Src- and confinement-dependent FAK activation causes E-cadherin relaxation and β-catenin activity.
Src- and confinement-dependent FAK activation causes E-cadherin relaxation and β-catenin activity.
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DOI：
10.1083/jcb.201706013
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发表时间：
2018-03-05
期刊：
影响因子：
--
通讯作者：
Borghi N
中科院分区：
文献类型：
--
作者：
Gayrard C;Bernaudin C;Déjardin T;Seiler C;Borghi N
钙粘蛋白-连环蛋白(β-catenin)是一种转录辅因子，被认为是E-钙粘蛋白在机械诱导磷酸化时释放出来的。然而，缺乏这种机制的证据。Gayrard等人。相反，在上皮到间质的转变过程中，依赖于src和多细胞限制的粘着斑激酶诱导的细胞骨架重塑导致E-钙粘素张力松弛和非磷酸化的β-catenin核移位。在上皮细胞中，E-钙粘附素胞质尾部通过含有β-连环蛋白的连接处于细胞骨架产生的张力之下。一种共转录因子，β-连环蛋白，也活跃在与上皮向间充质转化相关的形态发生过程中。β-连环蛋白信号似乎是机械诱导的，并被认为跟随着磷酸化诱导的β-连环蛋白从E-钙粘附素释放。这一机制缺乏证据，是否与E-钙粘附素紧张有关尚不清楚。为了验证这一点，我们将定量荧光显微镜与培养中上皮向间充质转化诱导的细胞的遗传和药理学扰动结合起来。我们发现，β-连环蛋白的核活动是在迁移细胞的细胞膜上大量释放出来的，需要多细胞去限制和src的活性。选择性核转位发生在粘着斑激酶激活的下游，它通过肌动蛋白重塑来靶向E-钙粘附素的张力松弛。相反，钙粘蛋白/连环蛋白复合体的磷酸化基本上不是必需的。这些数据表明，E-钙粘附素在与细胞-底物粘连的串扰中充当细胞内机制的传感器，以β-连环蛋白信号为靶点。
β-Catenin is a transcription cofactor proposed to be released from E-cadherin upon mechanically induced phosphorylation. However, evidence for this mechanism is lacking. Gayrard et al. show instead that during epithelial-to-mesenchymal transition, Src- and multicellular confinement–dependent FAK-induced cytoskeleton remodeling causes E-cadherin tension relaxation and phosphorylation-independent β-catenin nuclear translocation from the membrane. In epithelia, E-cadherin cytoplasmic tail is under cytoskeleton-generated tension via a link that contains β-catenin. A cotranscription factor, β-catenin, is also active in morphogenetic processes associated with epithelial-to-mesenchymal transition. β-Catenin signaling appears mechanically inducible and was proposed to follow phosphorylation-induced β-catenin release from E-cadherin. Evidence for this mechanism is lacking, and whether E-cadherin tension is involved is unknown. To test this, we combined quantitative fluorescence microscopies with genetic and pharmacological perturbations of epithelial-to-mesenchymal transition–induced cells in culture. We showed that β-catenin nuclear activity follows a substantial release from the membrane specific to migrating cells and requires multicellular deconfinement and Src activity. Selective nuclear translocation occurs downstream of focal adhesion kinase activation, which targets E-cadherin tension relaxation through actomyosin remodeling. In contrast, phosphorylations of the cadherin/catenin complex are not substantially required. These data demonstrate that E-cadherin acts as a sensor of intracellular mechanics in a crosstalk with cell-substrate adhesions that target β-catenin signaling.
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