Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

PNAS 99 (6): 4014-4019

Copyright © 2002 by the National Academy of Sciences.


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}

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

Generating pancreatic {beta}-cells from embryonic stem cells by manipulating signaling pathways.
S. Champeris Tsaniras and P. M. Jones (2010)
J. Endocrinol. 206, 13-26
   Abstract »    Full Text »    PDF »
The Large Hydrophilic Loop of Presenilin 1 Is Important for Regulating {gamma}-Secretase Complex Assembly and Dictating the Amyloid {beta} Peptide (A{beta}) Profile without Affecting Notch Processing.
J. Wanngren, J. Franberg, A. I. Svensson, H. Laudon, F. Olsson, B. Winblad, F. Liu, J. Naslund, J. Lundkvist, and H. Karlstrom (2010)
J. Biol. Chem. 285, 8527-8536
   Abstract »    Full Text »    PDF »
Notch activates Wnt-4 signalling to control medio-lateral patterning of the pronephros.
R. W. Naylor and E. A. Jones (2009)
Development 136, 3585-3595
   Abstract »    Full Text »    PDF »
A Nine-transmembrane Domain Topology for Presenilin 1.
H. Laudon, E. M. Hansson, K. Melen, A. Bergman, M. R. Farmery, B. Winblad, U. Lendahl, G. von Heijne, and J. Naslund (2005)
J. Biol. Chem. 280, 35352-35360
   Abstract »    Full Text »    PDF »
The Extreme C Terminus of Presenilin 1 Is Essential for {gamma}-Secretase Complex Assembly and Activity.
A. Bergman, H. Laudon, B. Winblad, J. Lundkvist, and J. Naslund (2004)
J. Biol. Chem. 279, 45564-45572
   Abstract »    Full Text »    PDF »
S. Cervantes, C. A. Saura, E. Pomares, R. Gonzalez-Duarte, and G. Marfany (2004)
J. Biol. Chem. 279, 36519-36529
   Abstract »    Full Text »    PDF »
Monoubiquitination and endocytosis direct {gamma}-secretase cleavage of activated Notch receptor.
N. Gupta-Rossi, E. Six, O. LeBail, F. Logeat, P. Chastagner, A. Olry, A. Israel, and C. Brou (2004)
J. Cell Biol. 166, 73-83
   Abstract »    Full Text »    PDF »
H. Laudon, H. Karlstrom, P. M. Mathews, M. R. Farmery, S. E. Gandy, J. Lundkvist, U. Lendahl, and J. Naslund (2004)
J. Biol. Chem. 279, 23925-23932
   Abstract »    Full Text »    PDF »
A presenilin dimer at the core of the {gamma}-secretase enzyme: Insights from parallel analysis of Notch 1 and APP proteolysis.
E. H. Schroeter, M. X. G. Ilagan, A. L. Brunkan, S. Hecimovic, Y.-m. Li, M. Xu, H. D. Lewis, M. T. Saxena, B. De Strooper, A. Coonrod, et al. (2003)
PNAS 100, 13075-13080
   Abstract »    Full Text »    PDF »
Partial Purification and Characterization of {gamma}-Secretase from Post-mortem Human Brain.
M. R. Farmery, L. O. Tjernberg, S. E. Pursglove, A. Bergman, B. Winblad, and J. Naslund (2003)
J. Biol. Chem. 278, 24277-24284
   Abstract »    Full Text »    PDF »
Signaling Receptome: A Genomic and Evolutionary Perspective of Plasma Membrane Receptors Involved in Signal Transduction.
I. Ben-Shlomo, S. Yu Hsu, R. Rauch, H. W. Kowalski, and A. J. W. Hsueh (2003)
Sci. STKE 2003, re9
   Abstract »    Full Text »    PDF »
Notch activates sonic hedgehog and both are involved in the specification of dorsal midline cell-fates in Xenopus.
S. L. Lopez, A. R. Paganelli, M. V. R. Siri, O. H. Ocana, P. G. Franco, and A. E. Carrasco (2003)
Development 130, 2225-2238
   Abstract »    Full Text »    PDF »
Growth Suppression of Pre-T Acute Lymphoblastic Leukemia Cells by Inhibition of Notch Signaling.
A. P. Weng, Y. Nam, M. S. Wolfe, W. S. Pear, J. D. Griffin, S. C. Blacklow, and J. C. Aster (2003)
Mol. Cell. Biol. 23, 655-664
   Abstract »    Full Text »    PDF »
A CADASIL-mutated Notch 3 receptor exhibits impaired intracellular trafficking and maturation but normal ligand-induced signaling.
H. Karlstrom, P. Beatus, K. Dannaeus, G. Chapman, U. Lendahl, and J. Lundkvist (2002)
PNAS 99, 17119-17124
   Abstract »    Full Text »    PDF »
A New Functional Screening System for Identification of Regulators for the Generation of Amyloid {beta}-Protein.
H. Komano, H. Shiraishi, Y. Kawamura, X. Sai, R. Suzuki, L. Serneels, M. Kawaichi, T. Kitamura, and K. Yanagisawa (2002)
J. Biol. Chem. 277, 39627-39633
   Abstract »    Full Text »    PDF »
Presenilins mediate a dual intramembranous {gamma}-secretase cleavage of Notch-1.
M. Okochi, H. Steiner, A. Fukumori, H. Tanii, T. Tomita, T. Tanaka, T. Iwatsubo, T. Kudo, M. Takeda, and C. Haass (2002)
EMBO J. 21, 5408-5416
   Abstract »    Full Text »    PDF »
Presenilin 1 Is Required for Maturation and Cell Surface Accumulation of Nicastrin.
J. Y. Leem, S. Vijayan, P. Han, D. Cai, M. Machura, K. O. Lopes, M. L. Veselits, H. Xu, and G. Thinakaran (2002)
J. Biol. Chem. 277, 19236-19240
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882