Amyloid precursor protein and presenilin1 interact with the adaptor GRB2 and modulate ERK1,2 signaling
Amyloid precursor protein and presenilin1 interact with the adaptor GRB2 and modulate ERK1,2 signaling
复制标题
DOI：
10.1074/jbc.m610146200
复制
发表时间：
2007-05-04
影响因子：
4.8
通讯作者：
Russo, Claudio
中科院分区：
文献类型：
--
作者：
Nizzari, Mario;Venezia, Valentina;Russo, Claudio
淀粉样前体蛋白 (APP) 以及早老素 1 和 2 在基因上与家族性阿尔茨海默病的发生有关。 APP 是一种单程跨膜蛋白，也是纤维状和有毒淀粉样β-肽的前体，这些肽被认为是导致阿尔茨海默病神经变性的原因。早老素是多通道膜蛋白，参与 APP 和其他信号受体和转导器的酶裂解。 APP 和早老素在阿尔茨海默病发展中的作用似乎与淀粉样β-肽的形成有关；然而，它们的生理功能、相互作用以及导致神经退行性变的分子机制尚不清楚。 APP 和早老素还参与与细胞内蛋白质的多种相互作用，其重要性正在研究中。在不同的 APP 相互作用蛋白中，我们的兴趣集中在 GRB2 接头蛋白上，它将细胞表面受体与细胞内信号通路连接起来。在这项研究中，我们通过免疫共沉淀实验、共聚焦和电子显微镜以及荧光共振能量转移实验提供了证据，证明 APP 和早老素1 与细胞中心体囊泡结构中的 GRB2 相互作用。这些相互作用的最终目标是 ERK1,2，它在有丝分裂中心体中以 PS1 和 APP 依赖性方式被激活。这些数据表明 APP 和早老素1 都可以成为调节 ERK1,2 和细胞周期的共同信号传导途径的一部分。
The amyloid precursor protein (APP) and the presenilins 1 and 2 are genetically linked to the development of familial Alzheimer disease. APP is a single-pass transmembrane protein and precursor of fibrillar and toxic amyloid-beta-peptides, which are considered responsible for Alzheimer disease neurodegeneration. Presenilins are multipass membrane proteins, involved in the enzymatic cleavage of APP and other signaling receptors and transducers. The role of APP and presenilins in Alzheimer disease development seems to be related to the formation of amyloid-beta-peptides; however, their physiological function, reciprocal interaction, and molecular mechanisms leading to neurodegeneration are unclear. APP and presenilins are also involved in multiple interactions with intracellular proteins, the significance of which is under investigation. Among the different APP-interacting proteins, we focused our interest on the GRB2 adaptor protein, which connects cell surface receptors to intracellular signaling pathways. In this study we provide evidence by co-immunoprecipitation experiments, confocal and electron microscopy, and by fluorescence resonance energy transfer experiments that both APP and presenilin1 interact with GRB2 in vesicular structures at the centrosome of the cell. The final target for these interactions is ERK1,2, which is activated in mitotic centrosomes in a PS1- and APP-dependent manner. These data suggest that both APP and presenilin1 can be part of a common signaling pathway that regulates ERK1,2 and the cell cycle.