Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
Mol Cell. 2022 May 19;82(10):1850-1864.e7. doi: 10.1016/j.molcel.2022.03.027. Epub 2022 Apr 15.
YAP and TAZ (YAP/TAZ), two major effectors of the Hippo signaling pathway, are frequently activated in human cancers. The activity of YAP/TAZ is strictly repressed upon phosphorylation by LATS1/2 tumor suppressors. However, it is unclear how LATS1/2 are precisely regulated by upstream factors such as Hippo kinases MST1/2. Here, we show that WWC proteins (WWC1/2/3) directly interact with LATS1/2 and SAV1, and SAV1, in turn, brings in MST1/2 to phosphorylate and activate LATS1/2. Hence, WWC1/2/3 play an organizer role in a signaling module that mediates LATS1/2 activation by MST1/2. Moreover, we have defined a minimum protein interaction interface on WWC1/2/3 that is sufficient to activate LATS1/2 in a robust and specific manner. The corresponding minigene, dubbed as SuperHippo, can effectively suppress tumorigenesis in multiple tumor models. Our study has uncovered a molecular mechanism underlying LATS1/2 regulation and provides a strategy for treating diverse malignancies related to Hippo pathway dysregulation.
YAP 和 TAZ（YAP/TAZ）是 Hippo 信号通路的两个主要效应物，在人类癌症中经常被激活。YAP/TAZ 的活性在被 LATS1/2 肿瘤抑制物磷酸化时受到严格抑制。然而，目前尚不清楚 Hippo 激酶 MST1/2 等上游因子如何精确调控 LATS1/2。在这里，我们表明 WWC 蛋白（WWC1/2/3）直接与 LATS1/2 和 SAV1 相互作用，而 SAV1 反过来又将 MST1/2 带入，使其磷酸化并激活 LATS1/2。因此，WWC1/2/3 在一个信号模块中发挥组织者的作用，该模块通过 MST1/2 介导 LATS1/2 的激活。此外，我们已经确定了 WWC1/2/3 上的最小蛋白质相互作用界面，该界面足以以强大且特异性的方式激活 LATS1/2。这个被称为 SuperHippo 的最小基因可以有效地抑制多种肿瘤模型中的肿瘤发生。我们的研究揭示了 LATS1/2 调节的分子机制，并为治疗与 Hippo 通路失调相关的多种恶性肿瘤提供了一种策略。
