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PNAS 99 (6): 4014-4019

Copyright © 2002 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / NEUROBIOLOGY

Notch receptor cleavage depends on but is not directly executed by presenilins

Yoshihito Taniguchi*,{dagger},{ddagger}, Helena Karlström{dagger},§, Johan Lundkvist§, Tomohiko Mizutani*, Akira Otaka, Monica Vestling||, Alan Bernstein**, Dorit Donoviel**,{ddagger}{ddagger}, Urban Lendahl§,{dagger}{dagger}, and Tasuku Honjo*

*Department of Medical Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Faculty of Medicine, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan; §Department of Cell and Molecular Biology, and ||Neurotec, Novum, Kliniskt Forsknings Centrum, Medical Nobel Institute, Karolinska Institute, Von Eulers vag 3, SE-171 77 Stockholm, Sweden; and **Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5

Contributed by Tasuku Honjo

Accepted for publication January 10, 2002.

Abstract: Notch receptors undergo three distinct proteolytic cleavages during maturation and activation. The third cleavage occurs within the plasma membrane and results in the release and translocation of the intracellular domain into the nucleus to execute Notch signaling. This so-called {gamma}-secretase cleavage is under the control of presenilins, but it is not known whether presenilins themselves carry out the cleavage or whether they act by means of yet-unidentified {gamma}-secretase(s). In this article, we show that Notch intracellular cleavage in intact cells completely depends on presenilins. In contrast, partial purification of the Notch cleavage activity reveals an activity, which is present only in protein extracts from presenilin-containing cells, and which does not comigrate with presenilin. This finding provides evidence for the existence of a specific Notch-processing activity, which is physically distinct from presenilins. We conclude from these experiments that presenilins are critically required for Notch intracellular cleavage but are not themselves directly mediating the cleavage.

Key Words: secretase||Alzheimer's disease||neurodegenerative disease||HES gene


{dagger} Y.T. and H.K. contributed equally to this work.

{ddagger} Present address: Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, 947 East 58th Street, MC 0926/Abbott 316, Chicago, IL 60637.

{ddagger}{ddagger} Present address: Lexicon Genetics, Inc., 8800 Technology Forest Place, The Woodlands, TX 77381.

{dagger}{dagger} To whom reprint requests should be addressed. E-mail: urban.lendahl{at}cmb.ki.se.

§§ Molinoff, B. P., Felsenstein, M. K., Smith, W. D. & Barten, M. D. (2000) Neurobiol. Aging 21, S136 (abstr.).


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