Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA.
Dev Cell. 2010 Feb 16;18(2):288-99. doi: 10.1016/j.devcel.2009.12.012.
The Hippo signaling pathway regulates organ size and tissue homeostasis from Drosophila to mammals. Central to this pathway is a kinase cascade wherein Hippo (Hpo), in complex with Salvador (Sav), phosphorylates and activates Warts (Wts), which in turn phosphorylates and inactivates the Yorkie (Yki) oncoprotein, known as the YAP coactivator in mammalian cells. The FERM domain proteins Merlin (Mer) and Expanded (Ex) are upstream components that regulate Hpo activity through unknown mechanisms. Here we identify Kibra as another upstream component of the Hippo signaling pathway. We show that Kibra functions together with Mer and Ex in a protein complex localized to the apical domain of epithelial cells, and that this protein complex regulates the Hippo kinase cascade via direct binding to Hpo and Sav. These results shed light on the mechanism of Ex and Mer function and implicate Kibra as a potential tumor suppressor with relevance to neurofibromatosis.
Hippo 信号通路从果蝇到哺乳动物，调节器官大小和组织平衡。该通路的核心是一个激酶级联反应，其中 Hippo（Hpo）与 Salvador（Sav）复合物磷酸化并激活 Warts（Wts），而 Wts 又磷酸化并失活 Yorkie（Yki）癌蛋白，在哺乳动物细胞中称为 YAP 共激活因子。FERM 结构域蛋白 Merlin（Mer）和 Expanded（Ex）是上游组件，通过未知机制调节 Hpo 活性。在这里，我们将 Kibra 鉴定为 Hippo 信号通路的另一个上游组件。我们表明，Kibra 与 Mer 和 Ex 一起在一个蛋白复合物中发挥作用，该复合物定位于上皮细胞的顶端域，并且该蛋白复合物通过直接与 Hpo 和 Sav 结合来调节 Hippo 激酶级联反应。这些结果阐明了 Ex 和 Mer 功能的机制，并暗示 Kibra 是一种潜在的肿瘤抑制因子，与神经纤维瘤病有关。
