| Project/Area Number |
15207018
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Developmental biology
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| Research Institution | RIKEN |
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Principal Investigator |
HAYASHI Shigeo RIKEN, Morphogenetic Signaling Group, Group Director, 生態形成シグナル研究グループ, グループディレクター (60183092)
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| Co-Investigator(Kenkyū-buntansha) |
TSUDA Leo RIKEN, Morphogenetic Signaling Group, Researcher, 生態形成シグナル研究グループ, 研究員 (30333355)
INOUE Yoshiko RIKEN, Morphogenetic Signaling Group, Researcher, 生態形成シグナル研究グループ, 研究員 (60217916)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥20,150,000 (Direct Cost: ¥15,500,000、Indirect Cost: ¥4,650,000)
Fiscal Year 2004: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000)
Fiscal Year 2003: ¥10,400,000 (Direct Cost: ¥8,000,000、Indirect Cost: ¥2,400,000)
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| Keywords | Signaling / Drosophila / imaginal disc / Notch / Nedd4 / Deltex / endocytosis / ubiqitination / 付属肢 / エンドサイトーシス / ユビキチン / 成虫原基 / gfp / 気管 / 翅 / 細胞移動 |
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| Research Abstract |
Ligand-induced proteolytic cleavage and internalization of the plasma membrane receptor Notch leads to its activation. Ligand-independent, steady state internalization of Notch, however, does not lead to activation. The mechanism by which downstream effectors discriminate these bipartite modes of Notch internalization is not understood. Nedd4 is a HECT domain-containing E3 ubiquitin ligase that targets transmembrane receptors containing the PPSY motif for endocytosis. Deltex is a positive regulator of Notch signaling and encodes a putative ubiquitin ligase of the ring finger type. We show that Notch is ubiquitinated, and destabilized by Nedd4 in a manner requiring the PPSY motif in the Notch intracellular domain. Loss of Nedd4 function dominantly suppresses the Notch and Deltex mutant phenotypes and its hyper activation attenuates Notch activity. In tissue culture cells, dominant-negative form of Nedd4 blocks steady-state Notch internalization and activates Notch signaling independently of ligand binding, and this effect was further potentiated by Deltex. Nedd4 destines Deltex to degradation in a Notch-dependent manner. Nedd4 antagonizes Notch signaling by promoting internalization of Notch and degradation of Notch and Deltex. Those functions of Nedd4 may be important for the protection of unstimulated cells from sporadic activation of Notch signaling.
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