Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Proc Natl Acad Sci U S A. 2010 Jun 8;107(23):10532-7. doi: 10.1073/pnas.1004279107. Epub 2010 May 24.
The Hippo signaling pathway regulates organ size and tissue homeostasis from Drosophila to mammals. At the core of the Hippo pathway is a kinase cascade extending from the Hippo (Hpo) tumor suppressor to the Yorkie (Yki) oncoprotein. The Hippo kinase cascade, in turn, is regulated by apical membrane-associated proteins such as the FERM domain proteins Merlin and Expanded (Ex), and the WW- and C2-domain protein Kibra. How these apical proteins are themselves regulated remains poorly understood. Here, we identify the transmembrane protein Crumbs (Crb), a determinant of epithelial apical-basal polarity in Drosophila embryos, as an upstream component of the Hippo pathway in imaginal disk growth control. Loss of Crb leads to tissue overgrowth and target gene expression characteristic of defective Hippo signaling. Crb directly binds to Ex through its juxtamembrane FERM-binding motif (FBM). Loss of Crb or mutation of its FBM leads to mislocalization of Ex to basolateral domain of imaginal disk epithelial cells. These results shed light on the mechanism of Ex regulation and provide a molecular link between apical-basal polarity and tissue growth. Furthermore, our studies implicate Crb as a putative cell surface receptor for Hippo signaling by uncovering a transmembrane protein that directly binds to an apical component of the Hippo pathway.
Hippo 信号通路调节从果蝇到哺乳动物的器官大小和组织稳态。Hippo 通路的核心是一个从 Hippo (Hpo) 肿瘤抑制因子到 Yorkie (Yki) 癌蛋白的激酶级联。反过来,Hippo 激酶级联又受到顶端膜相关蛋白的调节,如 FERM 结构域蛋白 Merlin 和 Expanded (Ex),以及 WW 和 C2 结构域蛋白 Kibra。这些顶端蛋白本身是如何被调节的,目前还知之甚少。在这里,我们鉴定了跨膜蛋白 Crumbs (Crb),它是果蝇胚胎上皮顶端-基底极性的决定因素,作为 Hippo 通路在成虫盘生长控制中的一个上游成分。Crb 的缺失导致组织过度生长和 Hippo 信号缺陷的特征靶基因表达。Crb 通过其跨膜 FERM 结合基序 (FBM) 直接与 Ex 结合。Crb 的缺失或其 FBM 的突变导致 Ex 错误定位到成虫盘上皮细胞的基底外侧域。这些结果阐明了 Ex 调节的机制,并为顶端-基底极性和组织生长之间提供了分子联系。此外,我们的研究通过揭示直接与 Hippo 通路的顶端成分结合的跨膜蛋白,暗示 Crb 作为 Hippo 信号的潜在细胞表面受体。