylate cyclase signal transduction pathway. Forskolin, an activator of adenylate cyclase, inhibited both the constitutive and phorbol ester-stimulated secretion of nexin II (NXII), the secreted product of the alpha-secretase cleavage of APP751. At 1 microM, forskolin inhibited secretion of NXII by approximately 50% without affecting either the intracellular levels of total APP or the secretion of secretory alkaline phosphatase. In contrast, 1,9-dideoxyforskolin, an inactive analogue of forskolin, did not affect secretion of NXII. These results indicated that forskolin specifically inhibited the alpha-secretase cleavage of APP751. Forskolin treatment increased the intracellular concentration of cyclic AMP (cAMP), suggesting that the forskolin effects on APP cleavage may be mediated by cAMP. In support of this suggestion, both dibutyryl cAMP, a cAMP analogue, and isoproterenol, an activator of adenylate cyclase, also inhibited secretion of NXII. These data indicate that forskolin inhibition of the nonamyloidogenic cleavage of APP is mediated by the second messenger cAMP, which together with the protein kinase C signal transduction pathway modulates the secretory cleavage of APP.
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PMID:Intracellular cyclic AMP inhibits constitutive and phorbol ester-stimulated secretory cleavage of amyloid precursor protein. 876 18

Conventional secretory processing of the amyloid precursor protein is nonamyloidogenic, releasing carboxyl-terminus-truncated amyloid precursor protein derivatives while cleaving the amyloid beta-peptide within its sequence. Alternative processing routes are potentially amyloidogenic, yielding the amyloid beta-peptide segment intact. In continuous cell lines, secretory processing of the amyloid precursor protein is regulated by both protein kinase C and muscarinic receptor stimulation. However, the first and second messenger systems that regulate amyloid precursor protein release in central neurons are still under investigation. In the present investigation, we examined whether or not first and second messengers of cholinergic neurotransmission increase production of soluble derivatives of the amyloid precursor protein in primary cultures of rat cortical neurons. Activation of protein kinase C by the phorbol esters phorbol 12,13-dibutyrate and phorbol 12-myristate 13-acetate increased production of the soluble form of the amyloid precursor protein dramatically. In contrast, activation of muscarinic receptors by oxotremorine-M or carbachol did not result in a significant increase in amyloid precursor protein release. Similarly, chemically induced depolarization using 35 mM KCl did not alter production of soluble amyloid precursor protein derivatives. Our data suggest that although protein kinase C stimulation plays an important role in regulating release of the amyloid precursor protein, cholinergic neurotransmission does not regulate its release in cultured rat cortical neurons.
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PMID:Phorbol esters but not the cholinergic agonists oxotremorine-M and carbachol increase release of the amyloid precursor protein in cultured rat cortical neurons. 885 34

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

Activation of protein kinase C (PKC) regulates the processing of Alzheimer amyloid precursor protein (APP) into its soluble form (sAPP) and amyloid beta-peptide (A beta). However, little is known about the intermediate steps between PKC activation and modulation of APP metabolism. Using a specific inhibitor of mitogen-activated protein (MAP) kinase kinase activation (PD 98059), as well as a dominant negative mutant of MAP kinase kinase, we show in various cell lines that stimulation of PKC by phorbol ester rapidly induces sAPP secretion through a mechanism involving activation of the MAP kinase cascade. In PC12-M1 cells, activation of MAP kinase by nerve growth factor was associated with stimulation of sAPP release. Conversely, M1 muscarinic receptor stimulation, which is known to act in part through a PKC-independent pathway, increased sAPP secretion mainly through a MAP kinase-independent pathway. A beta secretion and its regulation by PKC were not affected by PD 98059, supporting the concept of distinct secretory pathways for A beta and sAPP formation.
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PMID:Regulation of secretion of Alzheimer amyloid precursor protein by the mitogen-activated protein kinase cascade. 945 46


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