Role of APP phosphorylation in FE65-dependent gene transactivation mediated by AICD
Role of APP phosphorylation in FE65-dependent gene transactivation mediated by AICD
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DOI：
10.1111/j.1365-2443.2006.00968.x
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发表时间：
2006-06-01
期刊：
影响因子：
2.1
通讯作者：
Suzuki, Toshiharu
中科院分区：
文献类型：
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作者：
Nakaya, Tadashi;Suzuki, Toshiharu
阿尔茨海默氏病淀粉样β蛋白前体（APP）的连续切割产生胞内结构域片段（AICD）。APP和/或AICD与衔接蛋白FE 65的相互作用被认为调节APP的代谢和AICD的功能。APP和AICD在苏氨酸668（Thr 668）处的磷酸化或氨基酸取代抑制它们与FE 65的缔合。在此，我们分析了APP和AICD磷酸化在FE 65核转位中的作用。在脑中，AICD以磷酸化和非磷酸化形式存在，非磷酸化AICD主要在核中检测到。然而，突变型AICD（AICDA），其中AICD的Thr 668被替换为Ala，也主要定位于细胞核。这些观察结果表明，AICD的磷酸化不调节FE 65的易位，并且FE 65不伴随AICD进入细胞核。已知APP将FE 65拴系到膜上。我们发现APP的磷酸化释放了膜结合的FE 65，然后将其转运到细胞核中，在那里它上调了由AICD介导的基因反式激活，AICD独立于FE 65转运到细胞核中。因此，APP磷酸化而不是AICD通过调节FE 65细胞内定位来调节AICD介导的FE 65依赖性基因反式激活。
Consecutive cleavages of Alzheimer's amyloid beta-protein precursor (APP) generate intracellular domain fragment (AICD). Interaction of APP and/or AICD with the adaptor protein FE65 is thought to modulate the metabolism of APP and the function of AICD. Phosphorylation or amino acid substitution of APP and AICD at threonine 668 (Thr668) suppresses their association with FE65. Here, we analyzed the function of APP and AICD phosphorylation in the nuclear translocation of FE65. In brain, AICD was present as phosphorylated and non-phosphorylated forms with non-phosphorylated AICD being dominantly detected in the nucleus. However, a mutant AICD (AICDA), in which Thr668 of AICD was replaced with Ala, was also mostly localized to the nucleus. These observations indicate that phosphorylation of AICD does not regulate the translocation of FE65 and that FE65 does not accompany AICD into the nucleus. APP was known to tether FE65 to the membrane. We found that phosphorylation of APP liberated membrane-bound FE65, which was then translocated into the nucleus where it up-regulated gene transactivation mediated by AICD, which was translocated into the nucleus independently of FE65. Therefore, phosphorylation of APP but not AICD modulates FE65-dependent gene transactivation mediated by AICD through the regulation of FE65 intracellular localization.