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      A Kinome RNAi Screen in Drosophila Identifies Novel Genes Interacting with Lgl, aPKC, and Crb Cell Polarity Genes in Epithelial Tissues

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          Abstract

          In both Drosophila melanogaster and mammalian systems, epithelial structure and underlying cell polarity are essential for proper tissue morphogenesis and organ growth. Cell polarity interfaces with multiple cellular processes that are regulated by the phosphorylation status of large protein networks. To gain insight into the molecular mechanisms that coordinate cell polarity with tissue growth, we screened a boutique collection of RNAi stocks targeting the kinome for their capacity to modify Drosophila “cell polarity” eye and wing phenotypes. Initially, we identified kinase or phosphatase genes whose depletion modified adult eye phenotypes associated with the manipulation of cell polarity complexes (via overexpression of Crb or aPKC). We next conducted a secondary screen to test whether these cell polarity modifiers altered tissue overgrowth associated with depletion of Lgl in the wing. These screens identified Hippo, Jun kinase (JNK), and Notch signaling pathways, previously linked to cell polarity regulation of tissue growth. Furthermore, novel pathways not previously connected to cell polarity regulation of tissue growth were identified, including Wingless (Wg/Wnt), Ras, and lipid/Phospho-inositol-3-kinase (PI3K) signaling pathways. Additionally, we demonstrated that the “nutrient sensing” kinases Salt Inducible Kinase 2 and 3 ( SIK2 and 3) are potent modifiers of cell polarity phenotypes and regulators of tissue growth. Overall, our screen has revealed novel cell polarity-interacting kinases and phosphatases that affect tissue growth, providing a platform for investigating molecular mechanisms coordinating cell polarity and tissue growth during development.

          Most cited references72

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          The Salvador-Warts-Hippo pathway - an emerging tumour-suppressor network.

          Intense research over the past four years has led to the discovery and characterization of a novel signalling network, known as the Salvador-Warts-Hippo (SWH) pathway, involved in tissue growth control in Drosophila melanogaster. At present, eleven proteins have been implicated as members of this pathway, and several downstream effector genes have been characterized. The importance of this pathway is emphasized by its evolutionary conservation, and by increasing evidence that its deregulation occurs in human tumours. Here, we review the main findings from Drosophila and the implications that these have for tumorigenesis in mammals.
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            The apical polarity protein network in Drosophila epithelial cells: regulation of polarity, junctions, morphogenesis, cell growth, and survival.

            Epithelial tissue formation and function requires the apical-basal polarization of individual epithelial cells. Apical polarity regulators (APRs) are an evolutionarily conserved group of key factors that govern polarity and several other aspects of epithelial differentiation. APRs compose a diverse set of molecules including a transmembrane protein (Crumbs), a serine/threonine kinase (aPKC), a lipid phosphatase (PTEN), a small GTPase (Cdc42), FERM domain proteins (Moesin, Yurt), and several adaptor or scaffolding proteins (Bazooka/Par3, Par6, Stardust, Patj). These proteins form a dynamic cooperative network that is engaged in negative-feedback regulation with basolateral polarity factors to set up the epithelial apical-basal axis. APRs support the formation of the apical junctional complex and the segregation of the junctional domain from the apical membrane. It is becoming increasingly clear that APRs interact with the cytoskeleton and vesicle trafficking machinery, regulate morphogenesis, and modulate epithelial cell growth and survival. Not surprisingly, APRs have multiple fundamental links to human diseases such as cancer and blindness.
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              Regulation of Hippo signaling by EGFR-MAPK signaling through Ajuba family proteins.

              EGFR and Hippo signaling pathways both control growth and, when dysregulated, contribute to tumorigenesis. We find that EGFR activates the Hippo pathway transcription factor Yorkie and demonstrate that Yorkie is required for the influence of EGFR on cell proliferation in Drosophila. EGFR regulates Yorkie through the influence of its Ras-MAPK branch on the Ajuba LIM protein Jub. Jub is epistatic to EGFR and Ras for Yorkie regulation, Jub is subject to MAPK-dependent phosphorylation, and EGFR-Ras-MAPK signaling enhances Jub binding to the Yorkie kinase Warts and the adaptor protein Salvador. An EGFR-Hippo pathway link is conserved in mammals, as activation of EGFR or RAS activates the Yorkie homolog YAP, and EGFR-RAS-MAPK signaling promotes phosphorylation of the Ajuba family protein WTIP and also enhances WTIP binding to the Warts and Salvador homologs LATS and WW45. Our observations implicate the Hippo pathway in EGFR-mediated tumorigenesis and identify a molecular link between these pathways. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                G3 (Bethesda)
                Genetics
                G3: Genes, Genomes, Genetics
                G3: Genes, Genomes, Genetics
                G3: Genes, Genomes, Genetics
                G3: Genes|Genomes|Genetics
                Genetics Society of America
                2160-1836
                13 June 2017
                August 2017
                : 7
                : 8
                : 2497-2509
                Affiliations
                [* ]Cell Cycle and Development Laboratory, Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia
                []Department of Anatomy and Neuroscience, University of Melbourne, Victoria 3010, Australia
                []School of Biological Sciences, Monash University, Clayton, Victoria 3800, Australia
                [§ ]Sir Peter MacCallum Department of Oncology, Department of Biochemistry and Molecular Biology, University of Melbourne, Victoria 3010, Australia
                [** ]Department of Biochemistry and Genetics, La Trobe Institute of Molecular Sciences, La Trobe University, Melbourne, Victoria 3086, Australia
                Author notes
                [1 ]Corresponding authors: School of Biological Sciences, Building 18, Monash University, 25 Rainforest Walk, Clayton VIC 3800, Australia. E-mail: linda.parsons@ 123456monash.edu ; and Department of Biochemistry and Genetics, La Trobe Institute of Molecular Sciences, La Trobe University, Kingsbury Dr., Melbourne, VIC 3086, Australia. E-mail: h.richardson@ 123456latrobe.edu.au
                [2]

                Present address: Department of Cell Biology, University Medical Centre Groningen, The Netherlands

                [3]

                Present address: Department of Biochemistry and Genetics, La Trobe Institute of Molecular Sciences, La Trobe University, Melbourne, Victoria 3086, Australia

                [4]

                Present address: Cancer Models Group, ACRF Department of Cancer Biology and Therapeutics, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 2601, Australia

                Author information
                http://orcid.org/0000-0002-3911-6508
                http://orcid.org/0000-0003-3852-4953
                Article
                GGG_043513
                10.1534/g3.117.043513
                5555457
                28611255
                5af6a561-6d78-4b82-9d70-ef2b9943310d
                Copyright © 2017 Parsons et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 3 August 2016
                : 29 May 2017
                Page count
                Figures: 6, Tables: 1, Equations: 3, References: 86, Pages: 13
                Categories
                Investigations

                Genetics
                cell polarity,drosophila,phosphoprotein,kinase,phosphatase,hippo,wingless,wnt,ras,phosphoinositol,pi3k,nutrient sensing

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