@article{mihaly_sakamachi_ninomiya-tsuji_morioka_2017, title={Noncanocial cell death program independent of caspase activation cascade and necroptotic modules is elicited by loss of TGF beta-activated kinase 1}, volume={7}, ISSN={["2045-2322"]}, DOI={10.1038/s41598-017-03112-1}, abstractNote={Abstract}, journal={SCIENTIFIC REPORTS}, author={Mihaly, September R. and Sakamachi, Yosuke and Ninomiya-Tsuji, Jun and Morioka, Sho}, year={2017}, month={Jun} }
 @article{sakamachi_morioka_mihaly_takaesu_foley_fessler_ninomiya-tsuji_2017, title={TAK1 regulates resident macrophages by protecting lysosomal integrity}, volume={8}, ISSN={["2041-4889"]}, DOI={10.1038/cddis.2017.23}, abstractNote={Abstract}, journal={CELL DEATH & DISEASE}, author={Sakamachi, Yosuke and Morioka, Sho and Mihaly, September R. and Takaesu, Giichi and Foley, Julie F. and Fessler, Michael B. and Ninomiya-Tsuji, Jun}, year={2017}, month={Feb} }
 @article{morioka_sai_omori_ikeda_matsumoto_ninomiya-tsuji_2016, title={TAK1 regulates hepatic lipid homeostasis through SREBP}, volume={35}, ISSN={["1476-5594"]}, DOI={10.1038/onc.2015.453}, abstractNote={Sterol-regulatory element-binding proteins (SREBPs) are key transcription factors regulating cholesterol and fatty acid biosynthesis. SREBP activity is tightly regulated to maintain lipid homeostasis, and is modulated upon extracellular stimuli such as growth factors. While the homeostatic SREBP regulation is well studied, stimuli-dependent regulatory mechanisms are still elusive. Here we demonstrate that SREBPs are regulated by a previously uncharacterized mechanism through transforming growth factor-β activated kinase 1 (TAK1), a signaling molecule of inflammation. We found that TAK1 binds to and inhibits mature forms of SREBPs. In an in vivo setting, hepatocyte-specific Tak1 deletion upregulates liver lipid deposition and lipogenic enzymes in the mouse model. Furthermore, hepatic Tak1 deficiency causes steatosis pathologies including elevated blood triglyceride and cholesterol levels, which are established risk factors for the development of hepatocellular carcinoma (HCC) and are indeed correlated with Tak1-deficiency-induced HCC development. Pharmacological inhibition of SREBPs alleviated the steatosis and reduced the expression level of the HCC marker gene in the Tak1-deficient liver. Thus, TAK1 regulation of SREBP critically contributes to the maintenance of liver homeostasis to prevent steatosis, which is a potentially important mechanism to prevent HCC development.}, number={29}, journal={ONCOGENE}, author={Morioka, S. and Sai, K. and Omori, E. and Ikeda, Y. and Matsumoto, K. and Ninomiya-Tsuji, J.}, year={2016}, month={Jul}, pages={3829–3838} }
 @article{mihaly_morioka_ninomiya-tsuji_takaesu_2014, title={Activated Macrophage Survival Is Coordinated by TAK1 Binding Proteins}, volume={9}, ISSN={["1932-6203"]}, DOI={10.1371/journal.pone.0094982}, abstractNote={Macrophages play diverse roles in tissue homeostasis and immunity, and canonically activated macrophages are critically associated with acute inflammatory responses. It is known that activated macrophages undergo cell death after transient activation in some settings, and the viability of macrophages impacts on inflammatory status. Here we report that TGFβ- activated kinase (TAK1) activators, TAK1-binding protein 1 (TAB1) and TAK1-binding protein 2 (TAB2), are critical molecules in the regulation of activated macrophage survival. While deletion of Tak1 induced cell death in bone marrow derived macrophages even without activation, Tab1 or Tab2 deletion alone did not profoundly affect survival of naïve macrophages. However, in lipopolysaccharide (LPS)-activated macrophages, even single deletion of Tab1 or Tab2 resulted in macrophage death with both necrotic and apoptotic features. We show that TAB1 and TAB2 were redundantly involved in LPS-induced TAK1 activation in macrophages. These results demonstrate that TAK1 activity is the key to activated macrophage survival. Finally, in an in vivo setting, Tab1 deficiency impaired increase of peritoneal macrophages upon LPS challenge, suggesting that TAK1 complex regulation of macrophages may participate in in vivo macrophage homeostasis. Our results demonstrate that TAB1 and TAB2 are required for activated macrophages, making TAB1 and TAB2 effective targets to control inflammation by modulating macrophage survival.}, number={4}, journal={PLOS ONE}, author={Mihaly, September R. and Morioka, Sho and Ninomiya-Tsuji, Jun and Takaesu, Giichi}, year={2014}, month={Apr} }
 @article{ikeda_morioka_matsumoto_ninomiya-tsuji_2014, title={TAK1 Binding Protein 2 Is Essential for Liver Protection from Stressors}, volume={9}, ISSN={["1932-6203"]}, DOI={10.1371/journal.pone.0088037}, abstractNote={The liver is the first line of defense from environmental stressors in that hepatocytes respond to and metabolize them. Hence, hepatocytes can be damaged by stressors. Protection against hepatic cell damage and cell death is important for liver function and homeostasis. TAK1 (MAP3K7) is an intermediate of stressors such as bacterial moieties–induced signal transduction pathways in several cell types. Tak1 deficiency has been reported to induce spontaneous hepatocellular carcinoma. However, the regulatory mechanism of TAK1 activity in liver stress response has not yet been defined. Here we report that activation of TAK1 through TAK1 binding protein 2 (TAB2) is required for liver protection from stressors. We found that a bacterial moiety, lipopolysaccharides (LPS), activated TAK1 in primary hepatocytes, which was diminished by deletion of TAB2. Mice having hepatocyte-specific deletion of the Tab2 gene exhibited only late-onset moderate liver lesions but were hypersensitive to LPS-induced liver injury. Furthermore, we show that a chemical stressor induced greatly exaggerated liver injury in hepatocyte-specific Tab2-deficient mice. These results demonstrate that TAB2 is a sensor of stress conditions in the liver and functions to protect the liver by activating the TAK1 pathway.}, number={2}, journal={PLOS ONE}, author={Ikeda, Yuka and Morioka, Sho and Matsumoto, Kunihiro and Ninomiya-Tsuji, Jun}, year={2014}, month={Feb} }
 @misc{mihaly_ninomiya-tsuji_morioka_2014, title={TAK1 control of cell death}, volume={21}, ISSN={["1476-5403"]}, DOI={10.1038/cdd.2014.123}, abstractNote={Programmed cell death, a physiologic process for removing cells, is critically important in normal development and for elimination of damaged cells. Conversely, unattended cell death contributes to a variety of human disease pathogenesis. Thus, precise understanding of molecular mechanisms underlying control of cell death is important and relevant to public health. Recent studies emphasize that transforming growth factor-β-activated kinase 1 (TAK1) is a central regulator of cell death and is activated through a diverse set of intra- and extracellular stimuli. The physiologic importance of TAK1 and TAK1-binding proteins in cell survival and death has been demonstrated using a number of genetically engineered mice. These studies uncover an indispensable role of TAK1 and its binding proteins for maintenance of cell viability and tissue homeostasis in a variety of organs. TAK1 is known to control cell viability and inflammation through activating downstream effectors such as NF-κB and mitogen-activated protein kinases (MAPKs). It is also emerging that TAK1 regulates cell survival not solely through NF-κB but also through NF-κB-independent pathways such as oxidative stress and receptor-interacting protein kinase 1 (RIPK1) kinase activity-dependent pathway. Moreover, recent studies have identified TAK1's seemingly paradoxical role to induce programmed necrosis, also referred to as necroptosis. This review summarizes the consequences of TAK1 deficiency in different cell and tissue types from the perspective of cell death and also focuses on the mechanism by which TAK1 complex inhibits or promotes programmed cell death. This review serves to synthesize our current understanding of TAK1 in cell survival and death to identify promising directions for future research and TAK1's potential relevance to human disease pathogenesis.}, number={11}, journal={CELL DEATH AND DIFFERENTIATION}, author={Mihaly, S. R. and Ninomiya-Tsuji, J. and Morioka, S.}, year={2014}, month={Nov}, pages={1667–1676} }
 @article{morioka_broglie_omori_ikeda_takaesu_matsumoto_ninomiya-tsuji_2014, title={TAK1 kinase switches cell fate from apoptosis to necrosis following TNF stimulation}, volume={204}, number={4}, journal={Journal of Cell Biology}, author={Morioka, S. and Broglie, P. and Omori, E. and Ikeda, Y. and Takaesu, G. and Matsumoto, K. and Ninomiya-Tsuji, J.}, year={2014}, pages={607–623} }
 @article{morioka_omori_kajino_kajino-sakamoto_matsumoto_ninomiya-tsuji_2009, title={TAK1 kinase determines TRAIL sensitivity by modulating reactive oxygen species and cIAP}, volume={28}, ISSN={["1476-5594"]}, DOI={10.1038/onc.2009.110}, abstractNote={TNF-related apoptosis-inducing ligand (TRAIL) is a potent inducer of cell death in several cancer cells, but many cells are resistant to TRAIL. The mechanism that determines sensitivity to TRAIL-killing is still elusive. Here we report that deletion of TAK1 kinase greatly increased activation of caspase-3 and cell death after TRAIL stimulation in keratinocytes, fibroblasts and cancer cells. Although TAK1 kinase is involved in NF-κB pathway, ablation of NF-κB did not alter sensitivity to TRAIL. We found that TRAIL could induce accumulation of reactive oxygen species (ROS) when TAK1 was deleted. Furthermore, we found that TAK1 deletion induced TRAIL-dependent downregulation of cIAP, which enhanced activation of caspase-3. These results show that TAK1 deletion facilitates TRAIL-induced cell death by activating caspase through ROS and downregulation of cIAP. Thus, inhibition of TAK1 can be an effective approach to increase TRAIL sensitivity.}, number={23}, journal={ONCOGENE}, author={Morioka, S. and Omori, E. and Kajino, T. and Kajino-Sakamoto, R. and Matsumoto, K. and Ninomiya-Tsuji, J.}, year={2009}, month={Jun}, pages={2257–2265} }