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Overlapping functions of the MAP4K family kinases Hppy and Msn in Hippo signaling

机译：MAP4K家族激酶Hppy和Msn在河马信号中的重叠功能

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The Hippo (Hpo) tumor suppressor pathway is an evolutionarily conserved signaling pathway that controls tissue growth and organ size in species ranging from Drosophila to human, and its malfunction has been implicated in many types of human cancer. In this study, we conducted a kinome screen and identified Happyhour (Hppy)/MAP4K3 as a novel player in the Hpo pathway. Our biochemical study showed that Hppy binds and phosphorylates Wts. Our genetic experiments suggest that Hppy acts in parallel and partial redundantly with Misshapen (Msn)/MAP4K4 to regulate Yki nuclear localization and Hpo target gene expression in Drosophila wing imaginal discs. Furthermore, we showed that cytoskeleton stress restricts Yki nuclear localization through Hppy and Msn when Hpo activity is compromised, thus providing an explanation for the Wts-dependent but Hpo-independent regulation of Yki in certain contexts. Our study has unraveled an additional layer of complexity in the Hpo signaling pathway and laid down a foundation for exploring how different upstream regulators feed into the core Hpo pathway.
机译：河马（Hpo）肿瘤抑制途径是一种进化保守的信号传导途径，可控制果蝇至人类等物种的组织生长和器官大小，其功能失调已涉及许多类型的人类癌症。在这项研究中，我们进行了激酶组筛选，并确定欢乐时光（Hppy）/ MAP4K3是Hpo途径中的新型参与者。我们的生化研究表明，Hppy结合并磷酸化Wts。我们的遗传实验表明，Hppy与Misshapen（Msn）/ MAP4K4平行且部分重复地起作用，以调节果蝇翅假想盘中的Yki核定位和Hpo靶基因表达。此外，我们发现当Hpo活性受到损害时，细胞骨架应激会通过Hppy和Msn限制Yki核的定位，从而为某些情况下对Yki的Wts依赖性但与Hpo无关的调节提供了解释。我们的研究揭示了Hpo信号传导途径的另一层复杂性，并为探索不同的上游调节剂如何进入核心Hpo途径奠定了基础。

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