2006 Fiscal Year Final Research Report Summary
Elucidation of the activation mechanisms and functions of ASK1
| Project/Area Number |
14086204
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | The University of Tokyo (2003-2006)
Tokyo Medical and Dental University (2002) |
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Principal Investigator |
TAKEDA Kohsuke The University of Tokyo, Graduate School of Pharmaceutical Sciences, Associate Professor (10313230)
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| Co-Investigator(Kenkyū-buntansha) |
ICHIJO Hidenori The University of Tokyo, Graduate School of Pharmaceutical Sciences, Professor (00242206)
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| Project Period (FY) |
2002 – 2006
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| Keywords | Stress / Signal transduction / MAP kinase / Apoptosis |
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| Research Abstract |
Cells are continuously exposed to a wide variety of physical, chemical, and biological stressors from both the external and internal environments. In order to adapt to or resist stress, cells are equipped with multiple signaling systems that elicit a wide range of stress responses. As a component of such signaling systems, we focused on apoptosis signal-regulating kinase 1 (ASK1), a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) of the c-Jun N-terminal kinase (JNK) and p38 MAPK pathways. In this project, we investigated the molecular mechanisms of ASK1 activation and its function in cell survival and apoptosis as well as cell differentiation. Finally, we demonstrated the following:
1) Endogenous ASK1 forms a high molecular mass complex. ASK1 is activated through the dissociation of inhibitory factors from the ASK1 complex followed by the reciprocal recruitment of activation factors to the complex (J. Biol. Chem., 2005).
2) We have identified a novel MAP3K, ASK2, which interacts with ASK1. ASK2 plays important roles in stress responses by forming a functional heteromeric complex with ASK1, in which ASK1 and ASK2 facilitate each other's activity by distinct mechanisms (J. Biol. Chem., 2007).
3) We have identified a novel protein phosphatase, PGLM, as an interacting protein of ASK1. PGLM appears to activate ASK1 by direct dephosphorylation of the phosphorylation site(s) that inhibits ASK1 activity.
4) ASK1 is activated in response to lipopolysaccharide (LPS) through ROS that are produced downstream of TLR4, and plays critical roles in innate immune response through the p38 pathway (Nat. Immunol., 2005).
5) ASK1 is required for wounding-induced infiltration and activation of macrophages, and functions as an inducer of wounding-induced hair growth in mice.
These findings strongly suggest that ASK1 plays critical roles in cellular response to a variety of stressors as an intermediate of the intracellular signaling system.
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Research Products
(46 results)
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[Journal Article] ASK1-dependent recruitment and activation of macrophages induce hair growth in skin wounds.2007
Author(s)
Osaka, N., Takahashi, T., Murakami, S., Matsuzawa, A., Noguchi, T., Fujiwara, T., Aburatani, H., Moriyama, K., Takeda, K., Ichijo, H.
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Journal Title
J. Cell Biol. 176
Pages: 903-909
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Apoptosis signal-regulating kinase 2 (ASK2) functions as a MAP3K in a heteromeric complex with ASK1.2007
Author(s)
Takeda, K., Shimozono, R., Noguchi, T., Umeda, T., Morimoto, Y., Naguro, I., Tobiume, K., Saitoh, M., Matsuzawa, A., Ichijo, H.
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Journal Title
J. Biol. Chem. 282
Pages: 7522-7531
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] GTP binding is essential to the protien kinase activity of LRRK2, a causative gene product for familial parkinson's disease.2007
Author(s)
Ito, G., Okai, T., Fujino, G., Takeda, K., Ichijo, H., Katada, T., Iwatsubo, T.
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Journal Title
Biochemistry 46
Pages: 1380-1388
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Chk2 kinase is required for methylglyoxal-induced G(2)/M cell-cycle checkpoint arrest : implication of cell-cycle checkpoint regulation in dabetic oxidative stress signaling.2007
Author(s)
Kani, S., Nakayama, E, Yoda, A., Onishi, N., Sougawa, N., Hazaka, Y., Umeda, T., Takeda, K., Ichijo, H., Hamada, Y., Minami, Y.
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Journal Title
Genes Cells 12
Pages: 919-928
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] ROS-dependent activation of TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity.2005
Author(s)
Matsuzawa, A., Saegusa, K., Noguchi, T., Sadamitsu, C., Nishitoh, H., Nagai, S., Koyasu, S., Matsumoto, K., Takeda, K., Ichijo, H.
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Journal Title
Nat. Immunol. 6
Pages: 587-592
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Amyloid β induces neuronal cell death through ROS-mediated ASK1 activation.2005
Author(s)
Kadowaki, H., Nishitoh, H., Urano, F., Sadamitsu, C, Matsuzawa, A., Takeda, K., Masutani, H., Yodoi, J., Urano, Y., Nagano, T., Ichijo, H.
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Journal Title
Cell Death Differ. 12
Pages: 19-24
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Recruitment of tumor necrosis factor receptor-associated factor family proteins to apoptosis signal-regulating kinase 1 signalosome is essential for oxidative stress-induced cell death.2005
Author(s)
Noguchi, T., Takeda, K., Matsuzawa, A., Saegusa, K., Nakano, H., Gohda, J., Inoue, J., Ichijo, H.
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Journal Title
J. Biol. Chem. 280
Pages: 37033-37040
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Involvement of ASK1 in Ca^<2+>-induced p38 MAP kinase activation.2004
Author(s)
Takeda, K., Matsuzawa, A., Nishitoh, H., Tobiume, K., Kishida, S., Ninomiya-Tsuji, J., Matsumoto, K., Ichijo. H.
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Journal Title
EMBO Rep. 5
Pages: 161-166
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] MAP Kinases in Redox Signaling. In Signal transduction by reactive oxygen and nitrogen species : Pathways and chemical principles, (Forman, H. J., Ed).2003
Author(s)
Matsuzawa, A., Nishitoh, H., Takeda, K., Ichijo, H.
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Journal Title
Kluwer Academic.
Pages: 223-236
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Apotosis-signal regulating kinase-1 is involved in low potassium-induced activation of p38 mitogen-activated protein kinase and c-Jun in cultured cerebellar granule neurons.2003
Author(s)
Yamagishi, S., Yamada, M., Koshimizu, H., Takai, S., Hatanaka, H., Takeda, K., Ichijo, H., Shimoke, K., Ikeuchi, T.
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Journal Title
J. Biochem. (Tokyo) 133
Pages: 719-724
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Phosphorylation and inactivation of myeloid cell leukemia-1 by JNK in response to oxidative stress.2002
Author(s)
Inoshita, S., Takeda. K., Hatai, T., Terada, Y., Sano, M., Hata, J., Umezawa, A., Ichijo, H.
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Journal Title
J. Biol. Chem. 277
Pages: 43730-43734
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Phosphorylation-dependent scaffolding role of JSAP1/JIP3 in the ASK1-JNK signaling pathway : A new mode of regulation of the MAP kinase cascade.2002
Author(s)
Matsuura, H., Nishitoh, H., Takeda, K., Matsuzawa, A., Amagasa, T., Ito, M., Yoshioka, K., Ichijo, H.
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Journal Title
J. Biol. Chem. 277
Pages: 40703-40709
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats.2002
Author(s)
Nishitoh, H., Matsuzawa, A., Tobiume, K., Saegusa, K., Takeda, K., Inoue, K., Hori, S., Kakizuka, A., Ichijo, H.
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Journal Title
Genes Dev. 16
Pages: 1345-1355
Description
「研究成果報告書概要(欧文)」より
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