2. Academic Validation
  3. Neutralization of the γ-secretase activity by monoclonal antibody against extracellular domain of nicastrin

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

  • Oncogene. 2012 Feb 9;31(6):787-798. doi: 10.1038/onc.2011.265.
I Hayashi # 1,  S Takatori # 1,  Y Urano 2,  Y Miyake 3,  J Takagi 4,  M Sakata-Yanagimoto 3,  H Iwanari 2 5,  S Osawa 1,  Y Morohashi 1,  T Li 6,  P C Wong 6,  S Chiba 3,  T Kodama 2,  T Hamakubo 2,  T Tomita 1 7,  T Iwatsubo 1 7 8
Affiliations

Affiliations

  • 1 Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
  • 2 Department of Systems Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
  • 3 Department of Clinical and Experimental Hematology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
  • 4 Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, Osaka, Japan.
  • 5 Perseus Proteomics Inc., Tokyo, Japan.
  • 6 Department of Pathology, The Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
  • 7 Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama, Japan.
  • 8 Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • # Contributed equally.
PMID: 21725355 DOI: 10.1038/onc.2011.265
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.

Figures
Products