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首页> 外文期刊>American Journal of Physiology >Organized migration of epithelial cells requires control of adhesion and protrusion through Rho kinase effectors.
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Organized migration of epithelial cells requires control of adhesion and protrusion through Rho kinase effectors.

机译：上皮细胞的有组织迁移需要通过Rho激酶效应子控制粘附和突出。

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摘要

Migration of epithelial cell sheets, a process involving F-actin restructuring through Rho family GTPases, is both physiologically and pathophysiologically important. Our objective was to clarify the mechanisms whereby the downstream RhoA effector Rho-associated coil-coil-forming kinase (ROCK) influences coordinated epithelial cell motility. Although cells exposed to a pharmacological ROCK inhibitor (Y-27632) exhibited increased spreading in wound closure assays, they failed to migrate in a cohesive manner. Two main phenomena were implicated: the formation of aberrant protrusions at the migrating front and the basal accumulation of F-actin aggregates. Aggregates reflected increased membrane affiliation and detergent insolubility of the actin-binding protein ezrin and enhanced coassociation of ezrin with the membrane protein CD44. While F-actin aggregation following ROCK inhibition was recapitulated by inhibiting myosin light chain (MLC) phosphorylation with the MLC kinase inhibitor ML-7, the latter didnot influence protrusiveness and, in fact, significantly decreased cell migration. Our results suggest that excessive protrusiveness downstream of ROCK inhibition reflects an influence of ROCK on F-actin stability via LIM kinase 1 (LIMK-1), which phosphorylates and inactivates cofilin. Y-27632 reduced the levels of both active LIMK-1 and inactive cofilin (phospho forms), and expression of a dominant negative LIMK-1 mutant stimulated leading edge protrusiveness. Furthermore, Y-27632-induced protrusions were partially reversed by overexpression of LIMK-1 to restore cofilin phosphorylation. In summary, our results provide new evidence suggesting that adhesive and protrusive events involved in organized epithelial motility downstream of ROCK are separately coordinated through the phosphorylation of (respectively) MLC and cofilin.
机译：上皮细胞片的迁移是一个涉及F-肌动蛋白通过Rho家族GTPases进行重组的过程，在生理和病理生理上都是重要的。我们的目的是阐明下游RhoA效应子Rho相关的螺旋线圈形成激酶（ROCK）影响协调的上皮细胞运动性的机制。尽管暴露于药理性ROCK抑制剂（Y-27632）的细胞在伤口闭合试验中显示出增加的扩散，但它们未能以内聚方式迁移。涉及两个主要现象：在迁移前沿形成异常突起和F-肌动蛋白聚集体的基础积累。聚集体反映了肌动蛋白结合蛋白ezrin的膜结合性和去污剂不溶性增加，以及ezrin与膜蛋白CD44的共缔合增强。虽然用MLC激酶抑制剂ML-7抑制肌球蛋白轻链（MLC）磷酸化可以概括ROCK抑制后的F-肌动蛋白聚集，但后者不影响突起，实际上，明显减少了细胞迁移。我们的研究结果表明，ROCK抑制作用下游的过度突出反映了ROCK通过LIM激酶1（LIMK-1）对F-肌动蛋白稳定性的影响，LIM激酶1磷酸化并灭活了cofilin。 Y-27632降低了活跃的LIMK-1和不活跃的cofilin（磷酸形式）的水平，显性负性LIMK-1突变体的表达刺激了前缘突出。此外，Y-27632诱导的突起被LIMK-1的过表达部分逆转，从而恢复了cofilin磷酸化。总之，我们的结果提供了新的证据，表明与ROCK下游有组织的上皮运动有关的黏附和突出事件通过（分别）MLC和cofilin的磷酸化分别进行协调。

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