Kibra and Merlin Activate the Hippo Pathway Spatially Distinct from and Independent of Expanded.
Kibra and Merlin Activate the Hippo Pathway Spatially Distinct from and Independent of Expanded.
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DOI：
10.1016/j.devcel.2017.02.004
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发表时间：
2017-03-13
影响因子：
11.8
通讯作者：
Fehon RG
中科院分区：
文献类型：
--
作者：
Su T;Ludwig MZ;Xu J;Fehon RG
河马途径正在成为一种关键的进化保守的信号机制，控制器官的大小。三种膜相关蛋白Kibra、Merlin和Expanded调节通路活性，但它们发挥作用的确切分子机制仍然知之甚少。在这里，我们提供了梅林和Kibra在空间上不同的细胞域--内侧顶叶皮质--平行激活河马信号以扩展的证据。梅林和Kibra一起招募适配蛋白萨尔瓦多，而萨尔瓦多又招募核心激酶河马。此外，我们还证明了Crumbs对河马信号的双重影响。Crumbs促进了激活通路的能力，但也隔离了Kibra下调河马信号的能力。综上所述，我们的发现阐明了Merlin和Kibra激活河马途径的机制，确定了调节河马途径的亚细胞结构域，并证明了不同亚细胞结构域中上游调控因子的不同活性。Merlin、Kibra和Expanded被认为在细胞间连接处作用于一个复合体，以控制河马途径的活性。Su等人。相反，Merlin和Kibra在果蝇顶端内侧皮质的功能与Crumbs分开并扩展，从而确定了河马途径调节的额外亚细胞结构域。
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. Merlin, Kibra, and Expanded are believed to act in a complex at intercellular junctions to control Hippo pathway activity. Su et al. show that instead Merlin and Kibra function at the Drosophila apical medial cortex separately from Crumbs and Expanded, thereby identifying an additional subcellular domain for Hippo pathway regulation.