Bardelli A, Longati P, Gramaglia D, Stella M C, Comoglio P M
Institute for Cancer Research and Treatment (IRCC), University of Torino School of Medicine, Candiolo, Italy.
Oncogene. 1997 Dec 18;15(25):3103-11. doi: 10.1038/sj.onc.1201561.
Activation of the HGF receptor, encoded by the c-MET protooncogene (Met receptor), triggers motility, matrix-invasion and branching morphogenesis in epithelial cells. It has recently been shown that the Met receptor interacts with Gab-1, an IRS-like adaptor protein, via the docking site (Y1349VHVNATY1356VNV) known to bind Grb2 and multiple SH2-containing signal transducers. Here we show that Gab1 is the major phosphorylation-substrate of the Met receptor and of its oncogenic variant Tpr-Met. A series of point mutations in the docking site established a direct correlation between the ability to recruit and phosphorylate Gab1 and the transforming potential. Interestingly, the mutations of either Y1356 or N1358 abolished the binding of both Grb2 and Gab1 in intact cells. Furthermore, peptides designed to block either the SH2 or the SH3 domains of Grb2 interfered with the receptor-Gab1 interaction. These data indicate that Gab1 coupling to the Met receptor requires binding of Grb2 and correlates with the transforming potential of Tpr-Met.
由原癌基因c-MET（Met受体）编码的HGF受体的激活，可触发上皮细胞的运动、基质侵袭和分支形态发生。最近研究表明，Met受体通过已知可结合Grb2和多个含SH2信号转导分子的对接位点（Y1349VHVNATY1356VNV）与IRS样衔接蛋白Gab-1相互作用。在此我们表明，Gab1是Met受体及其致癌变体Tpr-Met的主要磷酸化底物。对接位点的一系列点突变在招募和磷酸化Gab1的能力与转化潜能之间建立了直接关联。有趣的是，Y1356或N1358的突变消除了完整细胞中Grb2和Gab1的结合。此外，设计用于阻断Grb2的SH2或SH3结构域的肽干扰了受体与Gab1的相互作用。这些数据表明，Gab1与Met受体的偶联需要Grb2的结合，并且与Tpr-Met的转化潜能相关。
