The Crumbs Complex Couples Cell Density Sensing to Hippo-Dependent Control of the TGF-β-SMAD Pathway
The Crumbs Complex Couples Cell Density Sensing to Hippo-Dependent Control of the TGF-β-SMAD Pathway
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DOI：
10.1016/j.devcel.2010.11.012
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发表时间：
2010-12-14
影响因子：
11.8
通讯作者：
Wrana, Jeffrey L.
中科院分区：
文献类型：
--
作者：
Varelas, Xaralabos;Samavarchi-Tehrani, Payman;Wrana, Jeffrey L.
Hippo通路通过调节转录调控因子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也调节tgf - β - smad信号，但这种作用是否与细胞密度感应有关尚不清楚。在这里，我们证明了TAZ/YAP决定了活性SMAD复合物的定位，以响应细胞密度介导的极性复合物的形成。在高密度细胞培养中，Hippo通路驱动TAZ/YAP的细胞质定位，从而隔离SMAD复合物，从而抑制tgf - β信号传导。我们发现，在小鼠胚胎发生过程中，TAZ/YAP定位的差异反映了这一点，TAZ/YAP定位定义了活跃SMAD2/3复合物的区域。干扰TAZ/YAP磷酸化可驱动TAZ/YAP和SMAD2/3的核积累。此外，我们证明了碎屑极性复合物与TAZ/YAP相互作用，通过促进TAZ/YAP磷酸化、细胞质保留和抑制tgf - β信号传导来传递细胞密度信息。因此，面包屑复合物的破坏增强了tgf - β信号传导，并使细胞容易发生tgf - β介导的上皮到间质转化。
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-beta-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-beta 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-beta signaling. Accordingly, disruption of the Crumbs complex enhances TGF-beta signaling and predisposes cells to TGF-beta-mediated epithelial-to-mesenchymal transitions.