Regulation of amyloid precursor protein (APP) phosphorylation and processing by p35.Cdk5 and p25/Cdk5
Regulation of amyloid precursor protein (APP) phosphorylation and processing by p35.Cdk5 and p25/Cdk5
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DOI：
10.1016/s0014-5793(03)00714-2
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发表时间：
2003-07-17
期刊：
影响因子：
3.5
通讯作者：
Ni, BH
中科院分区：
文献类型：
--
作者：
Liu, F;Su, Y;Ni, BH
提示淀粉样前体蛋白（APP）在Thr 668处的磷酸化状态在APP的蛋白水解裂解中起关键作用，其产生可溶性APP（β）（sAPP（β））和β-淀粉样肽（Abeta）（阿尔茨海默病（AD）患者大脑中老年斑的主要成分）或可溶性APP（α）（sAPP（α））和小于Abeta的肽。已知磷酸化App（Thr 668）的蛋白激酶之一是细胞周期蛋白依赖性激酶5（Cdk 5）。Cdk 5通过与其调节伴侣p35或其截短形式p25的结合而被激活，p25在AD脑中升高。然而，尚未报道p35和p25对APP（Thr 668）磷酸化和APP加工的比较作用。在本研究中，我们研究了APP（Thr 668）的磷酸化和APP加工介导的p35/Cdk 5和p25/Cdk 5在人神经母细胞瘤细胞株SH-SY 5 Y。p35和p25的瞬时过表达引起App（Thr 668）磷酸化的不同模式，具体地，p35增加成熟和未成熟APP的磷酸化，而p25主要升高未成熟APP的磷酸化。这些结果证实了Cdk 5参与APP加工，并表明p35和p25介导的Cdk 5活性导致离散的APP磷酸化。(C)2003年由Elsevier Science B. V.代表欧洲生物化学学会联合会出版。
The phosphorylation status of amyloid precursor protein (APP) at Thr668 is suggested to play a critical role in the proteolytic cleavage of APP, which generates either soluble APP(beta) (sAPP(beta)) and beta-amyloid peptide (Abeta), the major component of senile plaques in patient brains inflicted with Alzheimer's disease (AD), or soluble APP(alpha) (sAPP(alpha)) and a peptide smaller than Abeta. One of the protein kinases known to phosphorylate App(Thr668) is cyclin-dependent kinase 5 (Cdk5). Cdk5 is activated by the association with its regulatory partner p35 or its truncated form, p25, which is elevated in AD brains. The comparative effects of p35 and p25 on App(Thr668) phosphorylation and APP processing, however, have not been reported. In this study, we investigated APP(Thr668) phosphorylation and APP processing mediated by p35/Cdk5 and p25/Cdk5 in the human neuroblastoma cell line SH-SY5Y. Transient overexpression of p35 and p25 elicited distinct patterns of App(Thr668) phosphorylation, specifically, p35 increasing the phosphorylation of both mature and immature APP, whereas p25 primarily elevated the phosphorylation of immature APP. Despite these differential effects on APP phosphorylation, both p35 and p25 overexpression enhanced the secretion of Abeta, sAPP(beta), as well as sAPP,. These results confirm the involvement of Cdk5 in APP processing, and suggest that p35- and p25-mediated Cdk5 activities lead to discrete APP phosphorylation. (C) 2003 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.