Reactive oxygen species (ROS) are constantly generated as byproducts of respiration in normal cells, and upregulated by genotoxic stress and immune stimuli. Cell intrinsic elimination mechanisms for ROS normally function to prevent accumulation of ROS in cells. Ablation of such regulation results in ROS-induced cell death and inflammation, which is known to be causally associated with pathogenic conditions including chronic inflammatory diseases, diabetes and cancers. Therefore, better understanding of the cellular ROS regulation is integral for preventing these disease conditions.
Our research focuses on TAK1 kinase, a member of mitogen-activated protein kinase kinase kinase (MAPKKK), which is activated by stressors and immune stimuli. We utilized tissue-specific knockout mice of TAK1 kinase signaling and demonstrated that TAK1 signaling plays an indispensable role in the regulation of ROS in several tissues, and that ablation of TAK1 signaling impairs normal tissue homeostasis. Our current research is aimed at elucidation of the mechanisms of how TAK1 signaling regulates ROS and tissue homeostasis. We also focus on identification of the exact pathway of TAK1 activation in each tissue. Our research outcomes will provide better understanding of ROS regulation and may lead to new approaches to prevent ROS-mediated diseases.
- Sho Morioka Postdoctoral Research Associate
- September Mihaly Graduate Student
- Alicia Simmons Graduate Student
- Yosuke Sakamachi Graduate Student
- Kazuhito Sai Graduate Student
SELECTED PUBLICATIONS (2008-2013):
Takaesu, G., Inagaki, M., Takubo, K., Mishina, Y., Hess, P.R., Dean, G.A., Yoshimura, A., Matsumoto, K., Suda, T., and Ninomiya-Tsuji, J. (2012). TAK1 (MAP3K7) signaling regulates hematopoietic stem cells through TNF-dependent and -independent mechanisms. PLoS ONE 7, e51073.
Morioka, S., Inagaki, M., Komatsu, Y., Mishina, Y., Matsumoto, K., and Ninomiya-Tsuji, J. (2012). TAK1 kinase signaling regulates embryonic angiogenesis by modulating endothelial cell survival and migration. Blood 120, 3846-3857.
Omori, E., Inagaki, M., Mishina, Y., Matsumoto, K., and Ninomiya-Tsuji, J. (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. USA 109, 3365-3370.
Omori, E., Matsumoto, K., and Ninomiya-Tsuji, J. (2011). Non-canonical beta-catenin degradation mediates reactive oxygen species-induced epidermal cell death. Oncogene 30, 3336-3344.
Omori, E., Matsumoto, K., Zhu, S., Smart, R.C., and Ninomiya-Tsuji, J. (2010). Ablation of TAK1 upregulates reactive oxygen species and selectively kills tumor cells. Cancer Res. 70, 8417-8425.
Kajino-Sakamoto, R., Omori, E., Nighot, P.K., Blikslager, A.T., Matsumoto, K., and Ninomiya-Tsuji, J. (2010). TGF-β-activated kinase 1 signaling maintains intestinal integrity by preventing accumulation of reactive oxygen species in the intestinal epithelium. J. Immunol. 185, 4729-4737.
Broglie, P., Matsumoto, K., Akira, S., Brautigan, D.L., and Ninomiya-Tsuji, J. (2010). Transforming growth factor β-activated kinase 1 (TAK1) kinase adaptor, TAK1-binding protein 2, plays dual roles in TAK1 signaling by recruiting both an activator and an inhibitor of TAK1 kinase in tumor necrosis factor signaling pathway. J. Biol. Chem. 285, 2333-2339.
Morioka, S., Omori, E., Kajino, T., Kajino-Sakamoto, R., Matsumoto, K., and Ninomiya-Tsuji, J. (2009). TAK1 kinase determines TRAIL sensitivity by modulating reactive oxygen species and cIAP. Oncogene 28, 2257-2265.
Kim, J.Y., Kajino-Sakamoto, R., Omori, E., Jobin, C., and Ninomiya-Tsuji, J. (2009). Intestinal epithelial-derived TAK1 signaling is essential for cytoprotection against chemical-induced colitis. PLoS ONE 4, e4561.
Omori, E., Morioka, S., Matsumoto, K., and Ninomiya-Tsuji, J. (2008). TAK1 regulates reactive oxygen species and cell death in keratinocytes, which Is essential for skin integrity. J. Biol. Chem. 283, 26161-26168.
Kim, J.-Y., Omori, E., Matsumoto, K., Nunez, G., and Ninomiya-Tsuji, J. (2008). TAK1 is a central mediator of NOD2 signaling in epidermal cells. J. Biol. Chem. 283, 137-144.
Kajino-Sakamoto, R., Inagaki, M., Lippert, E., Akira, S., Robine, S., Matsumoto, K., Jobin, C., and Ninomiya-Tsuji, J. (2008). Enterocyte-derived TAK1 signaling prevents epithelium apoptosis and the development of ileitis and colitis. J. Immunol. 181, 1143-1152.
Inagaki, M., Omori, E., Kim, J.Y., Komatsu, Y., Scott, G., Ray, M.K., Yamada, G., Matsumoto, K., Mishina, Y., and Ninomiya-Tsuji, J. (2008). TAK1-binding protein 1, TAB1, mediates osmotic stress-induced TAK1 activation but Is dispensable for TAK1-mediated cytokine signaling. J. Biol. Chem. 283, 33080-33086.