由BCR-ABL诱导的瘤发生通过与GRB-2适应蛋白的SH2域的直接相互作用来介导
A M Pendergast1, L A Quilliam, L D Cripe
1Department of Pharmacology, Duke University Medical Center, Durham, North Carolina 27710.
Cell
|October 8, 1993
概括
BCR-ABL蛋白通过氨酸177与GRB-2结合,激活了对白血病发展至关重要的Ras信号传递. 这个部位的突变阻断了GRB-2的结合和转化,突出显示了Ras路径的致癌作用.
科学领域:
- 分子生物学分子生物学
- 在瘤学瘤学.
- 细胞信号传递 细胞信号传递
背景情况:
- BCR-ABL蛋白驱动费城染色体阳性白血病.
- Ras信号通路的激活对于细胞转化至关重要.
研究的目的:
- 为了研究BCR-ABL和GRB-2之间的相互作用.
- 确定这种相互作用在Ras通路激活和细胞转化中的作用.
主要方法:
- 共同免疫沉用于检测蛋白质复合体.
- 局部定向突变发生以改变氨酸177.
- 在初级骨髓和Rat1纤维细胞中进行细胞转化检测.
主要成果:
- 在体内,BCR-ABL与GRB-2形成复合体.
- 在BCR-ABL上,GRB-2与酸化氨酸177 (Y177) 结合.
- Y177转化为氨酸的突变取消了GRB-2结合和Ras激活.
- BCR-ABL Y177F突变体显示细胞转化受损.
结论:
- 由Y177调解的BCR-ABL-GRB-2相互作用对于Ras通路激活至关重要.
- 拉斯通路激活是BCR-ABL诱导瘤发生的关键机制.
- GRB-2在正常发育之外的瘤发生中发挥着重要作用.
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