Functional interaction of Fas-associated phosphatase-1 (FAP-1) with p75(NTR) and their effect on NF-kappa B activation

The common neurotrophin receptor p75(NTR), a member of the tumor necrosis f actor (TNF) receptor superfamily plays an important role in several cellula r signaling cascades, including that leading to apoptosis, FAP-1 (Fas-assoc iated phosphatase-1), which binds to the cytoplasmic tail of Fas, was origi nally identified as a negative regulator of Fas-mediated apoptosis. Here we have shown by co-immunoprecipitation that FAP-1 also binds to the p75(NTR) cytoplasmic domain in vivo through the interaction between the third PDZ d omain of FAP-1 and C-terminal Ser-Pro-Val residues of p75(NTR). Furthermore , cells expressing a FAP-1/green fluorescent protein showed intracellular c o-localization of FAP-1 and p75(NTR) at the plasma membrane, To elucidate t he functional role of this physical interaction, we examined TRAF6 (TNF rec eptor-associated factor 6)-mediated NF-kappa B activation and tamoxifen-ind uced apoptosis in 293T cells expressing p75(NTR). Th, results revealed that TRAF6-mediated NF-kappa B activation was suppressed by p75(NTR) and that t he p75(NTR)-mediated NF-kappa B suppression was reduced by FAP-1 expression . Interestingly, a mutant of the p75(NTR) intracellular domain with a singl e substitution of a Met for Val in its C-terminus, which cannot interact wi th FAP-1, displayed enhanced pro-apoptotic activity in 293T transfected cel ls, Thus, similar to Fas, FAP-1 may be involved in suppressing p75(NTR)-med iated pro-apoptotic signaling through its interaction with three C-terminal amino acids (tSPV), Thus, FAP-1 may regulate p75(NTR)-mediated signal tran sduction by physiological interaction through its third PDZ domain. (C) 199 9 Federation of European Biochemical Societies.