Cheng A M, Saxton T M, Sakai R, Kulkarni S, Mbamalu G, Vogel W, Tortorice C G, Cardiff R D, Cross J C, Muller W J, Pawson T
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Cell. 1998 Dec 11;95(6):793-803. doi: 10.1016/s0092-8674(00)81702-x.
Proteins with SH2 and SH3 domains link tyrosine kinases to intracellular pathways. To investigate the biological functions of a mammalian SH2/SH3 adaptor, we have introduced a null mutation into the mouse gene for Grb2. Analysis of mutant embryonic stem cells, embryos, and chimeras reveals that Grb2 is required during embyrogenesis for the differentiation of endodermal cells and formation of the epiblast. Grb2 acts physiologically as an adaptor, since replacing the C terminus of the Ras activator Sos1 with the Grb2 SH2 domain yields a fusion protein that largely rescues the defects caused by the Grb2 mutation. Furthermore, Grb2 is rate limiting for mammary carcinomas induced by polyomavirus middle T antigen. These data provide genetic evidence for a mammalian Grb2-Ras signaling pathway, mediated by SH2/SH3 domain interactions, that has multiple functions in embryogenesis and cancer.
具有SH2和SH3结构域的蛋白质将酪氨酸激酶与细胞内信号通路相连。为了研究一种哺乳动物SH2/SH3衔接蛋白的生物学功能，我们在小鼠Grb2基因中引入了无效突变。对突变胚胎干细胞、胚胎和嵌合体的分析表明，在胚胎发育过程中，Grb2是内胚层细胞分化和上胚层形成所必需的。Grb2在生理上作为一种衔接蛋白发挥作用，因为用Grb2的SH2结构域替换Ras激活剂Sos1的C末端会产生一种融合蛋白，该融合蛋白在很大程度上挽救了由Grb2突变引起的缺陷。此外，Grb2是多瘤病毒中T抗原诱导的乳腺癌的限速因素。这些数据为哺乳动物Grb2-Ras信号通路提供了遗传学证据，该信号通路由SH2/SH3结构域相互作用介导，在胚胎发生和癌症中具有多种功能。
