Activation of the small GTPase Rac is sufficient to disrupt cadherin-dependent cell-cell adhesion in normal human keratinocytes
Activation of the small GTPase Rac is sufficient to disrupt cadherin-dependent cell-cell adhesion in normal human keratinocytes
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DOI：
10.1091/mbc.11.11.3703
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发表时间：
2000-11-01
影响因子：
3.3
通讯作者：
Lamarche-Vane, N
中科院分区：
文献类型：
--
作者：
Braga, VMM;Betson, M;Lamarche-Vane, N
为了实现与相邻细胞的强粘附并维持压力和张力，上皮细胞发展出许多不同的专门粘附结构。这些结构的破坏发生在肿瘤进展过程中，伴随着转移细胞的成纤维细胞形态特征的发展。在lias转化过程中，Rac信号通路参与了钙粘蛋白依赖性粘附的破坏。我们表明，持续的Rac激活本身是足以拆解钙粘蛋白介导的接触角质形成细胞，在浓度和时间依赖性的方式。钙粘蛋白受体在整合素受体之前从连接处移除，这表明Rac激活的途径可以特异性地干扰钙粘蛋白功能。我们绘制了一个重要的区域，为中断的路口推定的第二效应结构域的Rac蛋白。有趣的是，虽然这个区域覆盖了诱导板状伪足所必需的结构域，但我们证明了钙粘蛋白复合物的分解是一种新的Rac活性，不同于Rac依赖的板状伪足形成。因为Rac活性对于迁移也是必需的，所以Rac是在肿瘤发生期间协调调节细胞-细胞和细胞-基质粘附的良好候选物。
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 lias 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 overlays 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.