State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, P.R. China.
PLoS Biol. 2013;11(8):e1001620. doi: 10.1371/journal.pbio.1001620. Epub 2013 Aug 6.
The evolutionarily conserved Hippo (Hpo) signaling pathway plays a pivotal role in organ size control by balancing cell proliferation and cell death. Here, we reported the identification of Par-1 as a regulator of the Hpo signaling pathway using a gain-of-function EP screen in Drosophila melanogaster. Overexpression of Par-1 elevated Yorkie activity, resulting in increased Hpo target gene expression and tissue overgrowth, while loss of Par-1 diminished Hpo target gene expression and reduced organ size. We demonstrated that par-1 functioned downstream of fat and expanded and upstream of hpo and salvador (sav). In addition, we also found that Par-1 physically interacted with Hpo and Sav and regulated the phosphorylation of Hpo at Ser30 to restrict its activity. Par-1 also inhibited the association of Hpo and Sav, resulting in Sav dephosphorylation and destabilization. Furthermore, we provided evidence that Par-1-induced Hpo regulation is conserved in mammalian cells. Taken together, our findings identified Par-1 as a novel component of the Hpo signaling network.
进化上保守的 Hippo (Hpo) 信号通路通过平衡细胞增殖和细胞死亡在控制器官大小方面发挥着关键作用。在这里，我们使用果蝇中的功能获得性 EP 筛选报告了 Par-1 作为 Hpo 信号通路的调节剂的鉴定。Par-1 的过表达提高了 Yorkie 的活性，导致 Hpo 靶基因表达增加和组织过度生长，而 Par-1 的缺失减少了 Hpo 靶基因的表达并减小了器官大小。我们证明 par-1 功能位于 fat 和 expanded 的下游，位于 hpo 和 salvador (sav) 的上游。此外，我们还发现 Par-1 与 Hpo 和 Sav 物理相互作用，并调节 Hpo 在 Ser30 上的磷酸化以限制其活性。Par-1 还抑制了 Hpo 和 Sav 的结合，导致 Sav 去磷酸化和不稳定。此外，我们提供了证据表明 Par-1 诱导的 Hpo 调节在哺乳动物细胞中是保守的。总之，我们的发现确定了 Par-1 作为 Hpo 信号网络的一个新组成部分。
