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Notch receptor cleavage depends on but is not directly executed by presenilins
Urban Lendahl,, and
*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.
Notch receptors undergo three distinct proteolytic cleavagesduring maturation and activation. The third cleavage occurswithin the plasma membrane and results in the release and translocationof the intracellular domain into the nucleus to execute Notchsignaling. This so-called -secretase cleavage is under the controlof presenilins, but it is not known whether presenilins themselvescarry out the cleavage or whether they act by means of yet-unidentified-secretase(s). In this article, we show that Notch intracellularcleavage in intact cells completely depends on presenilins.In contrast, partial purification of the Notch cleavage activityreveals an activity, which is present only in protein extractsfrom presenilin-containing cells, and which does not comigratewith presenilin. This finding provides evidence for the existenceof a specific Notch-processing activity, which is physicallydistinct from presenilins. We conclude from these experimentsthat presenilins are critically required for Notch intracellularcleavage but are not themselves directly mediating the cleavage.