Increasing β-catenin/Wnt3A activity levels drive mechanical strain-induced cell cycle progression through mitosis
Increasing β-catenin/Wnt3A activity levels drive mechanical strain-induced cell cycle progression through mitosis
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DOI：
10.7554/elife.19799
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发表时间：
2016-10-26
期刊：
影响因子：
7.7
通讯作者：
Nelson, William James
中科院分区：
文献类型：
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作者：
Benham-Pyle, Blair W.;Sim, Joo Yong;Nelson, William James
机械力和Wnt信号传导激活β-连环蛋白介导的转录以促进增殖和组织扩张。然而，目前尚不清楚机械力和Wnt信号是独立作用还是协同作用来激活β-连环蛋白信号和细胞分裂。我们发现，机械应变诱导Src依赖的磷酸化Y 654 β-连环蛋白和增加β-连环蛋白介导的转录在哺乳动物MDCK上皮细胞。在这些条件下，细胞在S/G2中积累（与DNA损伤无关），但不分裂。通过酪蛋白激酶I抑制或Wnt 3A添加激活β-连环蛋白增加了S/G2中β-连环蛋白介导的转录和应变诱导的细胞积累。值得注意的是，只有机械应变和Wnt/β-连环蛋白激活的组合触发S/G2中的细胞分裂。这些结果表明，菌株诱导的β-连环蛋白的Src磷酸化和Wnt依赖的β-连环蛋白稳定化协同作用，将β-连环蛋白介导的转录增加到有丝分裂所需的水平。因此，局部Wnt信号传导可以微调整体机械应变的影响，以限制组织发育和稳态期间的细胞分裂。
Mechanical force and Wnt signaling activate beta-catenin-mediated transcription to promote proliferation and tissue expansion. However, it is unknown whether mechanical force and Wnt signaling act independently or synergize to activate beta-catenin signaling and cell division. We show that mechanical strain induced Src-dependent phosphorylation of Y654 beta-catenin and increased beta-catenin-mediated transcription in mammalian MDCK epithelial cells. Under these conditions, cells accumulated in S/G2 (independent of DNA damage) but did not divide. Activating beta-catenin through Casein Kinase I inhibition or Wnt3A addition increased beta-catenin-mediated transcription and strain-induced accumulation of cells in S/G2. Significantly, only the combination of mechanical strain and Wnt/beta-catenin activation triggered cells in S/G2 to divide. These results indicate that strain-induced Src phosphorylation of beta-catenin and Wnt-dependent beta-catenin stabilization synergize to increase beta-catenin-mediated transcription to levels required for mitosis. Thus, local Wnt signaling may fine-tune the effects of global mechanical strain to restrict cell divisions during tissue development and homeostasis.