PS 1 activates the P13k/Akt cell survival pathway

PS 1 激活 P13k/Akt 细胞存活途径

• 批准号: 6836447
• 负责人: NIKOLAOS K ROBAKIS
• 金额: $ 39.2万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6836447
• 关键词: apoptosis; biological signal transduction; cadherins; cell population study; flavin adenine dinucleotide; genetically modified animals; laboratory mouse; phosphatidylinositol 3 kinase; presenilin; protein tyrosine kinase; tissue /cell culture; transfection

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.

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着关键作用。它的靶点包括细胞死亡机制的组件，如bcl2和FOXO家族，对细胞生存至关重要的转录因子，以及参与阿尔茨海默病神经原纤维缠结(NFT)产生的GSK3_等激酶。早老素1(PS1)是一种跨膜蛋白，与家族性阿尔茨海默病(FAD)有关。经典的钙粘附素，包括上皮钙粘附素和神经钙粘附素，是主要的细胞-细胞黏附受体，参与几乎所有固体组织的发育、维持和功能。PS1结合钙粘附素并调节其功能和处理。利用PSI+/+和PS1基因敲除(PS1-/-)成纤维细胞，我们注意到PS1的缺失与细胞死亡和PI3K/Akt细胞存活通路活性降低有关。在PSI-/-细胞中重新引入PS1可以激活PI3K/Akt通路，使细胞免于凋亡，提示PS1介导了生存信号的传递。PSI诱导的细胞存活需要PI3K活性。这些数据表明，PS1激活了PI3K/Akt通路。钙粘附素通过促进钙粘附素与PI3K的P85亚单位结合来刺激PI3K/Akt通路。我们的数据显示，PS1稳定了钙粘蛋白/P85的结合，这表明了PS1细胞存活效应的机制。此外，我们获得了PS1在胰岛素生长因子(IGF)诱导的PI3K/Akt通路刺激中的重要作用的证据，表明PS1可能参与了酪氨酸激酶受体信号转导。几个PS1 Fad突变体表现出激活Akt或磷酸化GSK3[3 Kinase]的能力降低。本研究旨在探讨PS1的细胞存活功能、PSI介导的PI3K/Akt通路激活机制以及PS1 FAD突变对PI3K/Akt通路激活和细胞存活的影响。