Phosphorylation and Spatial Localization of Tau Protein

Tau 蛋白的磷酸化和空间定位

• 批准号: 6529452
• 负责人: Gloria Lee
• 金额: $ 29.4万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-30 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6529452
• 关键词: PC12 cells; biological signal transduction; cell differentiation; cell line; cell membrane; enzyme activity; gel electrophoresis; immunoprecipitation; microtubules; neurons; phosphorylation; protein localization; protein protein interaction; protein structure function; protein tyrosine kinase; tau proteins; tissue /cell culture

DESCRIPTION (provided by applicant): Tau is a microtubule-associated protein that is the primary component of neurofibrillary tangles in Alzheimer's disease. Several other neurodegenerative disorders also exhibit abnormal tau lesions and mutations in the tau gene cause some of these diseases. The mechanisms underlying the formation of neurofibrillary tangles are unknown, as are the mechanisms through which mutations in the tau gene cause neurodegenerative disease. Tau's primary known function has been to stabilize and promote microtubule assembly. However, neurons have several microtubule-associated proteins endowed with similar properties and yet tau is uniquely associated with neurodegenerative disease. Similarly, tau is uniquely associated with axonal development although the basis for its role in the acquisition of neuronal cell polarity is not understood. Therefore, unique properties of tau may be responsible for its role in axonal development and neurodegenerative disease. Our laboratory has approached these issues by seeking to identify new functions for tau. We have found that the amino terminus of tau is associated with plasma membrane. We have also found that in neuronal cells, tau associates with the src family non-receptor tyrosine kinase fyn and that in vitro, a PXXP motif in tau interacts with the SH3 domain of src family non-receptor tyrosine kinases. In furthering these findings, we have obtained preliminary data suggesting that tau can increase the tyrosine kinase activity of fyn and that tau associates with membrane microdomains, also known as membrane rafts. We propose to (1) determine the effect of the tau-fyn interaction on the tyrosine kinase activity of fyn and on protein tyrosine phosphorylation in neuronal cells, (2) investigate the tyrosine phosphorylation of tau during signal transduction, (3) extend the characterization of tau in membrane rafts and determine if tau's localization in membrane rafts is dependent on fyn, and (4) investigate the role of tau in membrane rafts in neuronal differentiation. We hypothesize that the interaction between tau and fyn takes place in membrane rafts and that this interaction affects fyn activity, thereby affecting signal transduction. Also, given tau's location in membrane rafts, we speculate that the tyrosine phosphorylation of tau might act to transduce extracellular signals. Signal transduction pathways involving tau and A-beta may go awry during neurodegenerative diseases, leading to inappropriate cross talk between pathways that may culminate in abnormal tau phosphorylation and polymerization.

描述（由申请人提供）：Tau是一种微管相关蛋白 这是阿尔茨海默氏症神经系统缠结的主要成分 疾病其他几种神经退行性疾病也表现出异常的tau蛋白 Tau基因的损伤和突变导致其中一些疾病。的 神经元缠结形成的潜在机制尚不清楚， 是tau基因突变导致 神经退行性疾病Tau的主要已知功能是稳定 并促进微管组装。然而，神经元有几个 微管相关蛋白具有类似的特性，但tau是 与神经退行性疾病密切相关同样，tau是唯一 与轴突发育有关，尽管它在神经系统中的作用是基础， 神经元细胞极性的获得尚不清楚。因此，独特的 tau的性质可能是其在轴突发育中的作用的原因， 神经退行性疾病我们的实验室通过以下方式处理这些问题： 寻求确定tau的新功能。我们发现氨基 tau蛋白末端与质膜结合。我们还发现，在 在神经元细胞中，tau与src家族非受体酪氨酸激酶相关 在体外，tau蛋白中的PXXP基序与src的SH 3结构域相互作用 家族非受体酪氨酸激酶。为了进一步研究这些发现，我们 获得的初步数据表明，tau蛋白可以增加酪氨酸激酶， Fyn的活性和tau与膜微区的关联，也已知 作为膜筏。我们建议（1）确定tau-fyn的效果 对fyn酪氨酸激酶活性和蛋白酪氨酸的相互作用 （2）研究酪氨酸磷酸化 （3）扩展tau在信号转导过程中的特征， 膜筏，并确定tau蛋白在膜筏中的定位是否 依赖于fyn，和（4）研究tau蛋白在膜筏中的作用， 神经元分化我们假设tau蛋白和 fyn发生在膜筏，这种相互作用影响fyn 活性，从而影响信号转导。另外，考虑到陶的位置 膜筏，我们推测tau蛋白的酪氨酸磷酸化可能起作用， 来抑制细胞外信号。涉及tau蛋白的信号转导通路 和A-β可能会在神经退行性疾病中出错， 可能导致异常tau蛋白的通路之间的不适当串扰 磷酸化和聚合。