TAK1 signaling network in tissue homeostasis

说明(申请人提供)：TAK1激酶是一种重要的信号中间体，涉及多个信号通路，包括肿瘤坏死因子、白介素1和应激通路。我们最近证明，在多种上皮组织中，TAK1的靶向缺失会导致细胞死亡和炎症。因此，TAK1通过调节细胞死亡在组织动态平衡中起关键作用。尽管TAK1调节促炎信号导致细胞因子的产生已经得到了很好的研究，但调节细胞死亡的TAK1通路仍然难以捉摸。我们已经发现TAK1调节ROS的水平。TAK1结合蛋白TAB1和TAB2分别参与TAK1信号转导，TAB2介导细胞因子诱导的TAK1激活，而TAB1介导TAK1在应激反应中的特异性激活。我们假设，TAK1通过调节ROS来调节体内的细胞生存和炎症，TAB1和TAB2通过对每种蛋白质特有的刺激反应来调节TAK1细胞的生存信号。长期目标是描绘调节组织内稳态的TAK1信号网络。短期内，我们的目标是确定TAK1、TAB1和TAB2在ROS依赖的细胞死亡途径中的作用。该项目的成果将加强我们对组织稳态的理解，特别是对ROS、细胞死亡和炎症的调节，这可能导致改善与ROS相关的许多炎症状况的新方法。

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.