TAK1 signaling network in tissue homeostasis

描述（由申请人提供）：TAK1激酶是一种重要的信号传导介质，涉及多种信号通路，包括TNF， IL-1和应激通路。我们最近证明，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，在组织稳态中起关键作用。虽然TAK1调控促炎信号导致细胞因子的产生已经得到了很好的研究，但TAK1调控细胞死亡的途径仍然难以捉摸。我们已经确定TAK1调节活性氧（ROS）的水平。TAK1结合蛋白TAB1和TAB2参与TAK1信号传导；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调节体内细胞存活和炎症，TAB1和TAB2调节TAK1细胞存活信号以响应每种蛋白特有的刺激。长期目标是描述调节组织稳态的TAK1信号网络。短期内，我们的目标是确定TAK1、TAB1和TAB2在ros依赖性细胞死亡通路中的作用。该项目的结果将增强我们对组织稳态的理解，特别是对ROS、细胞死亡和炎症的调节，这可能会带来新的方法来改善与ROS相关的许多炎症状况。

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. PUBLIC HEALTH RELEVANCE: To maintain tissue integrity, cells need to prevent unscheduled cell death, which could induce tissue damages and inflammation. In many tissues, potential cell death inducers such as cytokines and stressors constantly present even in normal conditions; however cells are resistant to those inducers. We have found that mice having deletion of TAK1 kinase in the epithelial tissues spontaneously develop tissue damages associated with cell death. This suggests that TAK1 kinase activity is important to prevent cell death in normal tissues. In this project, we will determine the mechanism by which TAK1 controls cell death and define how TAK1 kinase activity is regulated in normal tissues. The outcomes enhance our understanding of the regulatory mechanism of tissue integrity, which could lead new approaches to prevent tissue damage-associated pathogenic conditions.