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Signal transduction for cell proliferation, apoptosis and differentiation via receptor-type tyrosine kinase and Shc molecule.

通过受体型酪氨酸激酶和Shc分子进行细胞增殖、凋亡和分化的信号转导。

基本信息

批准号：
10680662
负责人：
SHIBUYA Masabumi
金额：
$ 2.5万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

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.

在我们以前的研究中，我们已经证明了缺乏全部自磷酸化酪氨酸残基的EGF受体突变体仍然通过Shc接头分子激活Ras-MAP激酶途径。在本项目中，我们进一步扩展了对EGF受体和血管内皮生长因子受体-2(KDR/Flk-1)信号转导的研究，并检测了来自受体的阳性或阴性信号。EGFR的负信号转导人上皮性癌细胞株A431过度表达EGFR，高浓度的EGF可诱导生长抑制和细胞凋亡。在这个系统中，我们发现泛蛋白激酶C抑制剂和PKC-Delta抑制剂，而不是经典的PKC抑制剂，抑制了EGFR的这一负信号。这些结果表明PKC-Delta参与了这一信号传递。利用高表达VEGFR(Flt-1或KDR)的NIH3T3细胞和原代内皮细胞，我们清楚地表明这两种受体在生化上是完全不同的。Flt-1对血管内皮生长因子有很高的亲和力(Kd=10 nM)，而KDR对配体的亲和力低一个数量级。然而，就激酶活性而言，KDR具有很强的酪氨酸激酶活性，而Flt-1具有非常弱的酪氨酸激酶活性。此外，还发现KdR通过γ-PKC途径产生有丝分裂信号，而不是RAS途径。