Mechanisms for negative regulation ofTAK1/MAPKKK in innate immune responses
| Project/Area Number |
18570180
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Cell biology
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| Research Institution | Kyushu University |
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Principal Investigator |
TAKAESU Giichi Kyushu University, Medical Institute of Bioregulation, Assistant Professor (60403995)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥4,020,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥420,000)
Fiscal Year 2007: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | Innate Immunity / Toll-like receptor (TLR) / Inflammatory cytokines / TAK1 / TAB1 / TAB2 / Negative regulation / Ubiquitin / HTLV- 1 / Tax / Proteome / キナーゼ / TLR |
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| Research Abstract |
TAK1, a member of the MAPKKK family protein kinases, plays a pivotal role in interleukin-1 signaling pathway as well as Toll-like receptor signaling pathway. Upon ligand binding, TAK1 is rapidly and transiently activated. Although there have been extensive studies on the activation mechanism of TAK1, it is still unclear how TAK1 activation is terminated. To identify negative regulator(s) for TAK1, we searched protein(s) that form a complex with activated TAK1. To this end,we first established HeLa cells stably expressing Tandem affinity purification (TAP)-tagged TAK1 at the level close to the endogenous one. Then, TAP-TAK1 was purified from the cells stimulated with IL-1beta, and co-purifiying proteins were identified by mass spectrometry. We identified an E3 ubiquitinligase X as a novel TAK1-binding protein. Biochemical analysis revealed that X can strongly inhibit TAK1-induced activation of NF-κB and coexpression of X significantly reduces the amount of TAK1-activator, TAB1. These results suggest that X is a good candidate for yet-to-be-identified negative regulator of TAK1. This study will contribute to our full understanding of how TAK1 is regulated in cytokine signaling as well as innate immune responses.
We have also studied a mechanism of TAK1 activation by HTLV-1 Tax protein. We found that Tax interacts with an adapter protein TAB2 and activates TAK1. Ubiquitination of Tax is likely to be essential for its ability to activate TAK1. Importantly,we demonstrated that TRAF2, 5, and 6 ofTRAF family proteins can induce polyubiquitination of Tax. To our knowledge, this is the first report on the cellular E3 ubiquitinligases towards Tax. This study should shed light on the molecular mechanisms for the oncogenic action of Tax.
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Report
(3 results)
Research Products
(18 results)
