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Originally published In Press as doi:10.1074/jbc.M205324200 on October 9, 2002

J. Biol. Chem., Vol. 277, Issue 50, 48043-48050, December 13, 2002
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NRAGE, a p75 Neurotrophin Receptor-interacting Protein, Induces Caspase Activation and Cell Death through a JNK-dependent Mitochondrial Pathway*

Amir H. SalehiDagger §, Steven Xanthoudakis, and Philip A. BarkerDagger ||

From the Dagger  Centre for Neuronal Survival, Montreal Neurological Institute, McGill University, 3801 University Avenue, Montreal, Quebec H3A 2B4 and the  Merck-Frosst Centre for Therapeutic Research, Pointe Claire-Dorval, Quebec H9R 4P8, Canada

The p75 neurotrophin receptor (p75NTR) mediates signaling events leading to activation of the JNK pathway and cell death in a variety of cell types. We recently identified NRAGE, a protein that directly interacts with the p75NTR cytosolic region and facilitates p75NTR-mediated cell death. For the present study, we developed an inducible recombinant NRAGE adenovirus to dissect the mechanism of NRAGE-mediated apoptosis. Induced NRAGE expression resulted in robust activation of the JNK pathway that was not inhibited by the pharmacological mixed lineage kinase (MLK) inhibitor CEP1347. NRAGE induced cytosolic accumulation of cytochrome c, activation of Caspases-3, -9 and -7, and caspase-dependent cell death. Blocking JNK and c-Jun action by overexpression of the JNK-binding domain of JIP1 or dominant-negative c-Jun ablated NRAGE-mediated caspase activation and NRAGE-induced cell death. These findings identify NRAGE as a p75NTR interactor capable of inducing caspase activation and cell death through a JNK-dependent mitochondrial apoptotic pathway.

* This work was supported by grants from the Canadian Institute of Health Research (to P. A. B.).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.

§ Supported by a National Cancer Institute of Canada studentship.

|| A Killam Foundation Scholar. To whom correspondence should be addressed: Montreal Neurological Inst., McGill University, 3801 University St., Montreal, Quebec H3A 2B4, Canada. Tel.: 514-398-3064; Fax: 514-398-5214; E-mail: phil.barker@mcgill.ca.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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