PS1 REGULATES CLEAVAGE OF EPHRINB LIGAND AND EPHB RECEPTOR

PS1 调节 EPHRINB 配体和 EPHB 受体的裂解

• 批准号: 6932686
• 负责人: ANASTASIOS GEORGAKOPOULOS
• 金额: $ 12.5万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6932686
• 关键词: Alzheimer' s disease; aspartic endopeptidases; biological signal transduction; clinical research; ephrins; growth factor receptors; human tissue; neural degeneration; neural plasticity; neuropathology; pathologic process; phosphorylation; postmortem; posttranslational modifications; presenilin; protein localization; receptor expression

Missence mutations in Presenilin-1 (PS1) are the most common cause of autosomal dominant familial Alzheimer's disease (FAD). PS1 controls the gamma-secretase cleavage of many type I transmembrane proteins. EphrinB proteins are type I transmembrane proteins that function as ligands for the ephrinB receptors (EphBs). The ephrinB-EphB system transmits cellular signals from both the receptor and the ligand thus constituting a bi-directional signaling system. The ephrinB-EphB interactions regulate important cellular processes in development and adulthood including cell migration, axon guidance, dendritic spine morphogenesis, angiogenesis and synaptic plasticity as well as cognitive processes regulating two forms of long-term synaptic plasticity that are important for information storage in the brain, the long-term potentiation (LTP) and the long-term depression (LTD). We found that PS1 controls the proteolytic processing of both ephrinB and ephB proteins by a gamma-secretase-like activity, producing carboxy terminal ephrinB and ephB fragments. Our data shows that ephrinB and ephB proteins are first processed by a metalloproteinase (MMP) activity to produce a membrane-bound carboxy terminal fragments termed CTF1s. These fragments are subsequently cleaved by the PS1/gamma-secretase system to produce carboxy terminal fragments termed CTF2s. We obtained data that cytoplasmic sequence of both ephB and ephrinB translocate to the nucleus where they may act as transcription factors. Nuclear localization of these sequences is regulated by the PS1/gamma-secretase system. We also observed that the PS1/gamma-secretase system regulates the ephB-induced phosphorylation of Src kinase, a process initiated by the eprhinB-ephB interaction. Src kinase acts as a second messenger regulating various cellular functions like phosphorylation of cytoskeletal proteins, assembly of focal adhesions, memory formation and neurodegeneration, functions severely impaired in AD. Thus, PS1 may control synaptic structure and function by affecting the physiological processing of ephrinB ligands and ephB receptors and the ephrinB-ephB-mediated signaling.

早老素-1(PS1)基因缺失突变是常染色体显性遗传性家族性阿尔茨海默病(FAD)最常见的原因。PS1控制着许多I型跨膜蛋白的伽马分泌酶的切割。EphinB蛋白是一种I型跨膜蛋白，其功能是EphB受体(EphB)的配体。EphB-EphB系统同时从受体和配体传递细胞信号，从而构成双向信号系统。EphB-EphB相互作用调节发育和成年期的重要细胞过程，包括细胞迁移、轴突引导、树突棘形态形成、血管生成和突触可塑性，以及调节两种形式的长期突触可塑性的认知过程，这两种形式的突触可塑性对大脑中的信息存储至关重要 (LTP)和长期抑郁(LTD)。我们发现，PS1通过一种伽马分泌酶样活性控制ePhinB和EphB蛋白的蛋白质降解过程，产生羧基末端的EphinB和EphB片段。我们的数据显示，EphB和EphB蛋白首先被金属蛋白酶(MMPs)处理，产生一种膜结合的羧基末端片段，称为CTF1s。这些片段随后被PS1/伽马分泌酶系统切割，产生称为CTF2s的羧基末端片段。我们得到了EphB和EphinB的胞质序列都转移到了细胞核的数据 在那里它们可以作为转录因子。这些序列的核定位受PS1/伽马分泌酶系统的调节。我们还观察到PS1/γ-分泌酶系统调节EphB诱导的Src激酶的磷酸化，这一过程是由eprhinB-EphB相互作用启动的。SRC激酶作为第二信使调节多种细胞功能，如细胞骨架蛋白的磷酸化、局部粘连的组装、记忆的形成和神经退行性变，这些功能在AD中严重受损。 因此，PS1可能通过影响EphB配体和EphB受体的生理过程以及EphB-EphB介导的信号转导来控制突触的结构和功能。