| Project/Area Number |
11670498
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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 |
Gastroenterology
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| Research Institution | Osaka University |
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Principal Investigator |
ITO Nobuyuki Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (30273668)
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| Co-Investigator(Kenkyū-buntansha) |
INUI Yoshiaki Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (00294067)
TAMURA Shinji Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (30243223)
KAWATA Sumio Osaka University Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (90183285)
KISO Shinichi Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手
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| Project Period (FY) |
1999 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2000: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1999: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Keywords | angiogenesis / Flt-1 / Grap / signal transduction / endothelial cel / hepatocellular carcinom / SH2蛋白 |
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| Research Abstract |
We identified four tyrosine-phosphorylation sites on VEGF receptor-1 (Flt-1). PLC-γ, SHP-2, Grb2, Crk and Nck bind to Flt-1 in a phosphoyrosine-dependent manner. The analysis using mutant receptor-expressing cells indicates that the phosphorylation of Tyr1213 and Tyr1333 is essential for VEGF-induced endothelial cell growth. VEGF-induced signal was enhanced by coexpressing Flt-1 and another VEGF receptor, KDR.Heparin modulates the VEGF-induced signaling by enhancing PLC-γ phosphorylation.
We also identified a novel molecule that binds to Tyr1213 in a phosphotyrosine-dependent manner. Molecular cloning revealed this 27 kDa molecule has a high homology with human Grap (Grb2-related adaptor protein), indicating that this molecule was a mouse Grap. Grap has been shown to be expressed exclusively in hematopoietic cells. However, all kinds of endothelial cells we examined expressed Grap by RT-PCR, indicating the importance of this molecule in endothelial cell growth. In vitro studies showed that the SH3 domain of Grap binds c-Cb1 and Sos-1. Down stream of this signal transduction pathway should be further investigated.
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