A physiologic signaling role for the γ-secretase-derived intracellular fragment of APP
A physiologic signaling role for the γ-secretase-derived intracellular fragment of APP
复制标题
DOI：
10.1073/pnas.072033799
复制
发表时间：
2002-04-02
影响因子：
11.1
通讯作者：
LaFerla, FM
中科院分区：
文献类型：
--
作者：
Leissring, MA;Murphy, MP;LaFerla, FM
早老素介导称为γ-分泌酶的不寻常的膜内蛋白水解活性，其两种底物是Notch受体（Notch）和β-淀粉样前体蛋白（APP）。γ-分泌酶介导的APP裂解，如Notch的裂解，产生胞内片段[APP胞内结构域（AICD）1]，其形成转录活性复合物。我们现在证明了AICD在调节磷酸肌醇介导的钙信号传导中的功能作用。早老素的遗传消融或γ-分泌酶活性的药理学抑制（从而AICD的产生）通过涉及内质网钙储存调节的机制以剂量依赖性和可逆的方式减弱钙信号传导。缺乏APP（因此AICD）的细胞表现出类似的钙信号转导缺陷，和值得注意的是，这些干扰可以逆转与APP的结构包含一个完整的AICD转染，但不是由结构缺乏这个域。我们的研究结果表明，AICD调节磷酸肌醇介导的钙信号通过γ-分泌酶依赖的信号通路，这表明APP的膜内蛋白水解可能发挥类似于Notch的信号作用。
Presenilins mediate an unusual intramembranous proteolytic activity known as gamma-secretase, two substrates of which are the Notch receptor (Notch) and the beta-amyloid precursor protein (APP). gamma-Secretase-mediated cleavage of APP, like that of Notch, yields an intracellular fragment [APP intracellular domain (AICD)1 that forms a transcriptively active complex. We now demonstrate a functional role for AICD in regulating phosphoinositide-mediated calcium signaling. Genetic ablation of the presenilins or pharmacological inhibition of gamma-secretase activity (and thereby AICD production) attenuated calcium signaling in a dose-dependent and reversible manner through a mechanism involving the modulation of endoplasmic reticulum calcium stores. Cells lacking APP (and hence AICD) exhibited similar calcium signaling deficits, and-notably-these disturbances could be reversed by transfection with APP constructs containing an intact AICD, but not by constructs lacking this domain. Our findings indicate that the AICD regulates phosphoinositide-mediated calcium signaling through a gamma-secretase-dependent signaling pathway, suggesting that the intramembranous proteolysis of APP may play a signaling role analogous to that of Notch.