1] Department of New Materials and Biosystems, Max Planck Institute for Intelligent Systems, Stuttgart 70569, Germany [2] Department of Biophysical Chemistry, University of Heidelberg, Heidelberg 69120, Germany.
1] Hamamatsu Tissue Imaging and Analysis (TIGA) Center, BIOQUANT, University of Heidelberg, Heidelberg 69120, Germany [2] NCT National Center for Tumor Diseases, Department of Medical Oncology, University of Heidelberg, Heidelberg 69120, Germany.
Nat Cell Biol. 2015 Mar;17(3):276-87. doi: 10.1038/ncb3115. Epub 2015 Feb 23.
Collective movement of epithelial cells drives essential multicellular organization during various fundamental physiological processes encompassing embryonic morphogenesis, cancer and wound healing. Yet the molecular mechanism that ensures the coordinated movement of many cells remains elusive. Here we show that a tumour suppressor protein, merlin, coordinates collective migration of tens of cells, by acting as a mechanochemical transducer. In a stationary epithelial monolayer and also in three-dimensional human skin, merlin localizes to cortical cell-cell junctions. During migration initiation, a fraction of cortical merlin relocalizes to the cytoplasm. This relocalization is triggered by the intercellular pulling force of the leading cell and depends on the actomyosin-based cell contractility. Then in migrating cells, taking its cue from the intercellular pulling forces, which show long-distance ordering, merlin coordinates polarized Rac1 activation and lamellipodium formation on the multicellular length scale. Together, these results provide a distinct molecular mechanism linking intercellular forces to collective cell movements in migrating epithelia.
上皮细胞的集体运动在各种基本生理过程中驱动着重要的多细胞组织，包括胚胎形态发生、癌症和伤口愈合。然而，确保许多细胞协调运动的分子机制仍然难以捉摸。在这里，我们表明，一种肿瘤抑制蛋白 merlin 通过充当机械化学转导物，协调数十个细胞的集体迁移。在静止的上皮单层和三维人体皮肤中，merlin 定位于皮质细胞-细胞连接处。在迁移起始时，一部分皮质 merlin 重新定位到细胞质中。这种重定位是由领先细胞的细胞间拉力触发的，并且依赖于肌动球蛋白为基础的细胞收缩性。然后，在迁移细胞中，merlin 根据细胞间拉力的线索，这些拉力显示出长程有序性，协调 Rac1 在多细胞长度尺度上的极化激活和片状伪足形成。总之，这些结果提供了一个明确的分子机制，将细胞间力与迁移上皮中的细胞集体运动联系起来。
