Neurotrophin Receptor Interacting Factor (NRIF) Is an Essential Mediator of Apoptotic Signaling by the p75 Neurotrophin Receptor*
- Michelle S. Linggi‡,
- Tara L. Burke‡,
- B. Blairanne Williams‡,
- Anthony Harrington§,
- Rosemary Kraemer¶∥,
- Barbara L. Hempstead**,
- Sung Ok Yoon§ and
- Bruce D. Carter‡‡‡
- ‡Department of Biochemistry and Center for Molecular Neuroscience, Vanderbilt University Medical School, Nashville, Tennessee 37232, the §Department of Neuroscience, Ohio State University, Columbus, Ohio 43210, and the Departments of **Medicine, ¶Pathology, and ∥Cell Biology, Weill Medical College of Cornell University, New York, New York 10021
- ‡‡ To whom correspondence should be addressed: Dept. of Biochemistry, 655 Light Hall, Vanderbilt University School of Medicine, Nashville, TN 37232. Tel.: 615-936-3041; Fax: 615-343-0704; E-mail: bruce.carter{at}vanderbilt.edu.
Abstract
Activation of the p75 neurotrophin receptor leads to a variety of effects within the nervous system, including neuronal apoptosis. Both c-Jun N-terminal kinase (JNK) and the tumor suppressor p53 have been reported to be critical for this receptor to induce cell death; however, the mechanisms by which p75 activates these pathways is undetermined. Here we report that the neurotrophin receptor interacting factor (NRIF) is necessary for p75-dependent JNK activation and apoptosis. Upon nerve growth factor withdrawal, nrif–/– sympathetic neurons underwent apoptosis, whereas p75-mediated death was completely abrogated. The lack of cell death correlated with a lack of JNK activation in the nrif–/– neurons, suggesting that NRIF is a selective mediator for p75-dependent JNK activation and apoptosis. Moreover, we document that NRIF expression is sufficient to induce cell death through a mechanism that requires p53. Taken together, these results establish NRIF as an essential component of the p75 apoptotic pathway.
Footnotes
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↵1 The abbreviations used are: NGF, nerve growth factor; BDNF, brain-derived neurotrophic factor; JNK, c-Jun N-terminal kinase; GFP, green fluorescent protein; MEF, mouse embryo fibroblast; ProNGF, proform of NGF; DAPI, 4′,6-diamidino-2-phenylindole; NRIF, neurotrophin receptor interacting factor; MOPS, 4-morpholinepropanesulfonic acid; TRAF2, tumor necrosis factor receptor-associated factor 2; TrkA, tropomylosin-related kinase A.
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↵* This work was supported by Grants NS38220 (to B. D. C.), T32 HL07328 (to M. S. L.), NS39472 (to S. O. Y.), and NS30687 (to B. L. H.) from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Received September 10, 2004.
- Revision received December 14, 2004.
- The American Society for Biochemistry and Molecular Biology, Inc.
