Center for Systems Biology, Mount Sinai Hospital, Toronto, ON, Canada.
Dev Cell. 2010 Dec 14;19(6):831-44. doi: 10.1016/j.devcel.2010.11.012.
The Hippo pathway senses cell density information to control tissue growth by regulating the localization of the transcriptional regulators TAZ and YAP (TAZ/YAP). TAZ/YAP also regulate TGF-β-SMAD signaling, but whether this role is linked to cell density sensing is unknown. Here we demonstrate that TAZ/YAP dictate the localization of active SMAD complexes in response to cell density-mediated formation of polarity complexes. In high-density cell cultures, the Hippo pathway drives cytoplasmic localization of TAZ/YAP, which sequesters SMAD complexes, thereby suppressing TGF-β signaling. We show that during mouse embryogenesis, this is reflected by differences in TAZ/YAP localization, which define regions of active SMAD2/3 complexes. Interfering with TAZ/YAP phosphorylation drives nuclear accumulation of TAZ/YAP and SMAD2/3. Furthermore, we demonstrate that the Crumbs polarity complex interacts with TAZ/YAP, which relays cell density information by promoting TAZ/YAP phosphorylation, cytoplasmic retention, and suppressed TGF-β signaling. Accordingly, disruption of the Crumbs complex enhances TGF-β signaling and predisposes cells to TGF-β-mediated epithelial-to-mesenchymal transitions.
Hippo 通路通过调节转录调节因子 TAZ 和 YAP（TAZ/YAP）的定位来感知细胞密度信息，从而控制组织生长。TAZ/YAP 还调节 TGF-β-SMAD 信号通路，但这种作用是否与细胞密度感应有关尚不清楚。本文中，我们证明 TAZ/YAP 根据细胞密度介导的极性复合物形成来决定活性 SMAD 复合物的定位。在高密度细胞培养物中，Hippo 通路促使 TAZ/YAP 发生细胞质定位，从而隔离 SMAD 复合物，从而抑制 TGF-β 信号通路。我们发现，在小鼠胚胎发生过程中，TAZ/YAP 的定位差异反映了活性 SMAD2/3 复合物的分布区域。干扰 TAZ/YAP 的磷酸化会导致 TAZ/YAP 和 SMAD2/3 的核积累。此外，我们证明 Crumbs 极性复合物与 TAZ/YAP 相互作用，通过促进 TAZ/YAP 的磷酸化、细胞质滞留和抑制 TGF-β 信号通路来传递细胞密度信息。因此，破坏 Crumbs 复合物会增强 TGF-β 信号通路，并使细胞易发生 TGF-β 介导的上皮-间充质转化。
