Kimberly W T, Zheng J B, Guénette S Y, Selkoe D J
Department of Neurology, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA.
J Biol Chem. 2001 Oct 26;276(43):40288-92. doi: 10.1074/jbc.C100447200. Epub 2001 Sep 5.
The beta-amyloid precursor protein (APP) is a ubiquitous receptor-like molecule without a known function. However, the recent recognition that APP and Notch undergo highly similar proteolytic processing has suggested a potential signaling function for APP. After ligand binding, Notch is cleaved by the ADAM-17 metalloprotease followed by an intramembrane cleavage mediated by gamma-secretase. The gamma-secretase cut releases the Notch intracellular domain (NICD), which enters the nucleus and modulates transcription. Because APP is processed similarly by ADAM-17 and gamma-secretase, we reasoned that the APP intracellular domain (AICD) has a role analogous to the NICD. We therefore generated a plasmid encoding the AICD sequence and studied the subcellular localization of the expressed protein (C60). Our results demonstrate that the cytoplasmic domain of APP is a highly labile fragment that is stabilized by forming complexes with Fe65 and can then enter the nucleus in neurons and non-neural cells. These findings strongly support the hypothesis that APP signals in the nucleus in a manner analogous to the function of Notch.
β-淀粉样前体蛋白（APP）是一种普遍存在的类受体分子，其功能尚不清楚。然而，最近人们认识到APP和Notch经历高度相似的蛋白水解过程，这提示APP可能具有信号传导功能。配体结合后，Notch被ADAM-17金属蛋白酶切割，随后由γ-分泌酶介导进行膜内切割。γ-分泌酶切割释放出Notch细胞内结构域（NICD），其进入细胞核并调节转录。由于APP由ADAM-17和γ-分泌酶进行类似的加工，我们推测APP细胞内结构域（AICD）具有与NICD类似的作用。因此，我们构建了一个编码AICD序列的质粒，并研究了所表达蛋白（C60）的亚细胞定位。我们的结果表明，APP的细胞质结构域是一个高度不稳定的片段，通过与Fe65形成复合物而稳定，然后可进入神经元和非神经细胞的细胞核。这些发现有力地支持了以下假说：APP在细胞核中以类似于Notch功能的方式进行信号传导。
