PS 1 activates the P13k/Akt cell survival pathway

描述（由申请人提供）：细胞死亡增加是包括阿尔茨海默病（AD）在内的神经退行性疾病的标志。PI 3 K/Akt信号通路在细胞存活中起关键作用。它的靶点包括细胞死亡机制的组成部分，如BCL-2和FOXO家族，对细胞存活重要的转录因子，以及参与阿尔茨海默病神经元缠结（NFT）产生的激酶如GSK 3。早老素1（Presenilin 1，PS1）是一种跨膜蛋白，与家族性阿尔茨海默病（familial Alzheimer's disease，FAD）有关。经典的钙粘蛋白，包括上皮（E）-和神经（N）-钙粘蛋白，是参与几乎所有实体组织的发育、维持和功能的主要细胞-细胞粘附受体。PS1结合钙粘蛋白并调节其功能和加工。使用PSI+/+和PS1敲除（PS1-/-）成纤维细胞，我们注意到PS1的缺失与凋亡性细胞死亡和PI 3 K/Akt细胞存活途径活性降低相关。PS1在PSI-/-细胞中的重新引入激活PI 3 K/Akt通路并拯救细胞免于凋亡，表明PS1介导存活信号的传递。PSI诱导的细胞存活需要PI 3 K活性。这些数据表明PS1激活PI 3 K/Akt通路。钙粘蛋白粘附通过促进钙粘蛋白与PI 3 K的p85亚基的结合来刺激PI 3 K/Akt通路。我们的数据表明，PS1稳定的钙粘蛋白/p85协会建议的PS1细胞存活的影响机制。此外，我们获得的证据表明，PS1是重要的胰岛素生长因子（IGF）诱导的刺激PI 3 K/Akt途径，这表明PS1可能参与酪氨酸激酶受体信号。几种PS1 FAD突变体显示出激活Akt或磷酸化GSK 3 [3]激酶的能力降低。在这里，我们建议调查的细胞存活功能的PS1，参与的机制，在PS1介导的激活PI 3 K/Akt通路和PS1 FAD突变的PI 3 K/Akt通路的激活和细胞存活的影响。

DESCRIPTION (provided by applicant): Increased cell death is a hallmark of neurodegenerative diseases including Alzheimer's disease (AD). The PI3K/Akt signaling pathway plays critical roles in cell survival. Its targets include components of the cell death machinery, like the BCL-2 and FOXO families, transcription factors important for cell survival, and kinases like GSK3_ involved in the generation of neurofibrillary tangles (NFT) of Alzheimer's disease. Presenilin 1 (PS1) is a transmembrane protein involved in familial Alzheimer's disease (FAD). Classic cadherins, including epithelial (E)- and neural (N)-cadherins, are major cell-cell adhesion receptors involved in the development, maintenance and function of almost all solid tissues. PS1 binds cadherins and regulates their function and processing. Using PSI+/+ and PS1 knockout (PS1-/-) fibroblasts we noticed that absence of PS1 correlates with apoptotic cell death and decreased activity of the PI3K/Akt cell survival pathway. Re-introduction of PS1 in PSI-/- cells activates the PI3K/Akt pathway and rescues cells from apoptosis suggesting that PS1 mediates transmission of survival signals. PSI-induced cell survival requires PI3K activity. These data indicate that PS1 activates the PI3K/Akt pathway. Cadherin adhesion stimulates the PI3K/Akt pathway by promoting cadherin association with the p85 subunit of PI3K. Our data show that PS1 stabilizes the cadherin/p85 association suggesting a mechanism for the PS1 cell survival effects. Furthermore, we obtained evidence that PS1 is important for insulin growth factor (IGF)-induced stimulation of the PI3K/Akt pathway, suggesting that PS1 may be involved in tyrosine kinase receptor signaling. Several PS1 FAD mutants showed a decreased ability to activate Akt or to phosphorylate GSK3[3 kinase. Here we propose to investigate the cell survival function of PS1, the mechanisms involved in the PSI-mediated activation of the PI3K/Akt pathway and the effects of PS1 FAD mutations on the activation of the PI3K/Akt pathway and on cell survival.