Dissecting the roles of ROCK isoforms in stress-induced cell detachment.
Dissecting the roles of ROCK isoforms in stress-induced cell detachment.
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DOI：
10.4161/cc.24699
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发表时间：
2013-05-15
期刊：
影响因子：
--
通讯作者：
Wei L
中科院分区：
文献类型：
--
作者：
Shi J;Surma M;Zhang L;Wei L
同源Rho激酶ROCK 1和ROCK 2参与应力纤维组装和细胞粘附，并且被认为是功能冗余的。使用来自ROCK 1 −/−和ROCK 2 −/−小鼠的小鼠胚胎成纤维细胞（MEFs），我们最近报道了它们在调节阿霉素诱导的应力纤维分解和细胞分离中发挥不同的作用：ROCK 1参与了肌动蛋白细胞骨架和细胞分离的不稳定，而ROCK 2则需要稳定肌动蛋白细胞骨架和细胞粘附。在这里，我们提出了额外的见解ROCK 1和ROCK 2在调节应激诱导的细胞-基质和细胞-细胞粘附损伤的作用。在对阿霉素的反应中，ROCK 1 −/− MEFs显示出显著的局灶性粘连和粘连连接的保留，而ROCK 2 −/− MEFs显示出受损的局灶性粘连，但与野生型MEFs相比保留了粘连连接。此外，通过化学抑制剂抑制粘着斑或粘附连接形成，消除了ROCK 1缺失的抗脱离作用。最后，ROCK 1-/-MEFs，而不是ROCK 2-/-MEFs，也表现出保留的中央应力纤维和减少细胞脱离血清饥饿的反应。这些结果增加了新的见解，一种新的机制，潜在的抗脱离作用的ROCK 1删除介导的外周肌动球蛋白收缩减少和增加肌动蛋白的稳定性，以促进细胞-细胞和细胞-基质粘附。我们的研究进一步支持了ROCK亚型在调节应力诱导的中央应力纤维和局灶性粘连的损失以及细胞脱离中的不同作用。
The homologous Rho kinases, ROCK1 and ROCK2, are involved in stress fiber assembly and cell adhesion and are assumed to be functionally redundant. Using mouse embryonic fibroblasts (MEFs) derived from ROCK1−/− and ROCK2−/− mice, we have recently reported that they play different roles in regulating doxorubicin-induced stress fiber disassembly and cell detachment: ROCK1 is involved in destabilizing the actin cytoskeleton and cell detachment, whereas ROCK2 is required for stabilizing the actin cytoskeleton and cell adhesion. Here, we present additional insights into the roles of ROCK1 and ROCK2 in regulating stress-induced impairment of cell-matrix and cell-cell adhesion. In response to doxorubicin, ROCK1−/− MEFs showed significant preservation of both focal adhesions and adherens junctions, while ROCK2−/− MEFs exhibited impaired focal adhesions but preserved adherens junctions compared with the wild-type MEFs. Additionally, inhibition of focal adhesion or adherens junction formations by chemical inhibitors abolished the anti-detachment effects of ROCK1 deletion. Finally, ROCK1−/− MEFs, but not ROCK2−/− MEFs, also exhibited preserved central stress fibers and reduced cell detachment in response to serum starvation. These results add new insights into a novel mechanism underlying the anti-detachment effects of ROCK1 deletion mediated by reduced peripheral actomyosin contraction and increased actin stabilization to promote cell-cell and cell-matrix adhesion. Our studies further support the differential roles of ROCK isoforms in regulating stress-induced loss of central stress fibers and focal adhesions as well as cell detachment.
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