@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{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{omori_matsumoto_ninomiya-tsuji_2011, title={Non-canonical beta-catenin degradation mediates reactive oxygen species-induced epidermal cell death}, volume={30}, ISSN={["0950-9232"]}, DOI={10.1038/onc.2011.49}, abstractNote={β-Catenin is constantly degraded through the ubiquitin-proteasomal pathway. In this study, we report that a different type of β-catenin degradation is causally involved in epidermal cell death. We observed that reactive oxygen species (ROS) caused β-catenin degradation in the epidermal cells through a caspase-dependent mechanism, which results in disruption of cell adhesion. Disruption of cell adhesion increased ROS and activated caspases. Upregulation of the intact β-catenin blocked ROS accumulation and caspase activation. These results indicate that a feed-forward loop consisting of ROS, caspases activation and β-catenin degradation induces epidermal cell death.}, number={30}, journal={ONCOGENE}, author={Omori, E. and Matsumoto, K. and Ninomiya-Tsuji, J.}, year={2011}, month={Jul}, pages={3336–3344} }
 @article{kajino-sakamoto_omori_nighot_blikslager_matsumoto_ninomiya-tsuji_2010, title={TGF-β–Activated Kinase 1 Signaling Maintains Intestinal Integrity by Preventing Accumulation of Reactive Oxygen Species in the Intestinal Epithelium}, volume={185}, ISSN={0022-1767 1550-6606}, url={http://dx.doi.org/10.4049/jimmunol.0903587}, DOI={10.4049/jimmunol.0903587}, abstractNote={Abstract}, number={8}, journal={The Journal of Immunology}, publisher={The American Association of Immunologists}, author={Kajino-Sakamoto, Rie and Omori, Emily and Nighot, Prashant K. and Blikslager, Anthony T. and Matsumoto, Kunihiro and Ninomiya-Tsuji, Jun}, year={2010}, month={Sep}, pages={4729–4737} }
 @article{kim_kajino-sakamoto_omori_jobin_ninomiya-tsuji_2009, title={Intestinal Epithelial-Derived TAK1 Signaling Is Essential for Cytoprotection against Chemical-Induced Colitis}, volume={4}, ISSN={["1932-6203"]}, DOI={10.1371/journal.pone.0004561}, abstractNote={Background We have previously reported that intestinal epithelium-specific TAK1 deleted mice exhibit severe inflammation and mortality at postnatal day 1 due to TNF-induced epithelial cell death. Although deletion of TNF receptor 1 (TNFR1) can largely rescue those neonatal phenotypes, mice harboring double deletion of TNF receptor 1 (TNFR1) and intestinal epithelium-specific deletion of TAK1 (TNFR1KO/TAK1IEKO) still occasionally show increased inflammation. This indicates that TAK1 is important for TNF-independent regulation of intestinal integrity. Methodology/Principal Findings In this study, we investigated the TNF-independent role of TAK1 in the intestinal epithelium. Because the inflammatory conditions were sporadically developed in the double mutant TNFR1KO/TAK1IEKO mice, we hypothesize that epithelial TAK1 signaling is important for preventing stress-induced barrier dysfunction. To test this hypothesis, the TNFR1KO/TAK1IEKO mice were subjected to acute colitis by administration of dextran sulfate sodium (DSS). We found that loss of TAK1 significantly augments DSS-induced experimental colitis. DSS induced weight loss, intestinal damages and inflammatory markers in TNFR1KO/TAK1IEKO mice at higher levels compared to the TNFR1KO control mice. Apoptosis was strongly induced and epithelial cell proliferation was decreased in the TAK1-deficient intestinal epithelium upon DSS exposure. These suggest that epithelial-derived TAK1 signaling is important for cytoprotection and repair against injury. Finally, we showed that TAK1 is essential for interleukin 1- and bacterial components-induced expression of cytoprotective factors such as interleukin 6 and cycloxygenase 2. Conclusions Homeostatic cytokines and microbes-induced intestinal epithelial TAK1 signaling regulates cytoprotective factors and cell proliferation, which is pivotal for protecting the intestinal epithelium against injury.}, number={2}, journal={PLOS ONE}, author={Kim, Jae-Young and Kajino-Sakamoto, Rie and Omori, Emily and Jobin, Christian and Ninomiya-Tsuji, Jun}, year={2009}, month={Feb} }
 @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} }
 @article{kim_omori_matsumoto_nunez_ninomiya-tsuji_2008, title={TAK1 is a central mediator of NOD2 signaling in epidermal cells}, volume={283}, ISSN={["1083-351X"]}, DOI={10.1074/jbc.M704746200}, abstractNote={Muramyl dipeptide (MDP) is a peptidoglycan moiety derived from commensal and pathogenic bacteria, and a ligand of its intracellular sensor NOD2. Mutations in NOD2 are highly associated with Crohn disease, which is characterized by dysregulated inflammation in the intestine. However, the mechanism linking abnormality of NOD2 signaling and inflammation has yet to be elucidated. Here we show that transforming growth factor β-activated kinase 1 (TAK1) is an essential intermediate of NOD2 signaling. We found that TAK1 deletion completely abolished MDP-NOD2 signaling, activation of NF-κB and MAPKs, and subsequent induction of cytokines/chemokines in keratinocytes. NOD2 and its downstream effector RICK associated with and activated TAK1. TAK1 deficiency also abolished MDP-induced NOD2 expression. Because mice with epidermis-specific deletion of TAK1 develop severe inflammatory conditions, we propose that TAK1 and NOD2 signaling are important for maintaining normal homeostasis of the skin, and its ablation may impair the skin barrier function leading to inflammation.}, number={1}, journal={JOURNAL OF BIOLOGICAL CHEMISTRY}, author={Kim, Jae-Young and Omori, Emily and Matsumoto, Kunihiro and Nunez, Gabriel and Ninomiya-Tsuji, Jun}, year={2008}, month={Jan}, pages={137–144} }
 @article{omori_morioka_matsumoto_ninomiya-tsuji_2008, title={TAK1 regulates reactive oxygen species and cell death in keratinocytes, which is essential for skin integrity}, volume={283}, ISSN={["1083-351X"]}, DOI={10.1074/jbc.M804513200}, abstractNote={Mice with a keratinocyte-specific deletion of Tak1 exhibit severe skin inflammation due to hypersensitivity to tumor necrosis factor (TNF) killing. Here we have examined the mechanisms underlying this hypersensitivity. We found that TAK1 deficiency up-regulates reactive oxygen species (ROS) resulting in cell death upon TNF or oxidative stress challenge. Because blockade of NF-κB did not increase ROS or did not sensitize cells to oxidative stress in keratinocytes TAK1 regulates ROS mainly through the mechanisms other than those mediated by NF-κB. We found that c-Jun was decreased in TAK1-deficient keratinocytes and that ectopic expression of c-Jun could partially inhibit TNF-induced increase of ROS and cell death. Finally, we show that, in an in vivo setting, the antioxidant treatment could reduce an inflammatory condition in keratinocyte-specific Tak1 deletion mice. Thus, TAK1 regulates ROS partially through c-Jun, which is important for preventing ROS-induced skin inflammation.}, number={38}, journal={JOURNAL OF BIOLOGICAL CHEMISTRY}, author={Omori, Emily and Morioka, Sho and Matsumoto, Kunihiro and Ninomiya-Tsuji, Jun}, year={2008}, month={Sep}, pages={26161–26168} }
 @article{inagaki_omori_kim_komatsu_scott_ray_yamada_matsumoto_mishina_ninomiya-tsuji_2008, title={TAK1-binding Protein 1, TAB1, Mediates Osmotic Stress-induced TAK1 Activation but Is Dispensable for TAK1-mediated Cytokine Signaling}, volume={283}, ISSN={["1083-351X"]}, DOI={10.1074/jbc.M807574200}, abstractNote={TAK1 kinase is an indispensable intermediate in several cytokine signaling pathways including tumor necrosis factor, interleukin-1, and transforming growth factor-β signaling pathways. TAK1 also participates in stress-activated intracellular signaling pathways such as osmotic stress signaling pathway. TAK1-binding protein 1 (TAB1) is constitutively associated with TAK1 through its C-terminal region. Although TAB1 is known to augment TAK1 catalytic activity when it is overexpressed, the role of TAB1 under physiological conditions has not yet been identified. In this study, we determined the role of TAB1 in TAK1 signaling by analyzing TAB1-deficient mouse embryonic fibroblasts (MEFs). Tumor necrosis factor- and interleukin-1-induced activation of TAK1 was entirely normal in Tab1-deficient MEFs and could activate both mitogen-activated protein kinases and NF-κB. In contrast, we found that osmotic stress-induced activation of TAK1 was largely impaired in Tab1-deficient MEFs. Furthermore, we showed that the C-terminal 68 amino acids of TAB1 were sufficient to mediate osmotic stress-induced TAK1 activation. Finally, we attempted to determine the mechanism by which TAB1 activates TAK1. We found that TAK1 is spontaneously activated when the concentration is increased and that it is totally dependent on TAB1. Cell shrinkage under the osmotic stress condition increases the concentration of TAB1-TAK1 and may oligomerize and activate TAK1 in a TAB1-dependent manner. These results demonstrate that TAB1 mediates TAK1 activation only in a subset of TAK1 pathways that are mediated through spontaneous oligomerization of TAB1-TAK1.}, number={48}, journal={JOURNAL OF BIOLOGICAL CHEMISTRY}, author={Inagaki, Maiko and Omori, Emily and Kim, Jae-Young and Komatsu, Yoshihiro and Scott, Greg and Ray, Manas K. and Yamada, Gen and Matsumoto, Kunihiro and Mishina, Yuji and Ninomiya-Tsuji, Jun}, year={2008}, month={Nov}, pages={33080–33086} }
 @article{kajino_omori_ishii_matsumoto_ninomiya-tsuji_2007, title={TAK1 MAPK kinase kinase mediates transforming growth factor-beta signaling by targeting SnoN oncoprotein for degradation}, volume={282}, ISSN={["1083-351X"]}, DOI={10.1074/jbc.M700875200}, abstractNote={Abstract Transforming growth factor-β (TGF-β) regulates a variety of physiologic processes through essential intracellular mediators Smads. The SnoN oncoprotein is an inhibitor of TGF-β signaling. SnoN recruits transcriptional repressor complex to block Smad-dependent transcriptional activation of TGF-β-responsive genes. Following TGF-β stimulation, SnoN is rapidly degraded, thereby allowing the activation of TGF-β target genes. Here, we report the role of TAK1 as a SnoN protein kinase. TAK1 interacted with and phosphorylated SnoN, and this phosphorylation regulated the stability of SnoN. Inactivation of TAK1 prevented TGF-β-induced SnoN degradation and impaired induction of the TGF-β-responsive genes. These data suggest that TAK1 modulates TGF-β-dependent cellular responses by targeting SnoN for degradation.}, number={13}, journal={JOURNAL OF BIOLOGICAL CHEMISTRY}, author={Kajino, Taisuke and Omori, Emily and Ishii, Shunsuke and Matsumoto, Kunihiro and Ninomiya-Tsuji, Jun}, year={2007}, month={Mar}, pages={9475–9481} }