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 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

Release of large soluble NH2-terminal fragments of the amyloid precursor protein (APP) of Alzheimer's disease was measured in two Swiss 3T3 fibroblast cell lines (designated SF1.4 and SF3.2), overexpressing the alpha subtype of protein kinase C, and in two control cell lines (SC1 and SC2) (Eldar, H., Zisman, Y., Ullrich, A., and Livneh, E. (1990) J. Biol. Chem. 265, 13290-13296). Basal release of APP was significantly increased in SF1.4 cells, but not in SF3.2 cells, relative to controls. Phorbol 12-myristate 13-acetate, an activator of protein kinase C, elicited a concentration-dependent increase in APP release in all four cell lines. However, the estimated EC50 for this effect was lower in the two cell lines overexpressing protein kinase C-alpha (7 and 6 nM, in SF1.4 and SF3.2 cells, respectively) than in control SC1 and SC2 cells (56 and 22 nM, respectively). The absolute amount of APP released by maximal concentrations of phorbol ester was not altered by overexpression of protein kinase C alpha. The protein kinase C inhibitor H-7 (1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride) significantly reduced the response to phorbol esters in control (SC1) cells but not in cells (SF1.4) that overexpress protein kinase C alpha. Levels of cell-associated APP were slightly elevated, and rates of APP turnover were unchanged, in SF1.4 cells relative to controls. However, cell-associated APP levels were lower in SF3.2 cells than in controls. The results demonstrate that protein kinase C alpha regulates APP release in Swiss 3T3 fibroblasts, and perhaps in other tissues, including brain, and may be the isozyme that mediates receptor-evoked release of APP.
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PMID:Regulation by phorbol esters of amyloid precursor protein release from Swiss 3T3 fibroblasts overexpressing protein kinase C alpha. 840 46

The major component of amyloid plaque cores and cerebrovascular amyloid deposits found in Alzheimer disease is the beta/A4 peptide, which is derived from the Alzheimer amyloid protein precursor (APP). Recent evidence suggests that abnormalities in beta/A4 peptide production or beta/A4 peptide aggregation may underlie cerebral amyloidosis. In the present study, treatment of cells with phorbol dibutyrate, which activates protein kinase C, and/or okadaic acid, which inhibits protein phosphatases 1 and 2A, reduced beta/A4 peptide production by 50-80%. These effects were observed with APP695 and APP751 expressed in stably transfected CHO cells, as well as with endogenous APP in human glioma (Hs 683) cells. Phorbol dibutyrate also decreased beta/A4 peptide production in cells expressing various mutant forms of APP associated with familial Alzheimer disease, one of which was reported to manifest greatly increased beta/A4 peptide production in cultured cells. Mastoparan and mastoparan X, compounds which can activate phospholipase C and hence protein kinase C, also decreased beta/A4 peptide production in CHO cells stably transfected with APP695. A model is presented in which decreases in beta/A4 peptide production can be achieved by accelerating the metabolism of APP through a nonamyloidgenic secretory pathway.
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PMID:Protein phosphorylation inhibits production of Alzheimer amyloid beta/A4 peptide. 841 76

The present study shows that cultured fibroblasts from sporadic AD patients present: a) reduced (-30%) cytosolic protein kinase C (PKC) activity; b) increased KD of phorbol ester binding (+94%) in cytosolic fractions; c) reduced (-30%) soluble protein kinase C alpha immunoreactivity; d) lower (-27.5%) basal soluble APP secretion and e) reduced soluble APP secretion in response to low phorbol ester concentrations (over threefold difference using 9 nM phorbol-12,13-dibutyrate-PdBu). Since the PKC-stimulated secretion of APP leads to the cleavage of the precursor within the amyloidogenic beta-A4 fragment, the reduced PKC activity in AD patients may lead to accumulation of potentially amyloidogenic or toxic APP fragments. A defect in the secretion of soluble amyloid beta-protein precursor is indeed suggested by literature data on familial AD fibroblasts as well as by the reported results.
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PMID:Defective protein kinase C alpha leads to impaired secretion of soluble beta-amyloid precursor protein from Alzheimer's disease fibroblasts. 862 9

It has previously been shown that stimulation of muscarinic m1 or m3 receptors can, by generating diacylglycerol (DAG) and activating protein kinase C (PKC), accelerate the breakdown of the amyloid precursor protein (APP) to form soluble, non-amyloidogenic peptides (APPs). This relationship has been demonstrated in human glioma and neuroblastoma cells as well as in transfected human embryonic kidney (HEK) cells and PC12 cells. We now provide evidence that stimulation of metabotropic glutamate receptors (mGluRs), which also are coupled to DAG and PKC, similarly accelerates processing of APP into non-amyloidogenic APPs in hippocampal neurons and cortical astrocytes derived from normal fetal rats. The mGluR antagonist, L(+)-2-amino-3-phosphonopropionic acid (L-AP3), and GF 109203X, an inhibitor of PKC, both blocked the release of APPs from hippocampal neurons and astrocytes evoked by glutamate receptor stimulation. Inasmuch as glutamatergic neurons in cortex and hippocampus are known to be damaged in Alzheimer's disease, our findings suggest that amyloid formation may be enhanced by the resulting glutamate deficiency and that selective mGluR agonists may be useful in facilitating synaptic efficacy and treating the disease.
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PMID:Metabotropic glutamate receptors regulate APP processing in hippocampal neurons and cortical astrocytes derived from fetal rats. 862 10

The extracellular domains of a diverse group of membrane proteins are shed in response to protein kinase C activators such as phorbol 12-myristate 13-acetate (PMA). The lack of sequence similarity in the cleavage sites suggests the involvement of many proteases of diverse specificity in this process. However, a mutant Chinese hamster ovary cell line recently isolated for being defective in PMA-activated shedding of the membrane-anchored growth factor transforming growth factor alpha precursor (proTGF-alpha) is concomitantly defective in the shedding of many other unrelated membrane proteins. Here we show that independent mutagenesis and selection experiments yield shedding mutants having the same recessive phenotype and belonging to the same genetic complementation group. Furthermore, two structurally distinct agents, TAPI-2 and 1,10-phenanthroline, which are known to inhibit metalloproteases, block PMA-activated shedding of proTGF-alpha, cell adhesion receptor L-selectin, interleukin 6 receptor alpha subunit, beta-amyloid precursor protein, and an entire set of anonymous Chinese hamster ovary cell surface proteins. Certain serine protease inhibitors prevent release of these proteins by interfering with their maturation and transport to the cell surface but do not inhibit ectodomain shedding from the cell surface. The results suggest the existence of a common system for membrane protein ectodomain shedding involving one or several proteolytic activities sensitive to metalloprotease inhibitors, whose ability to act can be disrupted by recessive mutations in a single gene.
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PMID:Diverse cell surface protein ectodomains are shed by a system sensitive to metalloprotease inhibitors. 862 92

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

We have previously reported that a group of isoquinolinesulfonamide kinase inhibitors (H7, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine; H8, N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide; and H9, N-2-(aminoethyl)-5-isoquinolinesulfonamide) prevents apoptosis triggered in neurons by an inhibition of phosphatases 1 and 2A with okadaic acid, and by inhibition of protein kinase C with staurosporine and chelerythrine. In the present study we assessed the capability of isoquinolinesulfonamides (IQS) to prevent different types of apoptosis in primary cultures of cerebellar granule neurons. We induced apoptosis by: a) serum removal, b) potassium deficiency, c) serum removal + potassium deficiency, and d) beta-amyloid peptide (beta AP). The IQS prevented apoptosis in all the above models. Thus, it appears that the IQS-sensitive pathway is a common mechanism in different types of neuronal apoptosis, and that it might be used as a target in the development of novel neuroprotective drugs.
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PMID:Protective action of isoquinolinesulfonamides in in vitro models of neuronal apoptosis. 863 93

Various compounds that affect signal transduction regulate the relative utilization of alternative processing pathways for the beta-amyloid precursor protein (beta APP) in intact cells, increasing the production of nonamyloidogenic soluble beta APP (s beta APP) and decreasing that of amyloidogenic beta-amyloid peptide. In a recent study directed toward elucidating the mechanisms underlying phorbol ester-stimulated s beta APP secretion from cells, it was demonstrated that protein kinase C increases the formation from the trans-Golgi network (TGN) of beta APP-containing secretory vesicles. Here we present evidence that forskolin increases s beta APP production from intact PC12 cells, and protein kinase A stimulates formation from the TGN of beta APP-containing vesicles. Although protein kinase A and protein kinase C converge at the level of formation from the TGN of beta APP-containing vesicles, additional evidence indicates that the regulatory mechanisms involved are distinct.
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PMID:Metabolism of Alzheimer beta-amyloid precursor protein: regulation by protein kinase A in intact cells and in a cell-free system. 863 20

Amyloid beta peptide (beta A4) accumulates as plaques in the brains of individuals with Alzheimer's disease and Down's syndrome, and may contribute to the cognitive decline that is a feature of these diseases. beta A4 is a normal product of cell metabolism, derived from the amyloid precursor protein (APP), but the biological functions of these molecules are not fully known. A hypothetical, descriptive model of the biological interrelationships between beta A4 and APP is presented. APPs, the soluble form of APP, which is released at the neuronal surface, and beta A4 are envisaged as physiological ligands which have reciprocal paracrine effects on neuronal growth and neurite extension. Differential expression of these factors, manifest as changes in the APPs: beta A4 ratio, may therefore have growth-promoting or growth-inhibiting effects on neurons. These effects may be mediated through separate cell-surface interactions but common intracellular effector systems, such as calcium and protein kinase C. In turn, the intracellular events may control the relative production of each ligand from APP through negative feedback loops. Disturbances of these control mechanisms may permit pathological overproduction, and hence accumulation, of beta A4. Such a model may also have therapeutic implications.
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PMID:Physiological and pathological interrelationships of amyloid beta peptide and the amyloid precursor protein. 876 34


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