| Project/Area Number |
10680662
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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 | The University of Tokyo |
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Principal Investigator |
SHIBUYA Masabumi Inst. Med. Sci. Univ. Tokyo, Prof., 医科学研究所, 教授 (10107427)
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| Co-Investigator(Kenkyū-buntansha) |
GOTOH Noriko Inst. Med. Sci. Univ. Tokyo, Res. Assoc., 医科学研究所, 助手 (10251448)
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| Project Period (FY) |
1998 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 1999: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1998: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Keywords | EGFR / VEGFR / Shc / tyrosine kinase / C-kinase / Ras / 受容体 / アダプター / シグナル伝達 / アポトーシス / 分化 / 増殖 / EGF / 細胞増殖抑制 / p21 |
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| Research Abstract |
In our previous studies, we have shown that EGF receptor mutant lacking all autophosphorylation tyrosine residues still activates Ras-MAP kinase pathway via Shc adaptor molecule. In this project, we further extended our research on the signal transduction from EGF-receptor and VEGF-receptor-2 (KDR/Flk-1), and examined positive or negative signal from the receptors.
1). Negative signal transduction from EGFR.
Human epithelial carcinoma cell line A431 overexpresses EGFR, and a high concentration of EGF has been shown to induce grown suppression and apoptotic cell death. In this system we found that pan-Protein kinase-C inhibitor and PKC-delta-inhibitor, but not classical PKC-inhibitor suppressed this negative signal from EGFR. These results suggest that PKC-delta is involved in this signaling.
2). Signal transduction from VEGFRs.
Using NIH3T3 cells overexpressing VEGFR (Flt-1 or KDR) as well as primary endothelial cells, we clearly showed that these two receptors are biochemically quite different. Flt-1 has a high affinity (Kd= about 10 nM) to VEGF, whereas KDR showed one order lower affinity to the ligand. In terms of the kinase activity, however, KDR had a strong tyrosine kinase activity but Flt-1 had a very weak one. In addition, KDR was found to generate a mitotic signal via PLCγ-PKC pathway but not Ras pathway.
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