Zheng Yonggang, Wang Wei, Liu Bo, Deng Hua, Uster Eliza, Pan Duojia
Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Dev Cell. 2015 Sep 28;34(6):642-55. doi: 10.1016/j.devcel.2015.08.014. Epub 2015 Sep 10.
In Drosophila and mammals, the canonical Hippo kinase cascade is mediated by Hpo/Mst acting through the intermediary kinase Wts/Lats to phosphorylate the transcriptional coactivator Yki/YAP/TAZ. Despite recent reports linking Yki/YAP/TAZ activity to the actin cytoskeleton, the underlying mechanisms are poorly understood and/or controversial. Using Drosophila imaginal discs as an in vivo model, we show that Wts, but not Hpo, is genetically indispensable for cytoskeleton-mediated subcellular localization of Yki. Through a systematic screen, we identify the Ste-20 kinase Happyhour (Hppy) and its mammalian counterpart MAP4K1/2/3/5 as an alternative kinase that phosphorylates the hydrophobic motif of Wts/Lats in a similar manner as Hpo/Mst. Consistent with their redundant function as activating kinases of Wts/Lats, combined loss of Hpo/Mst and Hppy/MAP4K abolishes cytoskeleton-mediated regulation of Yki/YAP subcellular localization, as well as YAP cytoplasmic translocation induced by contact inhibition. These Hpo/Mst-like kinases provide an expanded view of the Hippo kinase cascade in development and physiology.
在果蝇和哺乳动物中，经典的Hippo激酶级联反应由Hpo/Mst介导，通过中间激酶Wts/Lats作用于转录共激活因子Yki/YAP/TAZ使其磷酸化。尽管最近有报道将Yki/YAP/TAZ活性与肌动蛋白细胞骨架联系起来，但其潜在机制仍知之甚少且存在争议。利用果蝇成虫盘作为体内模型，我们发现Wts而非Hpo对于Yki的细胞骨架介导的亚细胞定位在遗传学上是不可或缺的。通过系统筛选，我们鉴定出Ste-20激酶Happyhour（Hppy）及其哺乳动物对应物MAP4K1/2/3/5作为一种替代激酶，它以与Hpo/Mst类似的方式磷酸化Wts/Lats的疏水基序。与其作为Wts/Lats激活激酶的冗余功能一致，Hpo/Mst和Hppy/MAP4K的联合缺失消除了细胞骨架介导的Yki/YAP亚细胞定位调控以及接触抑制诱导的YAP细胞质易位。这些Hpo/Mst样激酶为发育和生理学中的Hippo激酶级联反应提供了更广阔的视角。
