PS1 regulates processing and signaling of ephrinB/EphB

PS1 调节 ephrinB/EphB 的加工和信号传导

• 批准号: 7617165
• 负责人: NIKOLAOS K ROBAKIS
• 金额: $ 32.29万
• 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/7617165
• 关键词: Actins; Adhesions; Adult; Alzheimer' s Disease; Binding; Binding Proteins; Biological; Biological Process; Blood Vessels; Brain; Calcium; Cell Communication; Cell Separation; Cell physiology; Cells; Complex; Cytoskeleton; Data; Dendritic Spines; Development; Endocytosis; Eph Family Receptors; EphB2 Receptor; Ephrin B Receptor; Ephrins; Event; Excitatory Synapse; Family; Lead; Ligands; Link; Long-Term Potentiation; Mammals; Mediating; Membrane; Membrane Proteins; Memory; Morphogenesis; Movement; Mutation; N-Methyl-D-Aspartate Receptors; Nervous system structure; Organ; Peptides; Phosphorylation; Play; Process; Proteins; Proteolysis; Receptor Protein-Tyrosine Kinases; Regulation; Reporting; Research Personnel; Role; Signal Transduction; Structure; Surface; Synapses; Synaptic plasticity; System; Tissues; axon guidance; base; cell motility; computerized data processing; depression; gamma secretase; receptor; secretase; src-Family Kinases; synaptogenesis

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（由申请人提供）：Eph受体（Eph）是最大的受体酪氨酸激酶家族。它们的配体，肝配蛋白，是膜结合肽，表明肝配蛋白系统调节细胞间相互作用。肝配蛋白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-ephrin 相互作用调节细胞迁移、轴突引导和突触发生，而在成人大脑中，它们调节记忆相关功能，包括突触结构和长时程增强。 Eph 受体与相对细胞或细胞过程表面的肝配蛋白的结合触发受体和配体表达细胞中的双向信号传导。这种信号传导可以导致相互作用的细胞的排斥和分离，或者导致粘附和突触形成的增加。 Eph-ephrin 系统通过向肌动蛋白细胞骨架发出信号、触发膜结合 Eph-ephrin 复合物的内吞作用以及促进其成分的蛋白水解来控制这些事件。最近的报告表明，EphB2-ephrinB2 结合可调节兴奋性突触的功能，包括 NMDA 受体的活性，从而调节突触可塑性，可能还调节记忆功能。此外，这种结合启动涉及 Src 激酶以及 EphB 和 ephrinB 磷酸化的信号级联反应。该提议基于我们的观察，即与阿尔茨海默病 (AD) 相关的蛋白质 PS1 与 EphB2 和 ephrinB2 形成复合物。 EphB2 与 ephrinB2 的结合刺激 PS1/γ 分泌酶对两种蛋白的裂解。此外，PS 1/gamma-secretase.system 调节下游信号级联的传播，包括 Src 活性和 ephrinB2 的磷酸化。在这里，我们建议阐明 PS1 调节 EphB2/ephrinB2 相互作用触发的信号事件的机制。我们还将研究 FAD 相关的 PS1 突变对这些信号事件的影响。