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。PI3K/Akt信号通路在细胞存活中起重要作用。它的靶标包括细胞死亡机制的组成部分，比如BCL-2和FOXO家族，对细胞存活很重要的转录因子，以及像GSK3_这样的激酶，这些激酶与阿尔茨海默病神经原纤维缠结（NFT）的产生有关。早老素1 （PS1）是一种参与家族性阿尔茨海默病（FAD）的跨膜蛋白。经典的钙粘蛋白，包括上皮(E)-和神经(N)-钙粘蛋白，是主要的细胞-细胞粘附受体，参与几乎所有实体组织的发育、维持和功能。PS1结合钙粘蛋白并调节其功能和加工。通过PSI+/+和PS1敲除（PS1-/-）成纤维细胞，我们发现PS1缺失与凋亡细胞死亡和PI3K/Akt细胞存活通路活性降低相关。在PSI-/-细胞中重新引入PS1，激活PI3K/Akt通路，使细胞免于凋亡，提示PS1介导了存活信号的传递。psi诱导的细胞存活需要PI3K活性。这些数据表明PS1激活PI3K/Akt通路。Cadherin粘附通过促进Cadherin与PI3K的p85亚基的关联来刺激PI3K/Akt通路。我们的数据表明，PS1稳定了钙粘蛋白/p85的关联，这表明PS1细胞存活效应的机制。此外，我们获得的证据表明，PS1在胰岛素生长因子（IGF）诱导的PI3K/Akt通路的刺激中起重要作用，这表明PS1可能参与酪氨酸激酶受体信号传导。一些PS1 FAD突变体表现出激活Akt或磷酸化GSK3[3激酶的能力下降。本研究拟探讨PS1的细胞存活功能、PS1介导的PI3K/Akt通路激活的机制以及PS1 FAD突变对PI3K/Akt通路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.