Keratin 8/18 regulation of cell stiffness-extracellular matrix interplay through modulation of Rho-mediated actin cytoskeleton dynamics.
Keratin 8/18 regulation of cell stiffness-extracellular matrix interplay through modulation of Rho-mediated actin cytoskeleton dynamics.
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DOI：
10.1371/journal.pone.0038780
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Marceau N
中科院分区：
文献类型：
--
作者：
Bordeleau F;Myrand Lapierre ME;Sheng Y;Marceau N
由细胞外基质（ECM）和肌动蛋白细胞骨架之间的相互作用产生的细胞机械活性对于正常和癌症发展期间的细胞粘附、扩散和迁移的调节是必不可少的。角蛋白是上皮细胞的中间丝（IF）蛋白，以谱系/分化方式成对表达。肝上皮细胞IF仅由角蛋白8/18（K8/K18）组成，角蛋白8/18是所有简单上皮的标志。值得注意的是，我们最近对这些上皮细胞的研究揭示了K8/K18 IF在粘附/迁移中的关键调节功能，通过调节整合素与ECM、肌动蛋白衔接子和信号分子在粘着斑处的相互作用。在这里，使用K8基因敲除大鼠H4肝癌细胞和他们的K8/K18含对应物接种在不同刚度的纤连蛋白包被的基质，我们表明，K8/K18 IF缺乏细胞失去了传播能力，并表现出改变肌动蛋白纤维组织，接种在低刚度的基质。我们还证明了伴随的局部细胞刚度减少，在局灶性粘连所产生的纤维连接蛋白包被的微珠连接到背侧细胞表面。此外，我们发现，这种K8/K18 IF调制的细胞硬度和肌动蛋白纤维组织发生通过RhoA-ROCK信号。总之，这些结果揭示了K8/K18 IF通过调节简单上皮细胞中的Rho依赖性肌动蛋白组织和动力学对细胞硬度-ECM硬度相互作用的贡献。
Cell mechanical activity generated from the interplay between the extracellular matrix (ECM) and the actin cytoskeleton is essential for the regulation of cell adhesion, spreading and migration during normal and cancer development. Keratins are the intermediate filament (IF) proteins of epithelial cells, expressed as pairs in a lineage/differentiation manner. Hepatic epithelial cell IFs are made solely of keratins 8/18 (K8/K18), hallmarks of all simple epithelia. Notably, our recent work on these epithelial cells has revealed a key regulatory function for K8/K18 IFs in adhesion/migration, through modulation of integrin interactions with ECM, actin adaptors and signaling molecules at focal adhesions. Here, using K8-knockdown rat H4 hepatoma cells and their K8/K18-containing counterparts seeded on fibronectin-coated substrata of different rigidities, we show that the K8/K18 IF-lacking cells lose their ability to spread and exhibit an altered actin fiber organization, upon seeding on a low-rigidity substratum. We also demonstrate a concomitant reduction in local cell stiffness at focal adhesions generated by fibronectin-coated microbeads attached to the dorsal cell surface. In addition, we find that this K8/K18 IF modulation of cell stiffness and actin fiber organization occurs through RhoA-ROCK signaling. Together, the results uncover a K8/K18 IF contribution to the cell stiffness-ECM rigidity interplay through a modulation of Rho-dependent actin organization and dynamics in simple epithelial cells.
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