2003 Fiscal Year Final Research Report Summary
The signal pthway and the role of the discoidin domain receptor 2 (DDR2) which is stimulated by type I collagen
| Project/Area Number |
14570022
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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 anatomy (including Histology/Embryology)
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| Research Institution | Osaka City University |
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Principal Investigator |
IKEDA Kazuo Osaka City University, Graduate School of Medicine, Associate Professor, 大学院・医学研究科, 助教授 (80275247)
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| Co-Investigator(Kenkyū-buntansha) |
KAWADA Norifumi Osaka City University, Graduate School of Medicine, Assistant Professor, 大学院・医学研究科, 講師 (30271191)
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| Project Period (FY) |
2002 – 2003
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| Keywords | DDR2 / collagen / stellate cells / liver fibrosis / Src / Shc / MMP-2 |
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| Research Abstract |
Discoidin domain receptor 2 (DDR2) is an unusual receptor tyrosine kinase in that its ligand is fibrillar collagen rather than a growth factor-like peptide. We tested the signal pathway and the role of DDR2. DDR2 mRNA and protein were induced in hepatic stellate cells activated by primary culture or in vivo during liver injury. The receptor became tyrosine phosphotylated in response to type I collagen. The signaling of DDR2 increased expression of active matrix metalloproteinase 2. We also showed that DDR2 is unusual in that it requires Src activity to be maximally tyrosine phosphorylated, and that Src activity also promotes association of DDR2 with adaptor protein Shc. The interaction with Shc involves a portion of Shc not previously implicated in interaction with receptor tyrosine kinases. These results identify Src kinase and the adaptor protein Shc as key signaling intermediates in DDR2 signal transudction. To further investigate the relation between Src kinase and DDR2 in fibrotic liver, dominant negative Src expressing adeno vector, which expression was regulated by collagen 1A2 promoter, were injected in Thioacetoamide treated rats. Overexpression of dominant negative Src inhibited the phosphoiylation of DDR2 and reduced the histological fibrotic change. The data support a model in which Src and the DDR2 receptor cooperate in a regulated fashion to direct the phosphrylation of both the receptor and its targets.
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Research Products
(17 results)
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[Publications] Inagaki Y, Nemoto T, Kushida M, Sheng Y, Higashi K, Ikeda K, Kawada N, Shirasaki F, Takehara K, Sugiyama K, Fujii M, Yamauchi H, Nakao A, De Crombrugghe B, Watanabe T, Okazaki I.: "Interferon alfa down-regulates collagen gene transcription and suppresses experimental hepatic fibrosis in mice"Hepatology. 38(4). 890-899 (2003)
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「研究成果報告書概要(欧文)」より
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[Publications] Ikeda K, Wang LH, Torres R, Zhao H, Olaso E, eng FJ, Labrador P, Klein R, Lovett D, Yancopoulos GD, Friedman SL, Lin HC.: "Discoidin domain receptor 2 interacts with Src and Shc following its activation by type I collagen"J Biol Chem. 277(21). 19206-19212 (2002)
Description
「研究成果報告書概要(欧文)」より
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