Smurf1 regulates tumor cell plasticity and motility through degradation of RhoA leading to localized inhibition of contractility.
Smurf1 regulates tumor cell plasticity and motility through degradation of RhoA leading to localized inhibition of contractility.
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DOI：
10.1083/jcb.200605135
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发表时间：
2007-01-01
期刊：
影响因子：
--
通讯作者：
Vial E
中科院分区：
文献类型：
--
作者：
Sahai E;Garcia-Medina R;Pouysségur J;Vial E
Rho GTP酶参与多种细胞过程，包括正常细胞和肿瘤细胞的迁移。据报道，RhoA在迁移细胞的前沿被E3泛素连接酶Smurf1靶向降解，这对于突起的形成是必需的。我们报道肿瘤细胞中依赖Smurf1的RhoA降解导致细胞周边的Rho激酶（ROCK）活性和肌球蛋白轻链2（MLC2）磷酸化下调。收缩力的局部抑制对于板状伪足的形成以及二维组织培养实验中肿瘤细胞的运动能力是必要的。在三维侵袭实验以及体内肿瘤细胞迁移中，Smurf1的抑制诱导一种间充质 - 阿米巴样转变，这与更具侵袭性的表型相关。我们的研究结果表明，Smurf1通过对RhoA信号传导的调节是肿瘤细胞运动的关键调节因子。
Rho GTPases participate in various cellular processes, including normal and tumor cell migration. It has been reported that RhoA is targeted for degradation at the leading edge of migrating cells by the E3 ubiquitin ligase Smurf1, and that this is required for the formation of protrusions. We report that Smurf1-dependent RhoA degradation in tumor cells results in the down-regulation of Rho kinase (ROCK) activity and myosin light chain 2 (MLC2) phosphorylation at the cell periphery. The localized inhibition of contractile forces is necessary for the formation of lamellipodia and for tumor cell motility in 2D tissue culture assays. In 3D invasion assays, and in in vivo tumor cell migration, the inhibition of Smurf1 induces a mesenchymal–amoeboid–like transition that is associated with a more invasive phenotype. Our results suggest that Smurf1 is a pivotal regulator of tumor cell movement through its regulation of RhoA signaling.
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