The mechanisms by which the mechanoresponsive actin crosslinking protein α-actinin-4 (ACTN4) regulates cell motility and invasiveness remains incompletely understood. Here we show that in addition to regulating protrusion dynamics and focal adhesion formation, ACTN4 transcriptionally regulates expression of non-muscle myosin IIB (NMM IIB), which is essential for mediating nuclear translocation during 3D invasion. We further demonstrate association between NMM IIA and ACTN4 at the cell front ensures retention of NMM IIA at the cell periphery. A protrusion-dependent model of confined migration recapitulating experimental observations predicts a dependence of protrusion forces on the degree of confinement and on the ratio of nucleus to matrix stiffness. Together, our results suggest that ACTN4 is a master regulator of cancer invasion that regulates invasiveness by controlling NMM IIB expression and NMM IIA localization.

中文翻译：

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α-actinin-4通过调节肌球蛋白IIB表达和肌球蛋白IIA定位来驱动侵袭性

机械反应性肌动蛋白交联蛋白α的机理-actinin-4（ACTN4）调节细胞运动性和侵袭性仍未完全了解。在这里我们显示，除了调节突出动态和粘着斑形成之外，ACTN4转录调节非肌肉肌球蛋白IIB（NMM IIB）的表达，这对于介导3D入侵过程中的核易位至关重要。我们进一步证明了NMM IIA和ACTN4在细胞前端之间的关联确保了NMM IIA在细胞外围的保留。有限迁移概述实验结果的依赖于突起的模型预测了突起力与约束程度以及核与基质刚度之比的依赖关系。总之，我们的结果表明ACTN4是癌症侵袭的主要调节因子，它通过控制NMM IIB表达和NMM IIA定位来调节侵袭性。