NRAGE, a novel MAGE protein, interacts with the p75 neurotrophin receptor and facilitates nerve growth factor-dependent apoptosis.

The mechanisms employed by the p75 neurotrophin receptor (p75NTR) to mediate neurotrophin-dependent apoptosis are poorly defined. Two-hybrid analyses were used to identify proteins involved in p75NTR apoptotic signaling, and a p75NTR binding partner termed NRAGE (for neurotrophin receptor-interacting MAGE homolog) was identified. NRAGE binds p75NTR in vitro and in vivo, and NRAGE associates with the plasma membrane when NGF is bound to p75NTR. NRAGE blocks the physical association of p75NTR with TrkA, and, conversely, TrkA overexpression eliminates NRAGE-mediated NGF-dependent death, indicating that interactions of NRAGE or TrkA with p75NTR are functionally and physically exclusive. NRAGE overexpression facilitates cell cycle arrest and permits NGF-dependent apoptosis within sympathetic neuron precursors cells. Our results show that NRAGE contributes to p75NTR-dependent cell death and suggest novel functions for MAGE family proteins.