Functional interaction of Fas‐associated phosphatase‐1 (FAP‐1) with p75NTR and their effect on NF‐κB activation

Abstract

The common neurotrophin receptor p75^NTR, a member of the tumor necrosis factor (TNF) receptor superfamily, plays an important role in several cellular signaling cascades, including that leading to apoptosis. FAP‐1 (Fas‐associated phosphatase‐1), which binds to the cytoplasmic tail of Fas, was originally 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 domain of FAP‐1 and C‐terminal Ser‐Pro‐Val residues of p75^NTR. Furthermore, cells expressing a FAP‐1/green fluorescent protein showed intracellular co‐localization of FAP‐1 and p75^NTR at the plasma membrane. To elucidate the functional role of this physical interaction, we examined TRAF6 (TNF receptor‐associated factor 6)‐mediated NF‐κB activation and tamoxifen‐induced apoptosis in 293T cells expressing p75^NTR. The results revealed that TRAF6‐mediated NF‐κB activation was suppressed by p75^NTR and that the p75^NTR‐mediated NF‐κB suppression was reduced by FAP‐1 expression. Interestingly, a mutant of the p75^NTR intracellular domain with a single substitution of a Met for Val in its C‐terminus, which cannot interact with FAP‐1, displayed enhanced pro‐apoptotic activity in 293T transfected cells. Thus, similar to Fas, FAP‐1 may be involved in suppressing p75^NTR‐mediated pro‐apoptotic signaling through its interaction with three C‐terminal amino acids (tSPV). Thus, FAP‐1 may regulate p75^NTR‐mediated signal transduction by physiological interaction through its third PDZ domain.