Lamorte L, Kamikura D M, Park M
Department of Biochemistry, McGill University Hospital Center, Montreal, Quebec, Canada.
Oncogene. 2000 Dec 7;19(52):5973-81. doi: 10.1038/sj.onc.1203977.
Cell transformation is associated with anchorage independent growth and morphological changes characterized by reduced adhesion and spreading. The molecular signals that control these events are poorly understood. The Met receptor tyrosine kinase is deregulated in human tumors and an oncogenic derivative of this receptor transforms cells. In this paper we demonstrate that fibroblasts transformed by the Met oncoprotein display decreased cell spreading consistent with the loss of actin stress fibers and vinculin staining focal adhesions. In contrast to control cells, focal adhesion kinase, p130Cas and paxillin are weakly or not detectably tyrosine phosphorylated in Met transformed cells. Moreover, although paxillin and p130Cas associate with the Crk adapter protein in control cells, they fail to associate with Crk in Met transformed cells, yet these cells are motile and capable of wound closure to the same extent as control cells. In Met transformed cells, Crk predominantly associates with the Cbl and Gab1docking proteins in a tyrosine phosphorylation dependent manner. The coupling of Gab1, but not Cbl, with Crk is retained in cells grown in suspension and enhances JNK activation. We propose that the loss of adhesion dependent signals required for cell cycle progression is compensated through Met induced Gab1/Crk signals.
细胞转化与不依赖贴壁生长以及形态变化相关，其特征为黏附减少和铺展受限。控制这些事件的分子信号尚不清楚。Met受体酪氨酸激酶在人类肿瘤中失调，该受体的一种致癌衍生物可使细胞发生转化。在本文中，我们证明由Met癌蛋白转化的成纤维细胞显示出细胞铺展减少，这与肌动蛋白应力纤维的丧失和粘着斑蛋白（vinculin）染色的粘着斑减少一致。与对照细胞相比，粘着斑激酶、p130Cas和桩蛋白（paxillin）在Met转化的细胞中酪氨酸磷酸化程度较弱或无法检测到。此外，尽管在对照细胞中桩蛋白和p130Cas与Crk衔接蛋白相关联，但在Met转化的细胞中它们无法与Crk相关联，然而这些细胞具有运动能力，并且能够在与对照细胞相同程度上实现伤口闭合。在Met转化的细胞中，Crk主要以酪氨酸磷酸化依赖的方式与Cbl和Gab1对接蛋白相关联。Gab1而非Cbl与Crk的偶联在悬浮培养的细胞中得以保留，并增强JNK激活。我们提出，细胞周期进程所需的依赖黏附信号的丧失通过Met诱导的Gab1/Crk信号得到补偿。
