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 mediat e 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 (n) under bar eurotrophin (r) un der bar eceptor-interacting M (A) under bar (G) under bar (E) under bar hom olog) was identified. NRAGE binds p75NTR in vitro and in vivo, and NRAGE as sociates with the plasma membrane when NGF is bound to p75NTR. NRAGE blocks the physical association of p75NTR with TrkA, and, conversely, TrkA overex pression eliminates NRAGE-mediated NGF-dependent death, indicating that int eractions of NRAGE or TrkA with p75NTR are functionally and physically excl usive. NRAGE over-expression 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 nov el functions for MAGE family proteins.