Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

J. Biol. Chem. 275 (23): 17566-17570

© 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

NADE, a p75NTR-associated Cell Death Executor, Is Involved in Signal Transduction Mediated by the Common Neurotrophin Receptor p75NTR*

Jun Mukai{ddagger}§, Takahisa Hachiya§||, Shisako Shoji-Hoshino{ddagger}§, Makoto T. Kimura{ddagger}§**, Daita Nadano{ddagger}, Petro Suvanto, Takaomi Hanaoka{ddagger}, Yin Li{ddagger}, Shinji Irie{ddagger}, Lloyd A. Greene§§, , and Taka-Aki Sato{ddagger}¶¶

From the {ddagger}Molecular Oncology Laboratory, Tsukuba Life Science Center, RIKEN (Institute of Physical and Chemical Research), Ibaraki 305-0074, Japan, the Division of Molecular Oncology, Department of Otolaryngology/Head & Neck Surgery and Pathology, College of Physicians & Surgeons, Columbia University, New York, New York 10032, the ||Ina Laboratory, Medical & Biological Laboratories Co., Ltd., Nagano 396-0002, Japan, the {ddagger}ZAIYA Inc., Kyoto 600-8815, Japan, the **Department of Molecular & Cell Genetics, School of Life Science, Tottori University, Tottori 683, Japan, and the §§Department of Pathology, College of Physicians & Surgeons, Columbia University, New York, New York 10032

ABSTRACT Back to Top

Abstract: The low affinity neurotrophin receptor p75NTR can mediate cell survival as well as cell death of neural cells by NGF and other neurotrophins. To elucidate p75NTR-mediated signal transduction, we screened p75NTR-associated proteins by a yeast two-hybrid system. We identified one positive clone and named NADE (p75NTR-associated cell deathexecutor). Mouse NADE has marked homology to the human HGR74 protein. NADE specifically binds to the cell-death domain of p75NTR. Co-expression of NADE and p75NTR induced caspase-2 and caspase-3 activities and the fragmentation of nuclear DNA in 293T cells. However, in the absence of p75NTR, NADE failed to induce apoptosis, suggesting that NADE expression is necessary but insufficient for p75NTR-mediated apoptosis. Furthermore, p75NTR/NADE-induced cell death was dependent on NGF but not BDNF, NT-3, or NT-4/5, and the recruitment of NADE to p75NTR (intracellular domain) was dose-dependent. We obtained similar results from PC12 cells, nnr5 cells, and oligodendrocytes. Taken together, NADE is the first signaling adaptor molecule identified in the involvement of p75NTR-mediated apoptosis induced by NGF, and it may play an important role in the pathogenesis of neurogenetic diseases.


Received for publication February 28, 2000. Revision received April 6, 2000.

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Genome-wide siRNA screen for mediators of NF-{kappa}B activation.
B. E. Gewurz, F. Towfic, J. C. Mar, N. P. Shinners, K. Takasaki, B. Zhao, E. D. Cahir-McFarland, J. Quackenbush, R. J. Xavier, and E. Kieff (2012)
PNAS 109, 2467-2472
   Abstract »    Full Text »    PDF »
Proneurotrophins, Seizures, and Neuronal Apoptosis.
W. J. Friedman (2010)
Neuroscientist 16, 244-252
   Abstract »    PDF »
Nuclear Localization of the p75 Neurotrophin Receptor Intracellular Domain.
C. N. Parkhurst, N. Zampieri, and M. V. Chao (2010)
J. Biol. Chem. 285, 5361-5368
   Abstract »    Full Text »    PDF »
Multiple Roles of the p75 Neurotrophin Receptor in the Nervous System.
Y. Chen, J. Zeng, Y. Chen, X. Wang, G. Yao, W. Wang, W. Qi, and K. Kong (2009)
Journal of International Medical Research 37, 281-288
   Abstract »    PDF »
Sall2 is a novel p75NTR-interacting protein that links NGF signalling to cell cycle progression and neurite outgrowth.
R. Pincheira, M. Baerwald, J. D. Dunbar, and D. B. Donner (2009)
EMBO J. 28, 261-273
   Abstract »    Full Text »    PDF »
Inhibition of apoptosis by downregulation of hBex1, a novel mechanism, contributes to the chemoresistance of Bcr/Abl+ leukemic cells.
K. Ding, Y. Su, L. Pang, Q. Lu, Z. Wang, S. Zhang, S. Zheng, J. Mao, and Y. Zhu (2009)
Carcinogenesis 30, 35-42
   Abstract »    Full Text »    PDF »
Induction of Proneurotrophins and Activation of p75NTR-Mediated Apoptosis via Neurotrophin Receptor-Interacting Factor in Hippocampal Neurons after Seizures.
M. Volosin, C. Trotter, A. Cragnolini, R. S. Kenchappa, M. Light, B. L. Hempstead, B. D. Carter, and W. J. Friedman (2008)
J. Neurosci. 28, 9870-9879
   Abstract »    Full Text »    PDF »
Zinc and 4-Hydroxy-2-Nonenal Mediate Lysosomal Membrane Permeabilization Induced by H2O2 in Cultured Hippocampal Neurons.
J. J. Hwang, S.-J. Lee, T.-Y. Kim, J.-H. Cho, and J.-Y. Koh (2008)
J. Neurosci. 28, 3114-3122
   Abstract »    Full Text »    PDF »
BEX2 Is Overexpressed in a Subset of Primary Breast Cancers and Mediates Nerve Growth Factor/Nuclear Factor-{kappa}B Inhibition of Apoptosis in Breast Cancer Cell Lines.
A. Naderi, A. E. Teschendorff, J. Beigel, M. Cariati, I. O. Ellis, J. D. Brenton, and C. Caldas (2007)
Cancer Res. 67, 6725-6736
   Abstract »    Full Text »    PDF »
Genome-Wide Analysis of Epigenetic Silencing Identifies BEX1 and BEX2 as Candidate Tumor Suppressor Genes in Malignant Glioma..
G. Foltz, G.-Y. Ryu, J.-G. Yoon, T. Nelson, J. Fahey, A. Frakes, H. Lee, L. Field, K. Zander, Z. Sibenaller, et al. (2006)
Cancer Res. 66, 6665-6674
   Abstract »    Full Text »    PDF »
Schwann cell-derived factor-induced modulation of the NgR/p75NTR/EGFR axis disinhibits axon growth through CNS myelin in vivo and in vitro.
Z. Ahmed, E. L. Suggate, E. R. Brown, R. G. Dent, S. J. Armstrong, L. B. Barrett, M. Berry, and A. Logan (2006)
Brain 129, 1517-1533
   Abstract »    Full Text »    PDF »
A Bex-cycle built for two.
B. D. Carter (2006)
EMBO Rep. 7, 382-384
   Full Text »    PDF »
Bex1, a novel interactor of the p75 neurotrophin receptor, links neurotrophin signaling to the cell cycle.
M. Vilar, M. Murillo-Carretero, H. Mira, K. Magnusson, V. Besset, and C. F. Ibanez (2006)
EMBO J. 25, 1219-1230
   Abstract »    Full Text »    PDF »
Human Bex2 interacts with LMO2 and regulates the transcriptional activity of a novel DNA-binding complex.
C. Han, H. Liu, J. Liu, K. Yin, Y. Xie, X. Shen, Y. Wang, J. Yuan, B. Qiang, Y.-J. Liu, et al. (2005)
Nucleic Acids Res. 33, 6555-6565
   Abstract »    Full Text »    PDF »
Neurotrophin Receptor Interacting Factor (NRIF) Is an Essential Mediator of Apoptotic Signaling by the p75 Neurotrophin Receptor.
M. S. Linggi, T. L. Burke, B. B. Williams, A. Harrington, R. Kraemer, B. L. Hempstead, S. O. Yoon, and B. D. Carter (2005)
J. Biol. Chem. 280, 13801-13808
   Abstract »    Full Text »    PDF »
Microglia-derived Pronerve Growth Factor Promotes Photoreceptor Cell Death via p75 Neurotrophin Receptor.
B. Srinivasan, C. H. Roque, B. L. Hempstead, M. R. Al-Ubaidi, and R. S. Roque (2004)
J. Biol. Chem. 279, 41839-41845
   Abstract »    Full Text »    PDF »
Apoptosis and Dependence Receptors: A Molecular Basis for Cellular Addiction.
D. E. BREDESEN, P. MEHLEN, and S. RABIZADEH (2004)
Physiol Rev 84, 411-430
   Abstract »    Full Text »    PDF »
The p75NTR-interacting protein SC1 inhibits cell cycle progression by transcriptional repression of cyclin E.
A. Chittka, J. C. Arevalo, M. Rodriguez-Guzman, P. Perez, M. V. Chao, and M. Sendtner (2004)
J. Cell Biol. 164, 985-996
   Abstract »    Full Text »    PDF »
Apoptosis Induced by p75NTR Overexpression Requires Jun Kinase-Dependent Phosphorylation of Bad.
A. L. Bhakar, J. L. Howell, C. E. Paul, A. H. Salehi, E. B. E. Becker, F. Said, A. Bonni, and P. A. Barker (2003)
J. Neurosci. 23, 11373-11381
   Abstract »    Full Text »    PDF »
Proteolytic Processing of the p75 Neurotrophin Receptor and Two Homologs Generates C-Terminal Fragments with Signaling Capability.
K. C. Kanning, M. Hudson, P. S. Amieux, J. C. Wiley, M. Bothwell, and L. C. Schecterson (2003)
J. Neurosci. 23, 5425-5436
   Abstract »    Full Text »    PDF »
NRAGE, a p75 Neurotrophin Receptor-interacting Protein, Induces Caspase Activation and Cell Death through a JNK-dependent Mitochondrial Pathway.
A. H. Salehi, S. Xanthoudakis, and P. A. Barker (2002)
J. Biol. Chem. 277, 48043-48050
   Abstract »    Full Text »    PDF »
Structure-Function Analysis of NADE: IDENTIFICATION OF REGIONS THAT MEDIATE NERVE GROWTH FACTOR-INDUCED APOPTOSIS.
J. Mukai, S. Shoji, M. T. Kimura, S. Okubo, H. Sano, P. Suvanto, Y. Li, S. Irie, and T.-A. Sato (2002)
J. Biol. Chem. 277, 13973-13982
   Abstract »    Full Text »    PDF »
Dissection of NT3 functions in vivo by gene replacement strategy.
V. Coppola, J. Kucera, M. E. Palko, J. Martinez-De Velasco, W. E. Lyons, B. Fritzsch, and L. Tessarollo (2001)
Development 128, 4315-4327
   Abstract »    Full Text »    PDF »
Characterization of a p75NTR Apoptotic Signaling Pathway Using a Novel Cellular Model.
X. Wang, J. H. Bauer, Y. Li, Z. Shao, F. S. Zetoune, E. Cattaneo, and C. Vincenz (2001)
J. Biol. Chem. 276, 33812-33820
   Abstract »    Full Text »    PDF »
A Prosurvival Function for the p75 Receptor Death Domain Mediated via the Caspase Recruitment Domain Receptor-Interacting Protein 2.
G. Khursigara, J. Bertin, H. Yano, H. Moffett, P. S. DiStefano, and M. V. Chao (2001)
J. Neurosci. 21, 5854-5863
   Abstract »    Full Text »    PDF »
The p75 Neurotrophin Receptor Activates Akt (Protein Kinase B) through a Phosphatidylinositol 3-Kinase-dependent Pathway.
P. P. Roux, A. L. Bhakar, T. E. Kennedy, and P. A. Barker (2001)
J. Biol. Chem. 276, 23097-23104
   Abstract »    Full Text »    PDF »
14-3-3 Is Involved in p75 Neurotrophin Receptor-mediated Signal Transduction.
M. T. Kimura, S. Irie, S. Shoji-Hoshino, J. Mukai, D. Nadano, M. Oshimura, and T.-A. Sato (2001)
J. Biol. Chem. 276, 17291-17300
   Abstract »    Full Text »    PDF »
Co-Induction of p75NTR and p75NTR-Associated Death Executor in Neurons After Zinc Exposure in Cortical Culture or Transient Ischemia in the Rat.
J. A. Park, J.-Y. Lee, T.-A. Sato, and J.-Y. Koh (2000)
J. Neurosci. 20, 9096-9103
   Abstract »    Full Text »    PDF »
Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system.
M. Bibel and Y.-A. Barde (2000)
Genes & Dev. 14, 2919-2937
   Full Text »
Chopper, a New Death Domain of the p75 Neurotrophin Receptor That Mediates Rapid Neuronal Cell Death.
E. J. Coulson, K. Reid, M. Baca, K. A. Shipham, S. M. Hulett, T. J. Kilpatrick, and P. F. Bartlett (2000)
J. Biol. Chem. 275, 30537-30545
   Abstract »    Full Text »    PDF »
Chopper, a New Death Domain of the p75 Neurotrophin Receptor That Mediates Rapid Neuronal Cell Death.
E. J. Coulson, K. Reid, M. Baca, K. A. Shipham, S. M. Hulett, T. J. Kilpatrick, and P. F. Bartlett (2000)
J. Biol. Chem. 275, 30537-30545
   Abstract »    Full Text »    PDF »
14-3-3 Is Involved in p75 Neurotrophin Receptor-mediated Signal Transduction.
M. T. Kimura, S. Irie, S. Shoji-Hoshino, J. Mukai, D. Nadano, M. Oshimura, and T.-A. Sato (2001)
J. Biol. Chem. 276, 17291-17300
   Abstract »    Full Text »    PDF »
Characterization of a p75NTR Apoptotic Signaling Pathway Using a Novel Cellular Model.
X. Wang, J. H. Bauer, Y. Li, Z. Shao, F. S. Zetoune, E. Cattaneo, and C. Vincenz (2001)
J. Biol. Chem. 276, 33812-33820
   Abstract »    Full Text »    PDF »
The p75 Neurotrophin Receptor Activates Akt (Protein Kinase B) through a Phosphatidylinositol 3-Kinase-dependent Pathway.
P. P. Roux, A. L. Bhakar, T. E. Kennedy, and P. A. Barker (2001)
J. Biol. Chem. 276, 23097-23104
   Abstract »    Full Text »    PDF »
Role of p75 Neurotrophin Receptor in the Neurotoxicity by {beta}-amyloid Peptides and Synergistic Effect of Inflammatory Cytokines.
G. Perini, V. Della-Bianca, V. Politi, G. Della Valle, I. Dal-Pra, F. Rossi, and U. Armato (2002)
J. Exp. Med. 195, 907-918
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882