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

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 ?-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 ?-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 ?-secretase complex on the cell surface, and inhibited the ?-secretase activity by competing with the substrate binding in vitro. Moreover, A5226A abolished the ?-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 ?-secretase, and that targeting NCT might be a novel therapeutic strategy against cancer caused by aberrant ?-secretase activity and Notch signaling.

SUBMITTER: Hayashi I 

PROVIDER: S-EPMC4058788 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature