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J. Biol. Chem. 278 (10): 7751-7754

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

ACCELERATED PUBLICATION
The Notch Ligands, Delta1 and Jagged2, Are Substrates for Presenilin-dependent "gamma -Secretase" Cleavage*

Takeshi IkeuchiDagger and Sangram S. Sisodia§

From the Department of Neurobiology, Pharmacology, and Physiology, The University of Chicago, Chicago, Illinois 60637

The evolutionary conserved Notch signaling pathway is involved in cell fate specification and mediated by molecular interactions between the Notch receptors and the Notch ligands, Delta, Serrate, and Jagged. In this report, we demonstrate that like Notch, Delta1 and Jagged2 are subject to presenilin (PS)-dependent, intramembranous "gamma -secretase" processing, resulting in the production of soluble intracellular derivatives. Moreover, and paralleling the observation that expression of familial Alzheimer's disease-linked mutant PS1 compromises production of Notch S3/NICD, we show that the PS-dependent production of Delta1 cytoplasmic derivatives are also reduced in cells expressing mutant PS1. These studies led us to conclude that a similar molecular apparatus is responsible for intramembranous processing of Notch and it's ligands. To assess the potential role of the cytoplasmic derivative on nuclear transcriptional events, we expressed a Delta1-Gal4VP16 chimera and demonstrated marked transcriptional stimulation of a luciferase-based reporter. Our findings offer the proposal that Delta1 and Jagged2 play dual roles as activators of Notch receptor signaling and as receptors that mediate nuclear signaling events via gamma -secretase-generated cytoplasmic domains.

* This work was supported by National Institutes of Health Grants AG021494 (to S. S. S.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Recipient of research fellowships from Uehara Memorial Foundation.

§ To whom correspondence should be addressed: Center for Molecular Neurobiology, The University of Chicago, Abbott 510, 947 East 58th St., Chicago, IL 60637. Tel.: 773-834-9186; Fax: 773-834-5311; E-mail: ssisodia@drugs.bsd.uchicago.edu.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

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