Department of Cell Fate Control, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan.
Development. 2011 Sep;138(18):3907-14. doi: 10.1242/dev.070987. Epub 2011 Aug 10.
The Hippo signaling pathway plays an important role in regulation of cell proliferation. Cell density regulates the Hippo pathway in cultured cells; however, the mechanism by which cells detect density remains unclear. In this study, we demonstrated that changes in cell morphology are a key factor. Morphological manipulation of single cells without cell-cell contact resulted in flat spread or round compact cells with nuclear or cytoplasmic Yap, respectively. Stress fibers increased in response to expanded cell areas, and F-actin regulated Yap downstream of cell morphology. Cell morphology- and F-actin-regulated phosphorylation of Yap, and the effects of F-actin were suppressed by modulation of Lats. Our results suggest that cell morphology is an important factor in the regulation of the Hippo pathway, which is mediated by stress fibers consisting of F-actin acting upstream of, or on Lats, and that cells can detect density through their resulting morphology. This cell morphology (stress-fiber)-mediated mechanism probably cooperates with a cell-cell contact (adhesion)-mediated mechanism involving the Hippo pathway to achieve density-dependent control of cell proliferation.
Hippo 信号通路在细胞增殖的调控中发挥着重要作用。细胞密度在培养细胞中调节 Hippo 通路；然而，细胞检测密度的机制仍不清楚。在这项研究中，我们证明了细胞形态的变化是一个关键因素。无需细胞间接触即可对单个细胞进行形态操作，分别导致细胞呈扁平伸展或圆形紧凑，核或细胞质中有 yap。细胞面积扩大导致应力纤维增加，F-actin 调节 yap 下游的细胞形态。yap 的细胞形态和 F-actin 调节的磷酸化作用，以及 F-actin 的作用均受到 Lats 的调节的抑制。我们的结果表明，细胞形态是 Hippo 通路调控的一个重要因素，该通路由 F-actin 组成的应力纤维介导，作用于 Lats 的上游或 Lats 上，并且细胞可以通过其产生的形态来检测密度。这种细胞形态（应力纤维）介导的机制可能与 Hippo 通路涉及的细胞间接触（粘附）介导的机制协同作用，以实现细胞增殖的密度依赖性控制。
