NRAGE, A Novel MAGE Protein, Interacts with the p75 Neurotrophin Receptor and Facilitates Nerve Growth Factor–Dependent Apoptosis

Abstract

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.

Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system

“…A further recently identified interactor of p75, designated NRAGE homolog (neurotrophin receptor-interacting MAGE; MAGE is a protein family expressed in cancer tissues), mediates NGF-dependent apoptosis in sympathetic neuron precursor cells (Salehi et al 2000). NRAGE is widely expressed, mostly in developing tissues.…”

Receptors that mediate cellular dependence

“…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. 95 Another proapoptotic transmembrane protein has been identified that has a death domain very similar to that of p75 NTR , and this protein interacts with p75 NTR .…”

“…48 This finding is reminiscent of what was observed for the common neurotrophin receptor, p75 NTR . 49 On the other hand, Unc5H2 and 3 do not interact with NRAGE, and appear to require their death domains to induce apoptosis.…”

Activation of Rac GTPase by p75 Is Necessary for c-junN-Terminal Kinase-Mediated Apoptosis

“…The mechanism by which p75 activates JNK is still unknown. Although nine different molecules are known to interact with p75 to date, none of them has been linked to the JNK pathway (Casademunt et al, 1999;Chittka and Chao, 1999;Irie et al, 1999;Khursigara et al, 1999;Yamashita et al, 1999;Ye et al, 1999;Salehi et al, 2000). We therefore sought to find an upstream regulator that may be most proximal to the receptor.…”