A γ-secretase-independent mechanism of signal transduction by the amyloid precursor protein
A γ-secretase-independent mechanism of signal transduction by the amyloid precursor protein
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DOI：
10.1074/jbc.m502861200
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发表时间：
2005-11-04
影响因子：
4.8
通讯作者：
Yankner, BA
中科院分区：
文献类型：
--
作者：
Hass, MR;Yankner, BA
已经提出，γ-分泌酶介导的淀粉样前体蛋白（APP）胞内结构域（AICD）的释放导致核转位和通过与接头蛋白Fe 65和组蛋白乙酰转移酶Tip 60的复合物的信号传导。在这里，我们表明，APP和Fe 65激活转录通过Gal 4-Tip 60报告早老素-1/2-缺陷细胞缺乏AICD的一代。APP和Fe 65还在γ-分泌酶抑制剂存在下激活转录，该抑制剂防止人胚肾293和SH-SY 5 Y细胞中淀粉样β-肽的产生。与转录活性Notch胞内结构域相反，AICD的表达不激活转录。APP信号转导的另一种机制是通过识别Tip 60中的必需细胞周期蛋白依赖性激酶（CDK）磷酸化位点来提出的。这些Tip 60磷酸化位点的突变或用CDK抑制剂roscovitine处理阻断了APP通过Tip 60发出信号的能力。此外，APP通过依赖于CDK的磷酸化稳定Tip 60。亚细胞分级和共聚焦免疫荧光显示，APP招募Tip 60的膜室。因此，APP可能通过γ-分泌酶非依赖性机制向细胞核发出信号，该机制涉及Tip 60的膜螯合和磷酸化。
It has been proposed that gamma-secretase-mediated release of the amyloid precursor protein (APP) intracellular domain ( AICD) results in nuclear translocation and signaling through a complex with the adaptor protein Fe65 and the histone acetyltransferase Tip60. Here, we show that APP and Fe65 activate transcription through a Gal4-Tip60 reporter in presenilin-1/2-deficient cells lacking generation of AICD. APP and Fe65 also activated transcription in the presence of gamma-secretase inhibitors that prevent amyloid beta-peptide production in human embryonic kidney 293 and SH-SY5Y cells. In contrast to the transcriptionally active Notch intracellular domain, expression of AICD did not activate transcription. An alternative mechanism for APP signal transduction is suggested by the identification of essential cyclin-dependent kinase (CDK) phosphorylation sites in Tip60. Mutation of these Tip60 phosphorylation sites or treatment with the CDK inhibitor roscovitine blocked the ability of APP to signal through Tip60. Moreover, APP stabilized Tip60 through CDK-dependent phosphorylation. Subcellular fractionation and confocal immunofluorescence showed that APP recruited Tip60 to membrane compartments. Thus, APP may signal to the nucleus by a gamma-secretase-independent mechanism that involves membrane sequestration and phosphorylation of Tip60.