Braga V M, Betson M, Li X, Lamarche-Vane N
Medical Research Council Laboratory for Molecular Cell Biology and the Department of Biochemistry and Molecular Biology, University College London, London WC1E 6BT, United Kingdom.
Mol Biol Cell. 2000 Nov;11(11):3703-21. doi: 10.1091/mbc.11.11.3703.
To achieve strong adhesion to their neighbors and sustain stress and tension, epithelial cells develop many different specialized adhesive structures. Breakdown of these structures occurs during tumor progression, with the development of a fibroblastic morphology characteristic of metastatic cells. During Ras transformation, Rac-signaling pathways participate in the disruption of cadherin-dependent adhesion. We show that sustained Rac activation per se is sufficient to disassemble cadherin-mediated contacts in keratinocytes, in a concentration- and time-dependent manner. Cadherin receptors are removed from junctions before integrin receptors, suggesting that pathways activated by Rac can specifically interfere with cadherin function. We mapped an important region for disruption of junctions to the putative second effector domain of the Rac protein. Interestingly, although this region overlaps the domain necessary to induce lamellipodia, we demonstrate that the disassembly of cadherin complexes is a new Rac activity, distinct from Rac-dependent lamellipodia formation. Because Rac activity is also necessary for migration, Rac is a good candidate to coordinately regulate cell-cell and cell-substratum adhesion during tumorigenesis.
为了与相邻细胞实现强黏附并承受压力和张力，上皮细胞会形成许多不同的特殊黏附结构。在肿瘤进展过程中，这些结构会遭到破坏，同时会出现转移细胞特有的成纤维细胞形态。在Ras转化过程中，Rac信号通路参与了钙黏蛋白依赖性黏附的破坏。我们发现，持续的Rac激活本身就足以以浓度和时间依赖性方式破坏角质形成细胞中钙黏蛋白介导的接触。钙黏蛋白受体在整合素受体之前从连接处移除，这表明Rac激活的信号通路可以特异性地干扰钙黏蛋白的功能。我们将连接处破坏的一个重要区域定位到Rac蛋白假定的第二个效应结构域。有趣的是，尽管该区域与诱导片状伪足所需的结构域重叠，但我们证明钙黏蛋白复合物的解体是一种新的Rac活性，不同于Rac依赖性片状伪足的形成。由于Rac活性对于迁移也是必需的，因此Rac很可能在肿瘤发生过程中协调调节细胞间和细胞与基质的黏附。
