| Project/Area Number |
15590249
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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 |
General medical chemistry
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| Research Institution | The University of Tokushima |
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Principal Investigator |
KISHI Kazuhiro The University of Tokushima, Institute for Enzyme Research, Associate Professor, 分子酵素学研究センター, 助教授 (70284320)
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| Co-Investigator(Kenkyū-buntansha) |
EBINA Yousuke The University of Tokushima, Institute for Enzyme Research, Professor, 分子酵素学研究センター, 教授 (00112227)
OBATA Toshiyuki The University of Tokushima, Institute for Enzyme Research, Associate Professor, 分子酵素学研究センター, 助教授 (40325296)
YUASA Tomoyuki The University of Tokushima, Institute for Enzyme Research, Research Associate, 分子酵素学研究センター, 助手 (50304556)
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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 |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | insulin receptor / ubiquitination / internalization / APS / インスリン受容体 / インスリンシグナル伝達 / ノックアウトマウス / インスリン感受性亢進 |
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| Research Abstract |
APS, a tyrosine kinase adaptor protein containing pleckstrin homology and Src homology 2 domains, is rapidly and strongly tyrosine-phosphorylated by insulin receptor kinase upon insulin stimulation. We have previously shown that APS knockout mice increased insulin sensitivity and this enhancement is possibly due to increased insulin-response on adipose tissues. However, the function of APS in insulin signaling has heretofore remained unknown. Here, we report that APS enhanced ligand-dependent multi-ubiquitination of insulin receptor (IR) in CHO cells overexpressing the IR. This ubiquitination required SH2 domain, but not PH domain and C-terminal phosphorylation site of APS. This also required kinase activity and activation loop of the IR, but did not require IRS-1 binding site and C-terminal tyrosine residues of the IR. Overexpression of c-Src kinase inhibited the insulin-dependent ubiquitination of the IR. In addition, APS-mediated ubiquitination of the IR induced enhancement of the IR internalization, but did not affect the IR degradation. The enhancement of the IR internalization mediated by APS may explain the physiological phenotype of APS knockout mice.
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