Neutralization of the γ-secretase activity by monoclonal antibody against extracellular domain of nicastrin

I. Hayashi, S. Takatori, Y. Urano, Y. Miyake, J. Takagi, M. Sakata-Yanagimoto, H. Iwanari, S. Osawa, Y. Morohashi, T. Li, P. C. Wong, S. Chiba, T. Kodama, T. Hamakubo, T. Tomita, T. Iwatsubo

Research output: Contribution to journalArticlepeer-review

Abstract

Several lines of evidence suggest that aberrant Notch signaling contributes to the development of several types of cancer. Activation of Notch receptor is executed through intramembrane proteolysis by γ-secretase, which is a multimeric membrane-embedded protease comprised of presenilin, nicastrin (NCT), anterior pharynx defective 1 and PEN-2. In this study, we report the neutralization of the γ-secretase activity by a novel monoclonal antibody A5226A against the extracellular domain of NCT, generated by using a recombinant budded baculovirus as an immunogen. This antibody recognized fully glycosylated mature NCT in the active γ-secretase complex on the cell surface, and inhibited the γ-secretase activity by competing with the substrate binding in vitro. Moreover, A5226A abolished the γ-secretase activity-dependent growth of cancer cells in a xenograft model. Our data provide compelling evidence that NCT is a molecular target for the mechanism-based inhibition of γ-secretase, and that targeting NCT might be a novel therapeutic strategy against cancer caused by aberrant γ-secretase activity and Notch signaling.

Original languageEnglish (US)
Pages (from-to)787-798
Number of pages12
JournalOncogene
Volume31
Issue number6
DOIs
StatePublished - Feb 2012

Keywords

  • Notch
  • functional antibody
  • g-secretase
  • intramembrane cleavage
  • membrane protein

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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