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Molecular Pharmacology

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Research ArticleArticle

Pharmacological Analysis of Drosophila melanogaster γ-Secretase with Respect to Differential Proteolysis of Notch and APP

Casper Groth, W. Gregory Alvord, Octavio A. Quiñones and Mark E. Fortini
Molecular Pharmacology April 2010, 77 (4) 567-574; DOI: https://doi.org/10.1124/mol.109.062471
Casper Groth
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W. Gregory Alvord
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Octavio A. Quiñones
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Mark E. Fortini
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Abstract

The γ-secretase aspartyl protease is responsible for the cleavage of numerous type I integral membrane proteins, including amyloid precursor protein (APP) and Notch. APP cleavage contributes to the generation of toxic amyloid β peptides in Alzheimer's disease, whereas cleavage of the Notch receptor is required for normal physiological signaling between differentiating cells. Mutagenesis studies as well as in vivo analyses of Notch and APP activity in the presence of pharmacological inhibitors indicate that these substrates can be differentially modulated by inhibition of mammalian γ-secretase, although some biochemical studies instead show nearly identical dose-response inhibitor effects on Notch and APP cleavages. Here, we examine the dose-response effects of several inhibitors on Notch and APP in Drosophila melanogaster cells, which possess a homogeneous form of γ-secretase. Four different inhibitors that target different domains of γ-secretase exhibit similar dose-response effects for both substrates, including rank order of inhibitor potencies and effective concentration ranges. For two inhibitors, modest differences in inhibitor dose responses toward Notch and APP were detected, suggesting that inhibitors might be identified that possess some discrimination in their ability to target alternative γ-secretase substrates. These findings also indicate that despite an overall conservation in inhibitor potencies toward different γ-secretase substrates, quantitative differences might exist that could be relevant for the development of therapeutically valuable substrate-specific inhibitors.

Footnotes

    fn-1
  • This work was supported by National Institutes of Health National Institute of General Medical Sciences [Grant GM087650]; Data Management Services contract HHSN2612008000016C; the Department of Biochemistry and Molecular Biology, Thomas Jefferson University; and the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.

  • fn-2
  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.062471.

  • fn-3
  • ABBREVIATIONS:

    APP
    amyloid precursor protein
    Aβ42
    amyloid β42 peptide
    PS1
    Presenilin-1
    PS2
    Presenilin-2
    Aph-1
    anterior pharynx defective-1
    APPL
    amyloid precursor protein-like
    APLP
    amyloid precursor-like protein
    ADAM
    A Disintegrin And Metalloproteinase enzyme
    NTF
    N-terminal fragment
    CTF
    C-terminal fragment
    NICD
    Notch intracellular domain
    AICD
    amyloid precursor protein intracellular domain
    DFK167
    difluoro-ketone peptidomimetic inhibitor-167
    DAPT
    N-[N-(3,5-difluorophenylacetyl)-l-alanyl]-S-phenylglycine t-butyl ester
    CpnE
    compound E [(S,S)-2-[2-(3,5-difluorophenyl)acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide]
    DBZ
    dibenzazepine [(S,S)-2-[2-(3,5-difluorophenyl)acetylamino]-N-(5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo[b,d]azepin-7-yl)propionamide]
    BB94
    batimastat
    GM6001
    N-[(2R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl]-l-tryptophan methylamide
    Tricine
    N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine.

    • Received November 16, 2009.
    • Accepted January 4, 2010.
  • U.S. Government work not protected by U.S. copyright
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Molecular Pharmacology: 77 (4)
Molecular Pharmacology
Vol. 77, Issue 4
1 Apr 2010
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Research ArticleArticle

Pharmacological Analysis of Drosophila melanogaster γ-Secretase with Respect to Differential Proteolysis of Notch and APP

Casper Groth, W. Gregory Alvord, Octavio A. Quiñones and Mark E. Fortini
Molecular Pharmacology April 1, 2010, 77 (4) 567-574; DOI: https://doi.org/10.1124/mol.109.062471

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Research ArticleArticle

Pharmacological Analysis of Drosophila melanogaster γ-Secretase with Respect to Differential Proteolysis of Notch and APP

Casper Groth, W. Gregory Alvord, Octavio A. Quiñones and Mark E. Fortini
Molecular Pharmacology April 1, 2010, 77 (4) 567-574; DOI: https://doi.org/10.1124/mol.109.062471
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