Laboratory of Molecular Physiology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218.
Proc Natl Acad Sci U S A. 2018 Feb 20;115(8):1925-1930. doi: 10.1073/pnas.1718177115. Epub 2018 Feb 5.
Actin polymerization and assembly into stress fibers (SFs) is central to many cellular processes. However, how SFs form in response to the mechanical interaction of cells with their environment is not fully understood. Here we have identified Piezo2 mechanosensitive cationic channel as a transducer of environmental physical cues into mechanobiological responses. Piezo2 is needed by brain metastatic cells from breast cancer (MDA-MB-231-BrM2) to probe their physical environment as they anchor and pull on their surroundings or when confronted with confined migration through narrow pores. Piezo2-mediated Ca influx activates RhoA to control the formation and orientation of SFs and focal adhesions (FAs). A possible mechanism for the Piezo2-mediated activation of RhoA involves the recruitment of the Fyn kinase to the cell leading edge as well as calpain activation. Knockdown of Piezo2 in BrM2 cells alters SFs, FAs, and nuclear translocation of YAP; a phenotype rescued by overexpression of dominant-positive RhoA or its downstream effector, mDia1. Consequently, hallmarks of cancer invasion and metastasis related to RhoA, actin cytoskeleton, and/or force transmission, such as migration, extracellular matrix degradation, and Serpin B2 secretion, were reduced in cells lacking Piezo2.
肌动蛋白聚合和组装成应力纤维（SFs）是许多细胞过程的核心。然而，SFs 如何响应细胞与环境的机械相互作用而形成，目前还不完全清楚。在这里，我们已经确定 Piezo2 机械敏感阳离子通道作为环境物理线索转化为机械生物学反应的传感器。Piezo2 是来自乳腺癌（MDA-MB-231-BrM2）的脑转移细胞在锚定和拉动周围环境或遇到通过狭窄孔隙的受限迁移时探测其物理环境所必需的。Piezo2 介导的 Ca2+内流激活 RhoA 来控制 SFs 和焦点黏附（FA）的形成和定向。Piezo2 介导的 RhoA 激活的一种可能机制涉及 Fyn 激酶向细胞前缘的募集以及钙蛋白酶的激活。在 BrM2 细胞中敲低 Piezo2 会改变 SFs、FA 和 YAP 的核转位；过表达显性阳性 RhoA 或其下游效应物 mDia1 可挽救该表型。因此，与 RhoA、肌动蛋白细胞骨架和/或力传递相关的癌症侵袭和转移的特征，如迁移、细胞外基质降解和 Serpin B2 分泌，在缺乏 Piezo2 的细胞中减少。
