Vlaams Instituut voor Biotechnologie (VIB) Center for Cancer Biology, University of Leuven, 3000 Leuven, Belgium.
Department of Oncology, University of Leuven, 3000 Leuven, Belgium.
Proc Natl Acad Sci U S A. 2018 Oct 16;115(42):10684-10689. doi: 10.1073/pnas.1807325115. Epub 2018 Sep 26.
The Hippo tumor-suppressor pathway regulates organ growth, cell proliferation, and stem cell biology. Defects in Hippo signaling and hyperactivation of its downstream effectors-Yorkie (Yki) in and YAP/TAZ in mammals-result in progenitor cell expansion and overgrowth of multiple organs and contribute to cancer development. Deciphering the mechanisms that regulate the activity of the Hippo pathway is key to understanding its function and for therapeutic targeting. However, although the Hippo kinase cascade and several other upstream inputs have been identified, the mechanisms that regulate Yki/YAP/TAZ activity are still incompletely understood. To identify new regulators of Yki activity, we screened in for suppressors of tissue overgrowth and Yki activation caused by overexpression of atypical protein kinase C (aPKC), a member of the apical cell polarity complex. In this screen, we identified mutations in the heterogeneous nuclear ribonucleoprotein Hrb27C that strongly suppressed the tissue defects induced by ectopic expression of aPKC. Hrb27C was required for aPKC-induced tissue growth and Yki target gene expression but did not affect general gene expression. Genetic and biochemical experiments showed that Hrb27C affects Yki phosphorylation. Other RNA-binding proteins known to interact with Hrb27C for mRNA transport in oocytes were also required for normal Yki activity, although they suppressed Yki output. Based on the known functions of Hrb27C, we conclude that Hrb27C-mediated control of mRNA splicing, localization, or translation is essential for coordinated activity of the Hippo pathway.
Hippo 肿瘤抑制途径调节器官生长、细胞增殖和干细胞生物学。Hippo 信号通路的缺陷和其下游效应物-Yorkie (Yki) 在果蝇中和 YAP/TAZ 在哺乳动物中的过度激活，导致祖细胞扩增和多个器官的过度生长，并促进癌症的发展。解析调节 Hippo 途径活性的机制是理解其功能和治疗靶向的关键。然而，尽管已经鉴定出 Hippo 激酶级联和其他几个上游输入，但调节 Yki/YAP/TAZ 活性的机制仍不完全清楚。为了鉴定 Yki 活性的新调节剂，我们在果蝇中筛选出抑制物，以抑制异常蛋白激酶 C (aPKC)过度表达引起的组织过度生长和 Yki 激活，aPKC 是顶端细胞极性复合物的成员。在这个筛选中，我们鉴定出异型核核糖核蛋白 Hrb27C 的突变，它强烈抑制了由 aPKC 异位表达引起的组织缺陷。Hrb27C 是 aPKC 诱导的组织生长和 Yki 靶基因表达所必需的，但不影响一般基因表达。遗传和生化实验表明，Hrb27C 影响 Yki 的磷酸化。其他已知与 Hrb27C 相互作用以在卵母细胞中进行 mRNA 运输的 RNA 结合蛋白，尽管它们抑制了 Yki 的输出，但也需要正常的 Yki 活性。基于 Hrb27C 的已知功能，我们得出结论，Hrb27C 介导的 mRNA 剪接、定位或翻译的控制对于协调 Hippo 途径的活性是必不可少的。
