Phosphorylation and Spatial Localization of Tau Protein

描述(申请人提供)：tau是一种微管相关蛋白 这是阿尔茨海默病患者神经原纤维缠结的主要成分 疾病。其他几种神经退行性疾病也表现出异常的tau Tau基因的损伤和突变导致了其中一些疾病。这个 神经原纤维缠结形成的潜在机制尚不清楚，因为 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 促进微管组装。然而，神经元有几个 微管相关蛋白具有相似的性质，而tau 与神经退行性疾病有关。同样，tau也是独一无二的 与轴突发育有关，尽管它在 神经元细胞极性的获得尚不清楚。因此，独一无二 Tau的性质可能是其在轴突发育和 神经退行性疾病。我们的实验室通过以下方式探讨了这些问题 寻求确定tau的新功能。我们发现氨基 Tau的末端与质膜有关。我们还发现在 神经细胞，tau与src家族非受体酪氨酸激酶相关。 Fyn和在体外，tau中的PXXP基序与src的SH3结构域相互作用 非受体酪氨酸激酶家族。为了进一步推进这些发现，我们已经 获得的初步数据表明tau可以增加酪氨酸激酶 Fyn和tau活性与膜微域相关，也称为 就像膜筏一样。我们建议(1)确定tau-fyn的效果 Fyn与蛋白质酪氨酸相互作用对酪氨酸激酶活性的影响 神经细胞中的磷酸化，(2)研究酪氨酸的磷酸化 在信号转导过程中，(3)扩展了tau的特性 并确定tau在膜筏中的定位是否 依赖于Fyn，以及(4)研究tau在膜筏中的作用。 神经元分化。我们假设tau和tau之间的相互作用 FYN发生在膜筏中，这种相互作用影响FYN 活动，从而影响信号转导。另外，鉴于陶的位置在 膜筏，我们推测tau的酪氨酸磷酸化可能起作用。 来传递细胞外信号。涉及tau的信号转导通路 在神经退行性疾病期间，A-β可能会出错，导致 通路之间不适当的串扰，可能最终导致tau异常 磷酸化和聚合。

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.