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      Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex

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          Abstract

          Liang et al. find that the tumor suppressors TSC1 and TSC2, defects in which underlie the genetic disease Tuberous Sclerosis Complex (TSC), drive the mTOR-dependent autophagosomal destruction of the transcriptional activator YAP. Blocking YAP inhibited the abnormal proliferation of TSC1/2-deficient human cells and reversed TSC-like disease symptoms in mosaic Tsc1 mutant mice.

          Abstract

          Genetic studies have shown that the tuberous sclerosis complex (TSC) 1–TSC2–mammalian target of Rapamycin (mTOR) and the Hippo–Yes-associated protein 1 (YAP) pathways are master regulators of organ size, which are often involved in tumorigenesis. The crosstalk between these signal transduction pathways in coordinating environmental cues, such as nutritional status and mechanical constraints, is crucial for tissue growth. Whether and how mTOR regulates YAP remains elusive. Here we describe a novel mouse model of TSC which develops renal mesenchymal lesions recapitulating human perivascular epithelioid cell tumors (PEComas) from patients with TSC. We identify that YAP is up-regulated by mTOR in mouse and human PEComas. YAP inhibition blunts abnormal proliferation and induces apoptosis of TSC1–TSC2-deficient cells, both in culture and in mosaic Tsc1 mutant mice. We further delineate that YAP accumulation in TSC1/TSC2-deficient cells is due to impaired degradation of the protein by the autophagosome/lysosome system. Thus, the regulation of YAP by mTOR and autophagy is a novel mechanism of growth control, matching YAP activity with nutrient availability under growth-permissive conditions. YAP may serve as a potential therapeutic target for TSC and other diseases with dysregulated mTOR activity.

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          Most cited references17

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          Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling.

          The Hippo pathway is crucial in organ size control, and its dysregulation contributes to tumorigenesis. However, upstream signals that regulate the mammalian Hippo pathway have remained elusive. Here, we report that the Hippo pathway is regulated by G-protein-coupled receptor (GPCR) signaling. Serum-borne lysophosphatidic acid (LPA) and sphingosine 1-phosphophate (S1P) act through G12/13-coupled receptors to inhibit the Hippo pathway kinases Lats1/2, thereby activating YAP and TAZ transcription coactivators, which are oncoproteins repressed by Lats1/2. YAP and TAZ are involved in LPA-induced gene expression, cell migration, and proliferation. In contrast, stimulation of Gs-coupled receptors by glucagon or epinephrine activates Lats1/2 kinase activity, thereby inhibiting YAP function. Thus, GPCR signaling can either activate or inhibit the Hippo-YAP pathway depending on the coupled G protein. Our study identifies extracellular diffusible signals that modulate the Hippo pathway and also establishes the Hippo-YAP pathway as a critical signaling branch downstream of GPCR. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP.

            The Drosophila TEAD ortholog Scalloped is required for Yki-mediated overgrowth but is largely dispensable for normal tissue growth, suggesting that its mammalian counterpart may be exploited for selective inhibition of oncogenic growth driven by YAP hyperactivation. Here we test this hypothesis genetically and pharmacologically. We show that a dominant-negative TEAD molecule does not perturb normal liver growth but potently suppresses hepatomegaly/tumorigenesis resulting from YAP overexpression or Neurofibromin 2 (NF2)/Merlin inactivation. We further identify verteporfin as a small molecule that inhibits TEAD-YAP association and YAP-induced liver overgrowth. These findings provide proof of principle that inhibiting TEAD-YAP interactions is a pharmacologically viable strategy against the YAP oncoprotein.
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              Hippo signaling: growth control and beyond.

              The Hippo pathway has emerged as a conserved signaling pathway that is essential for the proper regulation of organ growth in Drosophila and vertebrates. Although the mechanisms of signal transduction of the core kinases Hippo/Mst and Warts/Lats are relatively well understood, less is known about the upstream inputs of the pathway and about the downstream cellular and developmental outputs. Here, we review recently discovered mechanisms that contribute to the dynamic regulation of Hippo signaling during Drosophila and vertebrate development. We also discuss the expanding diversity of Hippo signaling functions during development, discoveries that shed light on a complex regulatory system and provide exciting new insights into the elusive mechanisms that regulate organ growth and regeneration.
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                Author and article information

                Journal
                J Exp Med
                J. Exp. Med
                jem
                jem
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                20 October 2014
                : 211
                : 11
                : 2249-2263
                Affiliations
                [1 ]Institut Necker-Enfants Malades, CS 61431, Paris, France
                [2 ]Institut National de la Santé et de la Recherche Médicale, U1151, F-75014 Paris, France
                [3 ]Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France
                [4 ]Department of Pediatric Neurology and Developmental Medicine, University Children’s Hospital Basel, University of Basel, 4056 Basel, Switzerland
                [5 ]Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390
                [6 ]Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
                [7 ]Department of Cellular Biology and Anatomy, Georgia Health Sciences University and Charlie Norwood VA Medical Center, Augusta, Georgia, GA 30192
                [8 ]Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160
                [9 ]Institut National de la Santé et de la Recherche Médicale U775 and Université Paris Descartes, 75006 Paris, France
                [10 ]Service de Néphrologie, Hôpital Européen Georges Pompidou, F-75015 Paris, France
                [11 ]Department of Biochemistry and Molecular Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030
                [12 ]Translational Medicine Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
                [13 ]Hospices Civils de Lyon, Hôpital E. Herriot, 69437 Lyon, France
                [14 ]Department of Pathology and Diagnostic, University of Verona, 37129 Verona, Italy
                [15 ]Pederzoli Hospital, Peschiera, 37134 Verona, Italy
                Author notes
                CORRESPONDENCE Mario Pende: mario.pende@ 123456inserm.fr
                Article
                20140341
                10.1084/jem.20140341
                4203941
                25288394
                6ab39713-7eed-4431-a7e4-a247d2be9ef9
                © 2014 Liang et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

                History
                : 19 February 2014
                : 27 August 2014
                Categories
                307
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                Medicine
                Medicine

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