PS1 REGULATES CLEAVAGE OF EPHRIN B LIGAND AND EPHB RECEPTOR

PS1 调节 Ephrin B 配体和 EPHB 受体的裂解

• 批准号: 7404585
• 负责人: ANASTASIOS GEORGAKOPOULOS
• 金额: $ 23.63万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7404585
• 关键词: Adult; Affect; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Binding; Brain; CD44 gene; Cell Nucleus; Cell Surface Receptors; Cell physiology; Cells; Cessation of life; Cleaved cell; Cognitive; Contractor; Cytoskeletal Proteins; Data; Dendritic Spines; Development; E-Cadherin; Ephrin B Receptor; ErbB4 gene; Focal Adhesions; Grant; Hippocampus (Brain); Information Storage; Integral Membrane Protein; Learning; Ligands; Link; Long-Term Depression; Long-Term Potentiation; Matrix Metalloproteinases; Mediating; Membrane; Memory; Metalloproteases; Morphogenesis; Mutation; Nerve Degeneration; Neurons; Nuclear; Phosphorylation; Physiological Processes; Play; Process; Proteins; Proteolytic Processing; Regulation; Research Personnel; Role; Second Messenger Systems; Signal Transduction; Structure; Surface; Synapses; Synaptic plasticity; System; Transactivation; angiogenesis; axon guidance; base; cell motility; familial Alzheimer disease; gamma secretase; neurotoxicity; presenilin-1; programs; protein function; receptor; second messenger; secretase; src-Family Kinases; synaptic function; tau phosphorylation; transcription factor; transmission process

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.

Presenilin-1 (PS1) 的错失突变是常染色体显性遗传家族性阿尔茨海默病 (FAD) 的最常见原因。 PS1 控制许多 I 型跨膜蛋白的 γ 分泌酶裂解。 EphrinB 蛋白是 I 型跨膜蛋白，作为 ephrinB 受体 (EphB) 的配体。 ephrinB-EphB 系统传递来自受体和配体的细胞信号，从而构成双向信号系统。 ephrinB-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、树突棘形态发生、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，这些过程对于大脑中的信息存储、长期增强非常重要。 （LTP）和长期抑郁（LTD）。我们发现 PS1 通过类似 γ 分泌酶的活性控制 ephrinB 和 ephB 蛋白的蛋白水解加工，产生羧基末端 ephrinB 和 ephB 片段。我们的数据显示，ephrinB 和 ephB 蛋白首先由金属蛋白酶 (MMP) 活性加工，产生膜结合的羧基末端片段，称为 CTF1。这些片段随后被 PS1/γ 分泌酶系统切割，产生称为 CTF2 的羧基末端片段。我们获得了 ephB 和 ephrinB 的细胞质序列易位到细胞核的数据 它们可以充当转录因子。这些序列的核定位由 PS1/γ 分泌酶系统调节。我们还观察到 PS1/γ 分泌酶系统调节 ephB 诱导的 Src 激酶磷酸化，这是由 eprhinB-ephB 相互作用启动的过程。 Src 激酶作为第二信使调节各种细胞功能，如细胞骨架蛋白的磷酸化、粘着斑的组装、记忆形成和神经变性，这些功能在 AD 中严重受损。 因此，PS1可能通过影响ephrinB配体和ephB受体的生理加工以及ephrinB-ephB介导的信号传导来控制突触结构和功能。