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      lgl Regulates the Hippo Pathway Independently of Fat/Dachs, Kibra/Expanded/Merlin and dRASSF/dSTRIPAK

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          Abstract

          In both Drosophila and mammalian systems, the Hippo (Hpo) signalling pathway controls tissue growth by inhibiting cell proliferation and promoting apoptosis. The core pathway consists of a protein kinase Hpo (MST1/2 in mammals) that is regulated by a number of upstream inputs including Drosophila Ras Association Factor, dRASSF. We have previously shown in the developing Drosophila eye epithelium that loss of the apico-basal cell polarity regulator lethal-(2)-giant-larvae ( lgl), and the concomitant increase in aPKC activity, results in ectopic proliferation and suppression of developmental cell death by blocking Hpo pathway signalling. Here, we further explore how Lgl/aPKC interacts with the Hpo pathway. Deregulation of the Hpo pathway by Lgl depletion is associated with the mislocalization of Hpo and dRASSF. We demonstrate that Lgl/aPKC regulate the Hpo pathway independently of upstream inputs from Fat/Dachs and the Kibra/Expanded/Merlin complex. We show depletion of Lgl also results in accumulation and mislocalization of components of the dSTRIPAK complex, a major phosphatase complex that directly binds to dRASSF and represses Hpo activity. However, depleting dSTRIPAK components, or removal of dRASSF did not rescue the lgl −/− or aPKC overexpression phenotypes. Thus, Lgl/aPKC regulate Hpo activity by a novel mechanism, independently of dRASSF and dSTRIPAK. Surprisingly, removal of dRASSF in tissue with increased aPKC activity results in mild tissue overgrowth, indicating that in this context dRASSF acts as a tumor suppressor. This effect was independent of the Hpo and Ras Mitogen Activated Protein Kinase (MAPK) pathways, suggesting that dRASSF regulates a novel pathway to control tissue growth.

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          Most cited references 26

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          The hippo signaling pathway in development and cancer.

           Duojia Pan (2010)
          First discovered in Drosophila, the Hippo signaling pathway is a conserved regulator of organ size. Central to this pathway is a kinase cascade leading from the tumor suppressor Hippo (Mst1 and Mst2 in mammals) to the oncoprotein Yki (YAP and TAZ in mammals), a transcriptional coactivator of target genes involved in cell proliferation and survival. Here, I review recent progress in elucidating the molecular mechanism and physiological function of Hippo signaling in Drosophila and mammals. These studies suggest that the core Hippo kinase cascade integrates multiple upstream inputs, enabling dynamic regulation of tissue homeostasis in animal development and physiology. Copyright © 2010 Elsevier Inc. All rights reserved.
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            Mosaic analysis with a repressible cell marker (MARCM) for Drosophila neural development.

             Yu Luo,  Belinda Lee (2001)
            We have modified an FLP/FRT-based genetic mosaic system to label either neurons derived from a common progenitor or isolated single neurons, in the Drosophila CNS. These uniquely labeled neurons can also be made homozygous for a mutation of interest within an otherwise phenotypically wild-type brain. Using this new mosaic system, not only can normal brain development be described with unprecedented single cell resolution, but also the underlying molecular mechanisms can be investigated by identifying genes that are required for these developmental processes.
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              The TEAD/TEF family protein Scalloped mediates transcriptional output of the Hippo growth-regulatory pathway.

              The Hippo (Hpo) kinase cascade restricts tissue growth by inactivating the transcriptional coactivator Yorkie (Yki), which regulates the expression of target genes such as the cell death inhibitor diap1 by unknown mechanisms. Here we identify the TEAD/TEF family protein Scalloped (Sd) as a DNA-binding transcription factor that partners with Yki to mediate the transcriptional output of the Hpo growth-regulatory pathway. The diap1 (th) locus harbors a minimal Sd-binding Hpo Responsive Element (HRE) that mediates transcriptional regulation by the Hpo pathway. Sd binds directly to Yki, and a Yki missense mutation that abrogates Sd-Yki binding also inactivates Yki function in vivo. We further demonstrate that sd is required for yki-induced tissue overgrowth and target gene expression, and that sd activity is conserved in its mammalian homolog. Our results uncover a heretofore missing link in the Hpo signaling pathway and provide a glimpse of the molecular events on a Hpo-responsive enhancer element.
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                Author and article information

                Affiliations
                [1 ]Cell Cycle and Development Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia; E-Mail: helena.richardson@ 123456petermac.org
                [2 ]Department of Genetics, University of Melbourne, Melbourne, Victoria 3010, Australia
                [3 ]Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria 3010, Australia
                [4 ]Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria 3010, Australia
                [5 ]Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria 3010, Australia
                Author notes
                [†]

                Present address: Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria 3010, Australia.

                [‡]

                Present address: Department of Cell Biology, University Medical Centre Groningen, Groningen, The Netherlands; E-Mail: n.a.grzeschik@ 123456umcg.nl (N.A.G.).

                [* ]Author to whom correspondence should be addressed; E-Mail: parsonsl@ 123456unimelb.edu.au ; Tel.: +61-3-8344-5990; Fax: +61-3-9347-5219.
                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                16 April 2014
                June 2014
                : 6
                : 2
                : 879-896
                cancers-06-00879
                10.3390/cancers6020879
                4074808
                24743776
                © 2014 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

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