Institute of Molecular Systems Biology, ETH Zürich, Wolfgang-Pauli-Strasse 16, 8093 Zürich, Switzerland.
Dev Cell. 2010 Feb 16;18(2):309-16. doi: 10.1016/j.devcel.2009.12.013.
The conserved Hippo kinase pathway plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. Whereas the function of the core kinase cascade, consisting of the serine/threonine kinases Hippo and Warts, in phosphorylating and thereby inactivating the transcriptional coactivator Yorkie is well established, much less is known about the upstream events that regulate Hippo signaling activity. The FERM domain proteins Expanded and Merlin appear to represent two different signaling branches that feed into the Hippo pathway. Signaling by the atypical cadherin Fat may act via Expanded, but how Merlin is regulated has remained elusive. Here, we show that the WW domain protein Kibra is a Hippo signaling component upstream of Hippo and Merlin. Kibra acts synergistically with Expanded, and it physically interacts with Merlin. Thus, Kibra predominantly acts in the Merlin branch upstream of the core kinase cascade to regulate Hippo signaling.
保守的 Hippo 激酶途径通过限制增殖和促进细胞凋亡在控制器官大小和抑制肿瘤方面发挥着关键作用。尽管丝氨酸/苏氨酸激酶 Hippo 和 Warts 组成的核心激酶级联在磷酸化并因此使转录共激活因子 Yorkie 失活方面的功能已得到很好的证实，但关于调节 Hippo 信号活性的上游事件知之甚少。FERM 结构域蛋白 Expanded 和 Merlin 似乎代表了两条不同的信号分支，它们都汇入 Hippo 途径。非典型钙黏蛋白 Fat 的信号可能通过 Expanded 传递，但 Merlin 如何被调节一直难以捉摸。在这里，我们表明 WW 结构域蛋白 Kibra 是 Hippo 和 Merlin 上游的 Hippo 信号成分。Kibra 与 Expanded 协同作用，并与 Merlin 发生物理相互作用。因此，Kibra 主要在核心激酶级联的 Merlin 分支上游发挥作用，以调节 Hippo 信号。
