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


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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    • "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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    ABSTRACT: Contact-mediated inhibition of cell proliferation is an essential part of organ growth control; the transcription coactivator Yes-associated protein (YAP) plays a pivotal role in this process. In addition to phosphorylation-dependent regulation of YAP, the integral membrane protein Angiomotin (AMOT) and AMOT family members control YAP through direct binding. Here we report that regulation of YAP activity occurs at the endosomal membrane through a dynamic interaction of AMOT with an endosomal integral membrane protein endotubin (EDTB). EDTB interacts with both AMOT and occludin and preferentially associates with occludin in confluent cells but with AMOT family members in subconfluent cells. EDTB competes with YAP for binding to AMOT proteins in subconfluent cells. Over-expression of the cytoplasmic domain or full-length EDTB induces translocation of YAP to the nucleus, an overgrowth phenotype and growth in soft agar. This increase in proliferation is dependent upon YAP activity and is complemented by overexpression of p130-AMOT. Furthermore, overexpression of EDTB inhibits the AMOT:YAP interaction. EDTB and AMOT have a greater association in subconfluent cells compared with confluent cells, and this association is regulated at the endosomal membrane. These data provide a link between the trafficking of tight junction proteins through endosomes and contact-inhibition-regulated cell growth. © 2015 by The American Society for Cell Biology.
    Molecular biology of the cell 05/2015; 26(14). DOI:10.1091/mbc.E15-04-0224 · 4.47 Impact Factor
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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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    ABSTRACT: Understanding the molecular nature of human cancer is essential to the development of effective and personalized therapies. Several different molecular signal transduction pathways drive tumorigenesis when deregulated and respond to different types of therapeutic interventions. The Hippo signaling pathway has been demonstrated to play a central role in the regulation of tissue and organ size during development. The deregulation of Hippo signaling leads to a concurrent combination of uncontrolled cellular proliferation and inhibition of apoptosis, two key hallmarks in cancer development. The molecular nature of this pathway was first uncovered in Drosophila melanogaster through genetic screens to identify regulators of cell growth and cell division. The pathway is strongly conserved in humans, rendering Drosophila a suitable and efficient model system to better understand the molecular nature of this pathway. In the present study, we review the current understanding of the molecular mechanism and clinical impact of the Hippo pathway. Current studies have demonstrated that a variety of deregulated molecules can alter Hippo signaling, leading to the constitutive activation of the transcriptional activator YAP or its paralog TAZ. Additionally, the Hippo pathway integrates inputs from a number of growth signaling pathways, positioning the Hippo pathway in a central role in the regulation of tissue size. Importantly, deregulated Hippo signaling is frequently observed in human cancers. YAP is commonly activated in a number of in vitro and in vivo models of tumorigenesis, as well as a number of human cancers. The common activation of YAP in many different tumor types provides an attractive target for potential therapeutic intervention.
    Clinical and Translational Medicine 07/2014; 3(1):25. DOI:10.1186/2001-1326-3-25
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    • "Several groups report that loss of Crb leads to upregulation of Yki target genes, and that reducing the genetic dose of yki can suppress Crb-dependent overgrowth (Chen et al., 2010; Grzeschik et al., 2010; Ling et al., 2010; Robinson et al., 2010; Hafezi et al., 2012). This strongly suggests that Crb-induced cell competition is mediated through inactivation of Hpo signalling. "
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    ABSTRACT: A conventional view of development is that cells cooperate to build an organism. However, based on studies of Drosophila, it has been known for years that viable cells can be eliminated by their neighbours through a process termed cell competition. New studies in mammals have revealed that this process is universal and that many factors and mechanisms are conserved. During cell competition, cells with lower translation rates or those with lower levels of proteins involved in signal transduction, polarity and cellular growth can survive in a homogenous environment but are killed when surrounded by cells of higher fitness. Here, we discuss recent advances in the field as well as the mechanistic steps involved in this phenomenon, which have shed light on how and why cell competition exists in developing and adult organisms.
    Development 03/2014; 141(5):988-1000. DOI:10.1242/dev.079129 · 6.46 Impact Factor
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