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

FEBS Letters

Reed, John C¹  Bredesen, Dale E¹  Mukai, Jun³  Irie, Shinji³  Maruyama, Wakae³  Sato, Taka-Aki³  Rabizadeh, Shahrooz¹  Hachiya, Takahisa²  Li, Yin² 

[1] Burnham Institute, La Jolla, CA 92037, USA;Division of Molecular Oncology, Department of Otolaryngology/Head and Neck Surgery and Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA;Molecular Oncology Laboratory, Tsukuba Life Science Center, Institute of Physical and Chemical Research (RIKEN), Ibaraki 305-0074, Japan

关键词: Fas-associated phosphatase-1;    Protein-tyrosine phosphatase;    PDZ;    p75NTR;    Nerve growth factor;    Nuclear factor κB;    NGF;    nerve growth factor;    TNF;    tumor necrosis factor;    FAP-1;    Fas-associated phosphatase-1;    PTP;    protein-tyrosine phosphatase;    ICD;    intercellular domain;    PCR;    polymerase chain reaction;    GST;    glutathione S-transferase;    RT-PCR;    reverse transcription polymerase chain reaction;    GFP;    green fluorescent protein;    PBS;    phosphate-buffered saline;    PAGE;    polyacrylamide gel electrophoresis;   

DOI  :  10.1016/S0014-5793(99)01324-1

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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.

【 授权许可】

Unknown