FUNCTION OF THE FE65/APP COMPLEX

描述（由申请人提供）：FE 65是由三个蛋白质-蛋白质相互作用结构域组成的衔接蛋白。它包含一个WW域和两个PI域。FE 65通过其羧基末端PI结构域（PID 2）结合APP。FE 65最初被描述为转录激活因子，其可以在细胞核和细胞质中发现。后来证明它结合APP的胞质结构域，并深刻地改变APP的加工和运输。最近的报道表明，FE 65可以定位于细胞核，全长APP作为FE 65的胞质锚。FE 65 PID 1可以与转录因子CP 2/LSF/LBP 1结合，也可以与细胞核中的组蛋白乙酰转移酶Tip 60结合并调节转录。与缺口胞内结构域（NICD）类似，提示FE 65结合APP的γ-切割的胞质尾（γ-CTF）并易位至细胞核，在细胞核中其结合Tip 60并激活转录。 该提议的中心假设是，包括APP的γ-CTF片段和衔接子FE 65的复合物是转录的调节因子。 这项建议的具体目标是： 具体目标1。鉴定涉及FE 65和APP γ-切割胞质尾区的核大分子复合物。 具体目标2。发现其转录受FE 65/γ-CTF复合物调控的基因。 具体目标3。阐明调节FE 65/γ-CTF复合物形成和核转位的信号。

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.