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

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 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.

Brain-Expressed X-linked (BEX) proteins in human cancers

“…Differential expression of mouse BEX3 has been described. Mouse brain, heart, and lung express the highest level of BEX3 mRNA while stomach, small intestine, and muscle tissues express comparatively low levels of BEX3 mRNA [28]. BEX3 protein was detected in PC12 and PCNA cells only after treatment with proteasomal inhibitors suggesting that BEX3 expression is regulated by proteasomal degradation [29].…”

“…Mouse BEX3 was isolated from an embryo cDNA library by a yeast two-hybrid screening and named as NADE as it was identified as a p75NTR-associating protein [28]. Differential expression of mouse BEX3 has been described.…”

Receptors that mediate cellular dependence

“…This may be a Trk-dependent phenomenon, since it has been described almost exclusively in systems in which mismatched Trk members (e.g., Trk B with NGF or Trk A with BDNF) have been expressed. 2,8 It is also possible that the decision between ligand-induced apoptosis and ligand-inhibited apoptosis mediated by p75 NTR may depend on specific downstream mediators: for example, the interaction of p75 NTR with NADE induces apoptosis following ligand binding; 93 in contrast, TRAF2 has been shown to interact preferentially with monomeric p75 NTR and to induce apoptosis in the absence of NGF. 94 Other potential death-mediating p75 NTR interactors include NRAGE 49 and NRIF.…”

TCEAL7, a putative tumor suppressor gene, negatively regulates NF-κB pathway

“…Transcription elongation factor A-like 7 encodes TCEAL7 protein and has a sequence similarity with a small family of brain-expressed (Bex) proteins, bex1, bex2 and bex3 (Rapp et al, 1990;Mukai et al, 2000;Chien et al, 2005). It shares amino acid sequence homology with transcription elongation factor A-like 1 (TCEAL1/p21/SIIR/pp21) and pp21 homolog (WBP5/ TCEAL6) (Mukai et al, 2000(Mukai et al, , 2002.…”

“…It shares amino acid sequence homology with transcription elongation factor A-like 1 (TCEAL1/p21/SIIR/pp21) and pp21 homolog (WBP5/ TCEAL6) (Mukai et al, 2000(Mukai et al, , 2002. Although very little is known about the role of these proteins in cancer, pp21 homolog (TCEAL1) has been shown to suppress Rous sarcoma virus long-terminal repeat promoter activity and inhibit the transformation mediated by it in chicken embryo fibroblast (Yeh and Shatkin, 1994).…”