PS1 regulates processing and signaling of ephrinB/EphB

描述（由申请人提供）：Eph受体（Eph）是受体酪氨酸激酶的最大家族。它们的配体，肝配蛋白，是膜结合肽，表明Eph-肝配蛋白系统调节细胞-细胞相互作用。Eph-肝配蛋白结合控制许多组织包括血管和神经系统的发育和功能。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上的肝配蛋白的结合在表达受体和配体的细胞中触发双向信号传导。这种信号可以导致相互作用的细胞的排斥和分离，或者增加粘附和突触形成。Eph-肝配蛋白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Eph-肝配蛋白复合物的内吞作用以及通过促进其组分的蛋白水解来控制这些事件。最近的研究表明EphB2-ephrinB2结合调节兴奋性突触的功能，包括NMDA受体的活性，从而调节突触可塑性和可能的记忆功能。此外，这种结合启动涉及Src激酶和EphB和ephrinB的磷酸化的信号级联。这个建议是基于我们的观察，PS1，一种参与阿尔茨海默病（AD）的蛋白质，与EphB2和ephrinB2形成复合物。EphB2与ephrinB2的结合刺激两种蛋白质的PS1/γ分泌酶切割。此外，PS 1/γ-分泌酶系统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相互作用引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。

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.