Stimulation of cortical myosin phosphorylation by p114RhoGEF drives cell migration and tumor cell invasion.
Stimulation of cortical myosin phosphorylation by p114RhoGEF drives cell migration and tumor cell invasion.
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P114RHOGEF刺激皮质肌球蛋白磷酸化驱动细胞迁移和肿瘤细胞侵袭。
DOI：
10.1371/journal.pone.0050188
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Matter K
中科院分区：
文献类型：
--
作者：
Terry SJ;Elbediwy A;Zihni C;Harris AR;Bailly M;Charras GT;Balda MS;Matter K
放线肌球蛋白活性是细胞运动的重要驱动因素，已被证明可以促进上皮细胞的集体迁移、单细胞迁移和肿瘤细胞的侵袭。然而，皮层肌球蛋白激活刺激单细胞运动的分子机制，以及驱动单细胞运动的机制与介导上皮细胞集体迁移的机制之间的关系尚不完全清楚。在这里，我们证明p114RhoGEF是RhoA的激活剂，与非肌肉肌球蛋白IIA相关，调节上皮片的集体细胞迁移和肿瘤细胞的侵袭。p114RhoGEF的缺失导致迁移上皮片和迁移单细胞皮层细胞间接触处肌球蛋白激活的特异性空间抑制，但仅影响肌球蛋白轻链的双磷酸化而非单磷酸化。与此一致的是，细胞的整体弹性和收缩性，依赖于持续和更恒定的力的过程，没有受到影响，这表明p114RhoGEF介导了过程特异性肌球蛋白激活。运动p114rhogef依赖于Matrigel，它有利于更圆的细胞和阿米巴样放线肌球蛋白驱动的运动，但不依赖于纤维连接蛋白，它刺激扁平细胞和板足驱动的间质样迁移。因此，p114RhoGEF的缺失导致RhoA降低，但Rac活性增加。在不需要金属蛋白酶活性的条件下，3D基质的侵袭依赖于p114RhoGEF，支持p114RhoGEF在肌球蛋白依赖的变形虫样运动中的作用。我们的数据表明，p114RhoGEF通过刺激肌球蛋白轻链双磷酸化来驱动皮质肌球蛋白激活，从而促进上皮细胞的集体迁移和肿瘤细胞的变形虫样运动。
Actinomyosin activity is an important driver of cell locomotion and has been shown to promote collective cell migration of epithelial sheets as well as single cell migration and tumor cell invasion. However, the molecular mechanisms underlying activation of cortical myosin to stimulate single cell movement, and the relationship between the mechanisms that drive single cell locomotion and those that mediate collective cell migration of epithelial sheets are incompletely understood. Here, we demonstrate that p114RhoGEF, an activator of RhoA that associates with non-muscle myosin IIA, regulates collective cell migration of epithelial sheets and tumor cell invasion. Depletion of p114RhoGEF resulted in specific spatial inhibition of myosin activation at cell-cell contacts in migrating epithelial sheets and the cortex of migrating single cells, but only affected double and not single phosphorylation of myosin light chain. In agreement, overall elasticity and contractility of the cells, processes that rely on persistent and more constant forces, were not affected, suggesting that p114RhoGEF mediates process-specific myosin activation. Locomotion was p114RhoGEF-dependent on Matrigel, which favors more roundish cells and amoeboid-like actinomyosin-driven movement, but not on fibronectin, which stimulates flatter cells and lamellipodia-driven, mesenchymal-like migration. Accordingly, depletion of p114RhoGEF led to reduced RhoA, but increased Rac activity. Invasion of 3D matrices was p114RhoGEF-dependent under conditions that do not require metalloproteinase activity, supporting a role of p114RhoGEF in myosin-dependent, amoeboid-like locomotion. Our data demonstrate that p114RhoGEF drives cortical myosin activation by stimulating myosin light chain double phosphorylation and, thereby, collective cell migration of epithelial sheets and amoeboid-like motility of tumor cells.
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