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

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

From the  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  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

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 death executor). 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.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EMBL Data Bank with accession number(s) AF187064, AF187065, and AF187066.