Salehi A H, Roux P P, Kubu C J, Zeindler C, Bhakar A, Tannis L L, Verdi J M, Barker P A
Centre for Neuronal Survival, Montreal Neurological Institute, McGill University, Quebec, Canada.
Neuron. 2000 Aug;27(2):279-88. doi: 10.1016/s0896-6273(00)00036-2.
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.
p75神经营养因子受体（p75NTR）介导神经营养因子依赖性细胞凋亡的机制尚不清楚。采用酵母双杂交分析来鉴定参与p75NTR凋亡信号传导的蛋白质，并鉴定出一个名为NRAGE（神经营养因子受体相互作用MAGE同源物）的p75NTR结合伴侣。NRAGE在体外和体内均能与p75NTR结合，当NGF与p75NTR结合时，NRAGE与质膜相关联。NRAGE阻断p75NTR与TrkA的物理结合，相反，TrkA的过表达消除了NRAGE介导的NGF依赖性死亡，表明NRAGE或TrkA与p75NTR的相互作用在功能和物理上是相互排斥的。NRAGE的过表达促进细胞周期停滞，并使交感神经元前体细胞内发生NGF依赖性细胞凋亡。我们的结果表明，NRAGE促成p75NTR依赖性细胞死亡，并提示MAGE家族蛋白具有新功能。
