Cell surface APP751 forms complexes with protease nexin 2 ligands and is internalized via the low density lipoprotein receptor-related protein (LRP)
Cell surface APP751 forms complexes with protease nexin 2 ligands and is internalized via the low density lipoprotein receptor-related protein (LRP)
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DOI：
10.1016/s0006-8993(96)00711-1
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发表时间：
1996-11-18
期刊：
影响因子：
2.9
通讯作者：
Glabe, CG
中科院分区：
文献类型：
--
作者：
Knauer, MF;Orlando, RA;Glabe, CG
含有Kunitz结构域的淀粉样前体蛋白（APP）的分泌型同种型也称为蛋白酶连接蛋白2（PN 2）。跨膜APP的正常蛋白水解加工（其导致大部分可溶性PN 2）在阿尔茨海默氏A β肽内裂解，从而阻止A β形成。最近的数据表明，可溶性PN 2通过低密度脂蛋白受体相关蛋白（LRP）被细胞内化，LRP结合多种配体，包括载脂蛋白E（apoE）[23]。然而，可溶性PN 2不能促进淀粉样蛋白的积累，因此我们检查了未加工的PN 2是否有助于淀粉样蛋白的积累。含有完整A β序列的APP 751的跨膜形式将与PN 2配体形成复合物。EGF结合蛋白（EGFBP），并被LRP内化。我们发现，向过表达APP 751的细胞中添加EGFBP可诱导这种淀粉样蛋白形式的APP的内化。39 kDa LRP受体相关蛋白（RAP）是LRP的拮抗剂，可阻断APP 751/PN 2的内化，这表明蛋白酶复合物形成后，可溶性和跨膜APP 751/PN 2存在共同的LRP介导的内化途径，先前的工作已经表明，跨膜APP的内化可以导致淀粉样蛋白生成羧基末端片段的形成和阿尔茨海默氏A β肽分泌的增加。我们的数据表明，PN 2的蛋白酶配体可能在改变APP加工途径以促进淀粉样蛋白形成中发挥重要作用，并且LRP可能是apoE和淀粉样蛋白加工途径交叉的点。
The secreted isoforms of the amyloid precursor protein (APP) that contain the Kunitz domain are also known as protease nexin 2 (PN2). Normal proteolytic processing of transmembrane APP, which results in the majority of soluble PN2, cleaves within the Alzheimer's A beta peptide, precluding A beta formation. Recent data indicate that soluble PN2 is internalized by cells via the low density lipoprotein receptor-related protein (LRP), which binds multiple Ligands including apolipoprotein E (apoE) [23]. However, soluble PN2 cannot contribute to amyloid accumulation, so we examined whether the unprocessed. transmembrane form of APP751 containing the intact A beta sequence would form complexes with a PN2 ligand. EGF binding protein (EGFBP), and be internalized by LRP. We found that the addition of EGFBP to cells overexpressing APP751 induced the internalization of this amyloidogenic form of APP. The 39 kDa LRP receptor associated protein (RAP), an antagonist for LRP, blocked the internalization of APP751/PN2, suggesting a common LRP-mediated internalization pathway for both soluble and transmembrane APP751/PN2 after protease complex formation, previous work has shown that internalization of transmembrane APP can lead to the formation of amyloidogenic carboxyl-terminal fragments and increased secretion of the Alzheimer's A beta peptide. Our data suggest the protease ligands for PN2 may play an important role in altering APP processing pathways to favor amyloid formation, and that LRP may be a point at which the apoE and amyloid processing pathways intersect.