Formin-like 2 drives amoeboid invasive cell motility downstream of RhoC
Formin-like 2 drives amoeboid invasive cell motility downstream of RhoC
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DOI：
10.1038/onc.2009.515
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发表时间：
2010-04-01
期刊：
影响因子：
8
通讯作者：
Grosse, R.
中科院分区：
文献类型：
--
作者：
Kitzing, T. M.;Wang, Y.;Grosse, R.
侵袭性细胞迁移是癌症转移的关键步骤，并且涉及Rho GTP酶控制的肌动蛋白细胞骨架的重组。在各种恶性肿瘤中发现Rho GT3表达改变。特别是，密切相关的GTP酶RhoA和RhoC在许多侵袭性肿瘤中上调，但尚未确定区分这两种GTP酶以解释机制差异的特定效应物。formins是迄今为止最大的Rho GT3效应子家族，其特征在于肌动蛋白成核同源性2结构域。使用针对所有15种人类formin的基于siRNA的筛选，我们使用三种不同的癌细胞系系统地分析了它们在3D细胞运动中的功能。这些结果揭示了变形虫与间充质侵入细胞迁移的特定formin的不同要求。重要的是，通过敲除所有Rho蛋白，我们鉴定了形成蛋白样2（FMNL 2）作为特异性RhoC效应子，显示FMNL 2与活性RhoC而不是RhoA或RhoB的选择性相互作用。功能分析表明，RhoC调节FMNL 2的自身抑制，而FMNL 2的抑制抑制RhoC依赖性的圆形侵袭性细胞迁移，但不抑制RhoA依赖性的圆形侵袭性细胞迁移。因此，我们的数据揭示了RhoC和FMNL 2之间用于调节细胞形状和侵袭力的新型调节和功能相互作用，并提供了RhoC特异性信号传导事件的机制见解。Oncogene（2010）29，2441-2448; doi：10.1038/onc.2009.515; 2010年1月25日在线发表
Invasive cell migration is a key step for cancer metastasis and involves Rho GTPase-controlled reorganization of the actin cytoskeleton. Altered Rho GTPase expression is found in various malignancies. Particularly, the closely related GTPases RhoA and RhoC are upregulated in many aggressive tumours, but specific effectors that distinguish between these two GTPases to explain mechanistic differences have not been identified. The formins are by far the largest family of Rho GTPase effectors and are characterized by the actin-nucleating formin homology 2 domain. Using siRNA-based screening against all 15 human formins, we systematically analysed their functions in 3D cell motility using three different cancer cell lines. These results reveal distinct requirements for specific formins in amoeboid versus mesenchymal invasive cell migration. Importantly, by knocking down all Rho proteins, we identified formin-like 2 ( FMNL2) as a specific RhoC effector, showing selective interaction of FMNL2 with active RhoC, but not RhoA or RhoB. Functional analysis shows that RhoC regulates auto-inhibition of FMNL2, whereas suppression of FMNL2 inhibits RhoC-, but not RhoA-dependent, rounded invasive cell migration. Thus, our data uncover a novel regulatory and functional interaction between RhoC and FMNL2 for modulating cell shape and invasiveness and provide mechanistic insight into RhoC-specific signalling events. Oncogene (2010) 29, 2441-2448; doi:10.1038/onc.2009.515; published online 25 January 2010