TRAF family proteins interact with the common neurotrophin receptor and modulate apoptosis induction

The common neurotrophin receptor, p75(NTR), has been shown to signal in the absence of Trk tyrosine kinase receptors, including induction of neural ap optosis and activation of NF-kappa B. However, the mechanisms by which p75N TR initiates these intracellular signal transduction pathways are unknown. Here we report interactions between p75(NTR) and the six members of TRAF (t umor necrosis factor receptor-associated factors) family proteins. The bind ing of different TRAF proteins to p75(NTR) was mapped to distinct regions i n p75NTR. Furthermore, TRAF4 interacted with dimeric p75(NTR), whereas TRAF 2 interacted preferentially with monomeric p75(NTR). TRAF2-p75(NTR), TRAF4- p75(NTR), and TRAF6-p75(NTR) interactions modulated p75(NTR)-induced cell d eath and NF-kappa B activation with contrasting effects. Coexpression of TR AF2 with p75NTR enhanced cell death, whereas coexpression of TRAF6 was cyto protective. Furthermore, overexpression of TRAF4 abrogated the ability of d imerization to prevent the induction of apoptosis normally mediated by mono meric p75NTR. TRAF4 also inhibited the NF-KB response, whereas TRAF2 and TR AF6 enhanced p75NTR-induced NF-kappa B activation. These results demonstrat e that TRAF family proteins interact with p75(NTR) and differentially modul ate its NF-kappa B activation and cell death induction.