14-3-3 Is Involved in p75 Neurotrophin Receptor-mediated Signal Transduction

The low affinity neurotrophin receptor (p75NTR) has been shown to mediate the apoptosis signaling to neural cells. However, the specific mechanisms of intracellular signal transduction of this process are largely unknown. To understand p75NTR-mediated signal transduction, we previously identified a protein that interacts with the intracellular domain of p75NTR, and we named it p75NTR-associated cell deathexecutor (NADE). To elucidate further the signaling mechanisms utilized by p75NTR and NADE, we screened for NADE-binding protein(s) with the yeast two-hybrid method, and we identified 14-3-3ε as a NADE-binding protein in vivo. To examine whether 14-3-3ε affects the induction of p75NTR-mediated apoptosis, wild type or various deletion mutant forms of 14-3-3ε were co-expressed in HEK293, PC12nnr5, and oligodendrocytes. Interestingly, transient expression of the mutant form of 14-3-3ε lacking the 208–255 amino acid region blocked nerve growth factor-dependent p75NTR/NADE-mediated apoptosis, although this mutant form of 14-3-3ε continued to associate with NADE. These results suggest that 14-3-3ε plays an important role in the modulation of nerve growth factor-dependent p75NTR/NADE-mediated apoptosis.