Su Ting, Ludwig Michael Z, Xu Jiajie, Fehon Richard G
Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL 60637, USA.
Department of Ecology and Evolutionary Biology, The University of Chicago, Chicago, IL 60637, USA.
Dev Cell. 2017 Mar 13;40(5):478-490.e3. doi: 10.1016/j.devcel.2017.02.004.
The Hippo pathway is emerging as a key evolutionarily conserved signaling mechanism that controls organ size. Three membrane-associated proteins, Kibra, Merlin, and Expanded, regulate pathway activity, but the precise molecular mechanism by which they function is still poorly understood. Here we provide evidence that Merlin and Kibra activate Hippo signaling in parallel to Expanded at a spatially distinct cellular domain, the medial apical cortex. Merlin and Kibra together recruit the adapter protein Salvador, which in turn recruits the core kinase Hippo. In addition, we show that Crumbs has a dual effect on Hippo signaling. Crumbs promotes the ability of Expanded to activate the pathway but also sequesters Kibra to downregulate Hippo signaling. Together, our findings elucidate the mechanism of Hippo pathway activation by Merlin and Kibra, identify a subcellular domain for Hippo pathway regulation, and demonstrate differential activity of upstream regulators in different subcellular domains.
Hippo信号通路正逐渐成为一种关键的、在进化上保守的控制器官大小的信号传导机制。三种膜相关蛋白，即Kibra、Merlin和Expanded，调节该信号通路的活性，但其发挥作用的确切分子机制仍知之甚少。在此，我们提供证据表明，Merlin和Kibra在一个空间上不同的细胞区域——内侧顶端皮质，与Expanded并行激活Hippo信号。Merlin和Kibra共同招募衔接蛋白Salvador，而Salvador进而招募核心激酶Hippo。此外，我们表明Crumb对Hippo信号具有双重作用。Crumb促进Expanded激活该信号通路的能力，但也隔离Kibra以下调Hippo信号。总之，我们的研究结果阐明了Merlin和Kibra激活Hippo信号通路的机制，确定了Hippo信号通路调节的一个亚细胞区域，并证明了上游调节因子在不同亚细胞区域的差异活性。
