FUNCTION OF THE FE65/APP COMPLEX

描述（由申请人提供）：FE65是一种由三个蛋白-蛋白相互作用结构域组成的适配器蛋白。它包含一个www域和两个PI域。FE65通过其羧基末端PI结构域（PID2）与APP结合。FE65最初被描述为转录激活因子，可以在细胞核和细胞质中发现。它后来被证明可以结合APP的细胞质结构域，并深刻地改变APP的加工和运输。最近的报道表明FE65可以定位到细胞核，全长APP可以作为FE65的细胞质锚点。FE65 PID1可以结合转录因子CP2/LSF/LBP1，也可以在细胞核内结合组蛋白乙酰转移酶Tip60并调节转录。与notch胞内结构域（NICD）类似，FE65结合到APP的γ -cleaved细胞质尾部（γ - ctf）并转运到细胞核，在那里它结合Tip60并激活转录。

DESCRIPTION (provided by applicant): FE65 is an adapter protein composed of three protein-protein interaction domains. It contains a WW domain and two PI domains. FE65 binds to APP through its carboxy-terminal PI domain (PID2). FE65 was initially described as a transcriptional activator, which can be found both in the nucleus and the cytoplasm. It was later shown to bind the cytoplasmic domain of APP and to profoundly alter APP processing and trafficking. Recent reports have shown that FE65 can localize to the nucleus and that full-length APP serves as a cytosolic anchor for FE65. FE65 PID1 can bind the transcription factor CP2/LSF/LBP1 and can also bind the histone acetyl transferase Tip60 in the nucleus and modulate transcription. In analogy to the notch intracellular domain (NICD), it is suggested that FE65 binds to the gamma-cleaved cytoplasmic tail of APP (gamma-CTF) and translocates to the nucleus where it binds Tip60 and activates transcription. The central hypothesis of this proposal is that a complex, including the gamma-CTF fragment of APP and the adaptor FE65, is a regulator of transcription. The specific aims of this proposal are: Specific Aim 1. To identify the nuclear macromolecular complex that involves FE65 and the gamma-cleaved cytoplasmic tail of APP. Specific Aim 2. To discover genes whose transcription is regulated by the FE65/gamma-CTF complex. Specific Aim 3. To elucidate signals that regulate the formation and nuclear translocation of the FE65/gamma-CTF complex.