The transmembrane protein Notch undergoes three successive cleavages before it can release its cytoplasmic domain to the nucleus to affect transcription. The final cleavage event involves gamma-secretase activity directed against its transmembrane domain. Although this final step requires the presence of the protein presenilin, it has not been clear whether presenilin itself acts as the gamma-secretase or whether it promotes cleavage indirectly. Taniguchi et al. have used a sensitive in vivo reporter assay system to detect Notch intracellular cleavage and confirmed that only presenilin-expressing cells support Notch cleavage. The authors then partially purified cleavage activity from the membranes of presenilin-expressing cells, and found that the isolated fraction did not contain presenilin. The activity was also not sensitive to inhibitors directed against presenilins. The authors propose that presenilin activates a distinct protease that then cleaves Notch.
Y. Taniguichi, H. Karlstrom, J. Lundkvist, T. Mizutani, A. Otaka, M. Vestling, A. Bernstein, D. Donoviel, U. Lendahl, T. Honjo, Notch receptor cleavage depends on but is not directly executed by presenilins. Proc. Natl. Acad. Sci. U.S.A. 99, 4014-4019 (2002). [Abstract] [Full Text]