The intracellular domain of the low density lipoprotein receptor-related protein modulates transactivation mediated by amyloid precursor protein and Fe65
The intracellular domain of the low density lipoprotein receptor-related protein modulates transactivation mediated by amyloid precursor protein and Fe65
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DOI：
10.1074/jbc.m306403200
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发表时间：
2003-10-17
影响因子：
4.8
通讯作者：
Hyman, BT
中科院分区：
文献类型：
--
作者：
Kinoshita, A;Shah, T;Hyman, BT
低密度脂蛋白相关蛋白（LRP）是一种跨膜受体，主要定位于肝细胞、成纤维细胞和神经元。它作为内吞受体和信号分子参与多种生物学过程。最近的报道表明，LRP在胞外域和跨膜结构域中经历连续的蛋白水解切割。后一种裂解由阿尔茨海默病相关γ-分泌酶活性介导，也裂解淀粉样前体蛋白（APP）和Notch，导致LRP胞质结构域（LRPICD）片段的释放。这个相对较小的胞质片段具有几个基序，LRP通过这些基序与各种细胞内衔接子和支架蛋白相互作用。然而，该片段的功能在很大程度上是未知的。在这里，我们表明，LRPICD易位到细胞核，在那里它与转录调节剂Tip 60共定位在细胞核中，Tip 60已知与Fe 65和APP衍生的细胞内结构域相互作用。LRPICD显著抑制由Tip 60介导的APP衍生的胞内结构域/Fe 65反式激活。LRPICD与细胞核中的Tip 60具有密切的相互作用，如荧光共振能量转移测定所示。这些观察结果表明，LRPICD具有一种新的信号传导功能，对细胞核中APP、Fe 65和Tip 60复合物的转录活性产生负面影响，并为LRP在转录调节中的功能提供了新的线索。
Low density lipoprotein-related protein (LRP) is a transmembrane receptor, localized mainly in hepatocytes, fibroblasts, and neurons. It is implicated in diverse biological processes both as an endocytic receptor and as a signaling molecule. Recent reports show that LRP undergoes sequential proteolytic cleavage in the ectodomain and transmembrane domain. The latter cleavage, mediated by the Alzheimer-related gamma-secretase activity that also cleaves amyloid precursor protein (APP) and Notch, results in the release of the LRP cytoplasmic domain (LRPICD) fragment. This relatively small cytoplasmic fragment has several motifs by which LRP interacts with various intracellular adaptor and scaffold proteins. However, the function of this fragment is largely unknown. Here we show that the LRPICD is translocated to the nucleus, where it colocalizes in the nucleus with a transcription modulator, Tip60, which is known to interact with Fe65 and with the APP-derived intracellular domain. LRPICD dramatically inhibits APP-derived intracellular domain/Fe65 transactivation mediated by Tip60. LRPICD has a close interaction with Tip60 in the nucleus, as shown by a fluorescence resonance energy transfer assay. These observations suggest that LRPICD has a novel signaling function, negatively impacting transcriptional activity of the APP, Fe65, and Tip60 complex in the nucleus, and shed new light on the function of LRP in transcriptional modulation.