Dept. of Biosciences & Bioengineering, IIT Bombay, Mumbai 400076, India.
IITB-Monash Research Academy, Mumbai 400076, India.
J Cell Sci. 2021 Dec 1;134(23). doi: 10.1242/jcs.258581. Epub 2021 Dec 6.
The mechanisms by which the mechanoresponsive actin crosslinking protein α-actinin-4 (ACTN4) regulates cell motility and invasiveness remain 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; heavy chain encoded by MYH10), which is essential for mediating nuclear translocation during 3D invasion. We further show that an indirect association between ACTN4 and NMM IIA (heavy chain encoded by MYH9) mediated by a functional F-actin cytoskeleton is essential for retention of NMM IIA at the cell periphery and modulation of focal adhesion dynamics. 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. This article has an associated First Person interview with the first author of the paper.
机械反应性肌动蛋白交联蛋白 α-辅肌动蛋白-4（ACTN4）调节细胞迁移和侵袭的机制仍不完全清楚。在这里，我们表明，除了调节突起动力学和焦点粘连形成外，ACTN4 还转录调节非肌肉肌球蛋白 IIB（NMM IIB；由 MYH10 编码的重链）的表达，这对于介导 3D 侵袭期间的核易位是必不可少的。我们进一步表明，ACTN4 和 NMM IIA（由 MYH9 编码的重链）之间的间接关联通过功能性 F-肌动蛋白细胞骨架介导，对于将 NMM IIA 保留在细胞外周和调节焦点粘连动力学至关重要。一种再现实验观察结果的受限迁移的突起依赖性模型预测，突起力取决于限制的程度和核与基质刚度的比值。总之，我们的研究结果表明，ACTN4 是癌症侵袭的主要调节因子，通过控制 NMM IIB 的表达和 NMM IIA 的定位来调节侵袭性。本文附有对该论文第一作者的第一人称采访。
