Protein Kinase C ϵ Suppresses Aβ Production and Promotes Activation of α-Secretase

Zhu, Guofen; Wang, Dan; Lin, Yu Huei; McMahon, Thomas; Koo, Edward H.; Messing, Robert O.

doi:10.1006/bbrc.2001.5273

Cited by 80 publications

(66 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Those cells reportedly do not express endogenous APP and therefore may not include the completely physiological machinery for APP processing. A more recent indication on the role of PKCe was reported by Zhu et al, 31 who showed that expression of a peptide inhibitor of PKCe reduced phorbol-ester-mediated sAPP release. This result ruled out the involvement of PKCa because of the ineffectiveness of Gö6976, which is a specific inhibitor of PKCa, b, and g isoforms.…”

Section: Discussionmentioning

confidence: 91%

“…We show here that Gö 6976, the specific inhibitor of Ca 2+ -dependent PKC isoforms a, b, and g, did not block the effect of carbachol, thus conclusively demonstrating that PKCa is not involved in receptor-mediated sAPPa release. Among the other isoforms present in SH-SY5Y cells and because of data in the literature concerning both APP metabolism [29][30][31] and the pharmacology of muscarinic receptor signalling, 35 we favor the specific involvement of PKCe and investigations of this hypothesis are under way.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Role of protein kinase Cα in the regulated secretion of the amyloid precursor protein

et al. 2003

View full text Add to dashboard Cite

Protein kinase C (PKC) has a key role in the signal transduction machinery involved in the regulation of amyloid precursor protein (APP) metabolism. Direct and indirect receptor-mediated activation of PKC has been shown to increase the release of soluble APP (sAPPa) and reduce the secretion of b-amyloid peptides. Experimental evidence suggests that specific isoforms of PKC, such as PKCa and PKCe, are involved in the regulation of APP metabolism. In this study, we characterized the role of PKCa in the regulated secretion of APP using wild-type SH-SY5Y neuroblastoma cells and cells transfected with a plasmid expressing PKCa antisense cDNA. Cells expressing antisense PKCa secrete less sAPPa in response to phorbol esters. In contrast, carbachol increases the secretion of sAPPa to similar levels in wild-type cells and in cells transfected with antisense PKCa by acting on APP metabolism through an indirect pathway partially involving the activation of PKC. These results suggest that the direct PKC-dependent activation of the APP secretory pathway is compromised by reduced PKCa expression and a specific role of this isoform in these mechanisms. On the other hand, indirect pathways that are also partially dependent on the mitogen-activated protein kinase signal transduction mechanism remain unaffected and constitute a redundant, compensatory mechanism within the APP secretory pathway.

show abstract

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Role of protein kinase Cα in the regulated secretion of the amyloid precursor protein

et al. 2003

View full text Add to dashboard Cite

show abstract

“…Moreover, among all PKC isozymes, PKCa and PKCq are the most tightly associated with APP processing. Activation of PKCa and PKCq is known to enhance sAPPa production (Kinouchi et al, 1995;Yeon et al, 2001) and reduce Ah production (Zhu et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Amyloid beta peptide directly inhibits PKC activation

Lee

Boo

Jung

et al. 2004

Molecular and Cellular Neuroscience

View full text Add to dashboard Cite

“…2C Right). Moreover, pretreatment with PKC-specific translocation-inhibitor peptide (13), the general kinase inhibitor curcumin (7), PKC-specific inhibitor calphostin-C (8), or general PKC inhibitor bisindolylmaleimide (BIM) (18) prevented total complexing of the proteins (Fig. 2C Right).…”

Section: Ugt Inhibition By Curcumin and Calphostin-c And [ 33 P]orthomentioning

confidence: 97%

Phosphorylation of a UDP-glucuronosyltransferase regulates substrate specificity

Basu

Kovářová

Garza

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

UDP-glucuronosyltransferase (UGT) isozymes catalyze detoxification of numerous chemical toxins present in our daily diet and environment by conjugation to glucuronic acid. The special properties and enzymatic mechanism(s) that enable endoplasmic reticulum-bound UGT isozymes to convert innumerable structurally diverse lipophiles to excretable glucuronides are unknown. Inhibition of cellular UGT1A7 and UGT1A10 activities and of [ 33 P]orthophosphate incorporation into immunoprecipitable proteins after exposure to curcumin or calphostin-C indicated that the isozymes are phosphorylated. Furthermore, inhibition of UGT phosphorylation and activity by treatment with PKC-specific inhibitor peptide supported PKC involvement. Coimmunoprecipitation, colocalization by means of immunofluorescence, and crosslinking studies of PKC and UGT1A7His revealed that the proteins reside within 11.4 Å of each other. Moreover, mutation of three PKC sites in each UGT isozyme demonstrated that T73A͞G and T202A͞G caused null activity, whereas S432G-UGT1A7 caused a major shift of its pH-8.5 optimum to 6.4 with new substrate selections, including 17␤-estradiol. S432G-UGT1A10 exhibited a minor pH shift without substrate alterations. PKC involvement was confirmed by the demonstration that PKC overexpression enhanced activity of UGT1A7 but not of its S432 mutant and the conversion of 17␤-[ 14 C]estradiol by S432G-UGT1A7 but not by UGT1A7. Consistent with these observations, treatment of UGT1A7-transfected cells with PKC-specific inhibitor peptide or general PKC inhibitors increased 17␤-estradiol catalysis between 5-and 11-fold, with parallel decreases in phosphoserine-432. Here, we report a mechanism involving PKC-mediated phosphorylation of UGT such that phosphoserine͞threonine regulates substrate specificity in response to chemical exposures, which possibly confers survival benefit.PKC ͉ PKC inhibitors ͉ detoxifying enzymes ͉ UDP-glucuronosyltransferase mutants ͉ immunofluorescence M ammalian UDP-glucuronosyltransferase (UGT) isozymes detoxify numerous lipid-soluble chemicals, including metabolites, such as neurotoxic bilirubin, as well as dietary and environmental agents͞toxins and medicines (1). UGT facilitates detoxification of chemicals by attaching glucuronic acid molecules to form water-soluble, readily excretable glucuronides. Failure to attach glucuronic acid (glucuronidation) to toxins allows high levels to accumulate in tissues, causing deleterious effects, including mutations of genes and the development of cancer (2). Mutations in UGT1 genes lead to lethal hyperbilirubinemic Crigler-Najjar disease (3) and to toxic tissue levels of the commonly used analgesic acetaminophen (Tylenol) in rats (4). The fact that a limited number of UGT isozymes facilitate excretion of a vast number of structurally diverse chemicals suggests a mechanism evolved to confer flexibility on an isozyme to metabolize multiple toxins. Because UGTs are bound to membranes of the endoplasmic reticulum (ER) that cause difficulties associated with purification and s...

show abstract

Protein Kinase C ϵ Suppresses Aβ Production and Promotes Activation of α-Secretase

Cited by 80 publications

References 48 publications

Role of protein kinase Cα in the regulated secretion of the amyloid precursor protein

Role of protein kinase Cα in the regulated secretion of the amyloid precursor protein

Amyloid beta peptide directly inhibits PKC activation

Phosphorylation of a UDP-glucuronosyltransferase regulates substrate specificity

Contact Info

Product

Resources

About