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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM068812-08
Application #
8247818
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Marino, Pamela
Project Start
2004-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
8
Fiscal Year
2012
Total Cost
$349,446
Indirect Cost
$108,722
Name
North Carolina State University Raleigh
Department
Public Health & Prev Medicine
Type
Schools of Earth Sciences/Natur
DUNS #
042092122
City
Raleigh
State
NC
Country
United States
Zip Code
27695
Simmons, A N; Kajino-Sakamoto, R; Ninomiya-Tsuji, J (2016) TAK1 regulates Paneth cell integrity partly through blocking necroptosis. Cell Death Dis 7:e2196
Morioka, S; Sai, K; Omori, E et al. (2016) TAK1 regulates hepatic lipid homeostasis through SREBP. Oncogene 35:3829-38
Sai, Kazuhito; Morioka, Sho; Takaesu, Giichi et al. (2016) TAK1 determines susceptibility to endoplasmic reticulum stress and leptin resistance in the hypothalamus. J Cell Sci 129:1855-65
Lane, Jamie; Yumoto, Kenji; Azhar, Mohamad et al. (2015) Tak1, Smad4 and Trim33 redundantly mediate TGF-β3 signaling during palate development. Dev Biol 398:231-41
Mihaly, S R; Ninomiya-Tsuji, J; Morioka, S (2014) TAK1 control of cell death. Cell Death Differ 21:1667-76
Mihaly, September R; Morioka, Sho; Ninomiya-Tsuji, Jun et al. (2014) Activated macrophage survival is coordinated by TAK1 binding proteins. PLoS One 9:e94982
Ikeda, Yuka; Morioka, Sho; Matsumoto, Kunihiro et al. (2014) TAK1 binding protein 2 is essential for liver protection from stressors. PLoS One 9:e88037
Morioka, Sho; Broglie, Peter; Omori, Emily et al. (2014) TAK1 kinase switches cell fate from apoptosis to necrosis following TNF stimulation. J Cell Biol 204:607-23
Omori, Emily; Inagaki, Maiko; Mishina, Yuji et al. (2012) Epithelial transforming growth factor β-activated kinase 1 (TAK1) is activated through two independent mechanisms and regulates reactive oxygen species. Proc Natl Acad Sci U S A 109:3365-70
Takaesu, Giichi; Inagaki, Maiko; Takubo, Keiyo et al. (2012) TAK1 (MAP3K7) signaling regulates hematopoietic stem cells through TNF-dependent and -independent mechanisms. PLoS One 7:e51073

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