TAK1 signaling network in tissue homeostasis

描述（由申请人提供）：TAK 1激酶是一种重要的信号传导中间体，涉及多种信号传导途径，包括TNF、IL-1和应激途径。我们最近证明，在多种上皮组织中靶向缺失TAK 1会导致细胞死亡和炎症。因此，TAK 1通过调节细胞死亡关键地参与组织稳态。尽管TAK 1对导致细胞因子产生的促炎信号传导的调节已经被很好地研究，但是调节细胞死亡的TAK 1途径仍然难以捉摸。我们已经确定TAK 1调节活性氧（ROS）的水平。TAK 1结合蛋白，TAB 1和TAB 2，差异参与TAK 1信号传导; TAB 2介导的奎宁诱导的TAK 1激活，而TAB 1介导的TAK 1激活特异性响应于应激。我们假设TAK 1通过调节ROS调节体内细胞存活和炎症，TAB 1和TAB 2调节TAK 1细胞存活信号，以响应每个蛋白质特有的刺激。长期目标是描绘TAK 1信号网络调节组织稳态。在短期内，我们的目标是确定TAK 1，TAB 1和TAB 2在ROS依赖性细胞死亡途径中的作用。该项目的结果将增强我们对组织稳态的理解，特别是ROS，细胞死亡和炎症的调节，这可能导致新的方法来改善许多与ROS相关的炎症状况。

DESCRIPTION (provided by applicant): TAK1 kinase is an essential signaling intermediate involving multiple signaling pathways including TNF, IL-1, and stress pathways. We have recently demonstrated that the targeted deletion of TAK1 in multiple epithelial tissues causes cell death and inflammatory conditions. Thus, TAK1 is critically involved in tissue homeostasis by regulating cell death. Although TAK1 regulation of pro-inflammatory signaling leading to cytokine production has been well studied, the TAK1 pathways regulating cell death remain elusive. We have identified that TAK1 regulates the level of reactive oxygen species (ROS). TAK1 binding proteins, TAB1 and TAB2, differentially participate in TAK1 signaling; TAB2 mediates cytokine-induced TAK1 activation, whereas TAB1 mediates activation of TAK1 specifically in response to stress. We hypothesize that TAK1 regulates cell survival and inflammation in vivo by modulating ROS, and that TAB1 and TAB2 regulate TAK1-cell survival signaling in response to stimulus unique to each protein. The long-term objective is to delineate the TAK1 signaling network regulating tissue homeostasis. In short- term, we aim to determine the roles of TAK1, TAB1 and TAB2 in ROS-dependent cell death pathway. Outcomes from this project will enhance our understanding of tissue homeostasis specifically regulation of ROS, cell death and inflammation, which could lead to new approaches to improve many inflammatory conditions that are associated with ROS.