spacer gif spacer gif spacer gif spacer gif spacer gif
QUICK SEARCH:   [advanced]


spacer gif
     Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents    

First published online 27 July 2004
doi: 10.1242/jcs.01263

Journal of Cell Science 117, 4099-4111 (2004)
Published by The Company of Biologists 2004
This Article
Right arrow Figures Only
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jcs.01263v1
117/18/4099    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gowrishankar, K.
Right arrow Articles by Vincenz, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gowrishankar, K.
Right arrow Articles by Vincenz, C.

Research Article

Release of a membrane-bound death domain by {gamma}-secretase processing of the p75NTR homolog NRADD

Kavitha Gowrishankar1, Michael G. Zeidler1 and Claudius Vincenz2,*

1 Department of Pathology, University of Michigan Medical School, 1150 West Medical Center Drive, Ann Arbor, MI 48109, USA
2 Howard Hughes Medical Institute, University of Michigan Medical School, 1150 West Medical Center Drive, Ann Arbor, MI 48109, USA

* Author for correspondence (e-mail: vincenz{at}umich.edu)

Accepted 7 April 2004

Neurotrophin receptor alike death domain protein (NRADD) is a death-receptor-like protein with a unique ectodomain and an intracellular domain homologous to p75NTR. Expression of NRADD results in apoptosis, but only in certain cell types. This paper characterizes the expression and proteolytic processing of the mature 55 kDa glycoprotein. N-terminally truncated NRADD is processed by a {gamma}-secretase activity that requires presenilins and has the same susceptibility to {gamma}-secretase inhibitors as the secretion of amyloid ß (Aß). The ectodomain of endogenous NRADD is shed by activation of metalloproteinases. Inhibitor studies provide evidence that NRADD is cleaved in two steps typical of regulated intramembrane proteolysis (RIP). Inhibition of {gamma}-secretase abrogates both the production of the soluble intracellular domain of NRADD and the appearance of NRADD in subnuclear structures. Thus, solubilized death domains with close homology to p75NTR might have a nuclear function. Furthermore, presenilin deficiency leads to abnormally glycosylated NRADD and overexpression of presenilin 2 inhibits NRADD maturation, which is dependent on the putative active site residue D366 but not on {gamma}-secretase activity. Our results demonstrate that NRADD is an additional {gamma}-secretase substrate and suggest that drugs against Alzheimer's disease will need to target {gamma}-secretase in a substrate-specific manner.

Key words: {gamma}-Secretase, Death domain, Metalloproteinases, NRADD, Presenilin




This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
D. Y. Kim, L. A. M. Ingano, B. W. Carey, W. H. Pettingell, and D. M. Kovacs
Presenilin/{gamma}-Secretase-mediated Cleavage of the Voltage-gated Sodium Channel {beta}2-Subunit Regulates Cell Adhesion and Migration
J. Biol. Chem., June 17, 2005; 280(24): 23251 - 23261.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. W. Cowan, X. Wang, R. Guan, K. He, J. Jiang, G. Baumann, R. A. Black, M. S. Wolfe, and S. J. Frank
Growth Hormone Receptor Is a Target for Presenilin-dependent {gamma}-Secretase Cleavage
J. Biol. Chem., May 13, 2005; 280(19): 19331 - 19342.
[Abstract] [Full Text] [PDF]


© The Company of Biologists Ltd 2004