PS1 regulates processing and signaling of ephrinB/EphB

PS1 调节 ephrinB/EphB 的加工和信号传导

• 批准号: 7061271
• 负责人: NIKOLAOS K ROBAKIS
• 金额: $ 33.93万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7061271
• 关键词: NMDA receptors; aspartic endopeptidases; biological signal transduction; cell line; ephrins; flavin adenine dinucleotide; genetically modified animals; growth factor receptors; laboratory mouse; phosphorylation; presenilin; protein binding; protein structure function; protein tyrosine kinase; receptor expression

DESCRIPTION (provided by applicant): Eph receptors (Eph) are the largest family of receptor tyrosine kinases. Their ligands, the ephrin proteins, are membrane-bound peptides indicating that the Eph-ephrin system regulates cell-cell interactions. Eph-ephrin binding controls development and function of many tissues including the vascular and nervous systems. In the developing CNS, Eph-ephrin interactions regulate cell migration, axon guidance and synaptogenesis while in the adult brain they regulate memory-related functions, including synaptic structure and long-term potentiation. Binding of Eph receptors to ephrins on the surface of opposing cells or cellular processes triggers bi-directional signaling in both the receptor and the ligand expressing cells. This signaling can lead to repulsion and separation of the interacting cells or to increased adhesion and synapse formation. The Eph-ephrin systems control these events by signaling to the actin cytoskeleton, by triggering endocytosis of the membrane-bound Eph-ephrin complexes and by promoting proteolysis of their components. Recent reports show that EphB2-ephrinB2 binding regulates function of excitatory synapses, including activity of NMDA receptor, thus modulating synaptic plasticity and probably memory function. In addition, this binding initiates signaling cascades that involve Src kinases and phosphorylation of both EphB and ephrinB. This proposal is based on our observation that PS1, a protein involved in Alzheimer's disease (AD), forms complexes with both EphB2 and ephrinB2. Binding of EphB2 to ephrinB2 stimulates the PS1/gammasecretase cleavage of both proteins. Furthermore, the PS 1/gamma-secretase.system regulates propagation of downstream signaling cascades including Src activity and phosphorylation of ephrinB2. Here we propose to elucidate the mechanism by which PS1 regulates signaling events triggered by the EphB2/ephrinB2 interaction. We will also examine the effects of FAD-linked PS1 mutations on these signaling events.

描述(申请人提供)：Eph受体(Eph)是最大的受体酪氨酸激酶家族。它们的配基--伊弗林蛋白是膜结合肽，表明伊弗林系统调节细胞与细胞之间的相互作用。肾上腺素结合控制许多组织的发育和功能，包括血管和神经系统。在发育中的中枢神经系统中，Eph-eaffin相互作用调节细胞迁移、轴突引导和突触发生，而在成年大脑中，它们调节与记忆相关的功能，包括突触结构和长时程增强。Eph受体与对立细胞或细胞突起表面的肾上腺素结合，在表达受体和配体的细胞中触发双向信号。这种信号可以导致相互作用的细胞的排斥和分离，或者增加黏附和突触的形成。肾上腺素系统通过向肌动蛋白细胞骨架发出信号，通过触发膜结合的肾上腺素复合体的内吞作用以及通过促进其组成部分的蛋白分解来控制这些事件。最近的研究表明，EphB2-ewitinB2结合调节兴奋性突触的功能，包括NMDA受体的活性，从而调节突触的可塑性，可能还有记忆功能。此外，这种结合启动了涉及Src激酶和EphB和ePhinB的磷酸化的信号级联反应。这一建议是基于我们的观察，即PS1，一种与阿尔茨海默病(AD)有关的蛋白质，与EphB2和ePhinB2形成复合体。与EphB2结合可刺激两种蛋白的PS1/Gammasecrease裂解。此外，PS-1/γ-分泌酶系统调节下游信号级联信号的传播，包括src活性和ewitinB2的磷酸化。在这里，我们建议阐明PS1调节由EphB2/ewitinB2相互作用触发的信号事件的机制。我们还将研究FAD连锁PS1突变对这些信号事件的影响。