Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States.
Elife. 2019 Sep 30;8:e46592. doi: 10.7554/eLife.46592.
Hippo signalling integrates diverse stimuli related to epithelial architecture to regulate tissue growth and cell fate decisions. The Hippo kinase cascade represses the growth-promoting transcription co-activator Yorkie. The FERM protein Expanded is one of the main upstream Hippo signalling regulators in as it promotes Hippo kinase signalling and directly inhibits Yorkie. To fulfil its function, Expanded is recruited to the plasma membrane by the polarity protein Crumbs. However, Crumbs-mediated recruitment also promotes Expanded turnover via a phosphodegron-mediated interaction with a Slimb/β-TrCP SCF E3 ligase complex. Here, we show that the Casein Kinase 1 (CKI) family is required for Expanded phosphorylation. CKI expression promotes Expanded phosphorylation and interaction with Slimb/β-TrCP. Conversely, CKI depletion in S2 cells impairs Expanded degradation downstream of Crumbs. In wing imaginal discs, CKI loss leads to elevated Expanded and Crumbs levels. Thus, phospho-dependent Expanded turnover ensures a tight coupling of Hippo pathway activity to epithelial architecture.
Hippo 信号通路整合了与上皮结构相关的多种刺激因素，以调节组织生长和细胞命运决定。Hippo 激酶级联反应抑制促进生长的转录共激活因子 Yorkie。在 中，FERM 蛋白 Expanded 是主要的上游 Hippo 信号通路调节剂之一，因为它促进 Hippo 激酶信号通路，并直接抑制 Yorkie。为了发挥其功能，Expanded 通过极性蛋白 Crumbs 被招募到质膜。然而，Crumbs 介导的招募也通过与 Slimb/β-TrCP SCF E3 连接酶复合物的磷酸化依赖性相互作用促进 Expanded 的周转。在这里，我们表明 Casein Kinase 1 (CKI) 家族是 Expanded 磷酸化所必需的。CKI 表达促进 Expanded 的磷酸化和与 Slimb/β-TrCP 的相互作用。相反，在 S2 细胞中耗尽 CKI 会损害 Crumbs 下游的 Expanded 降解。在翅 imaginal 盘，CKI 的缺失导致 Expanded 和 Crumbs 水平升高。因此，磷酸化依赖性 Expanded 周转确保了 Hippo 通路活性与上皮结构的紧密偶联。
