Article

Ling C, Zheng Y, Yin F, Yu J, Huang J, Hong Y, et al. The apical transmembrane protein Crumbs functions as a tumor suppressor that regulates Hippo signaling by binding to Expanded. Proc Natl Acad Sci U S A. 2010;107(23):10532-7

Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2010; 107(23):10532-7. DOI: 10.1073/pnas.1004279107
Source: PubMed

ABSTRACT

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.

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Available from: Shian Wu, Apr 23, 2014
    • "Furthermore, quantitative PCR shows that transcription factors and markers associated with EMT are decreased (Supplemental Figure S2D). Surprisingly, the levels of the transcription factor Snail are increased without a significant reduction in the proteins levels of E-cadherin and only a small decrease in E-cadherin message or an increase in Zeb as Crumbs, adherens proteins such as E-cadherin, mechanotransduction , and growth factors, all through upstream regulation of the kinase cascade, regulate the Hippo pathway (Faust et al., 2005; Grzeschik et al., 2010; Ling et al., 2010; Dupont et al., 2011; Kim et al., 2011; Halder et al., 2012). However, an additional mode of regulation of YAP is through angiomotin (AMOT) family members (Chan et al., 2011; Wang et al., 2011; Zhao et al., 2011). "
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    • "Furthermore, our setup can be modified and extended to include quantification of other parts of the body, such as the eyes. Many studies of Drosophila use the eye disc as a model organ (Leevers et al. 1996;Ling et al. 2010;Koontz et al. 2013;Nowak et al. 2013) and require quantification of adult eye size, the usual readout for the amount of growth, and proliferation in the eye disc. All features on the body that are amenable to detection and quantification by machine vision, such as bristles and bristle number, could also be implemented easily. "
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    • "The expression of Fat and Dachsous integrates information encoded by morphogen gradients (Hedgehog, Wingless) to provide a molecular mechanism regulating organ size through Hippo activity [20]. Crumbs, a protein involved in maintaining apical-basal polarity, was identified as an upstream regulator of Hippo signaling which acts through the localization of Expanded [21-23]. Although homologs of Crumbs, Fat, and Dachsous have identified human homologs, their specific roles in vertebrate Hippo signaling are not as well understood. "
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