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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 references 42

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          mTOR signaling in growth control and disease.

          The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis. The pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration. Here, we review recent advances in our understanding of the mTOR pathway and its role in health, disease, and aging. We further discuss pharmacological approaches to treat human pathologies linked to mTOR deregulation. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Autophagy: renovation of cells and tissues.

            Autophagy is the major intracellular degradation system by which cytoplasmic materials are delivered to and degraded in the lysosome. However, the purpose of autophagy is not the simple elimination of materials, but instead, autophagy serves as a dynamic recycling system that produces new building blocks and energy for cellular renovation and homeostasis. Here we provide a multidisciplinary review of our current understanding of autophagy's role in metabolic adaptation, intracellular quality control, and renovation during development and differentiation. We also explore how recent mouse models in combination with advances in human genetics are providing key insights into how the impairment or activation of autophagy contributes to pathogenesis of diverse diseases, from neurodegenerative diseases such as Parkinson disease to inflammatory disorders such as Crohn disease. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Regulation mechanisms and signaling pathways of autophagy.

              Autophagy is a process of self-degradation of cellular components in which double-membrane autophagosomes sequester organelles or portions of cytosol and fuse with lysosomes or vacuoles for breakdown by resident hydrolases. Autophagy is upregulated in response to extra- or intracellular stress and signals such as starvation, growth factor deprivation, ER stress, and pathogen infection. Defective autophagy plays a significant role in human pathologies, including cancer, neurodegeneration, and infectious diseases. We present our current knowledge on the key genes composing the autophagy machinery in eukaryotes from yeast to mammalian cells and the signaling pathways that sense the status of different types of stress and induce autophagy for cell survival and homeostasis. We also review the recent advances on the molecular mechanisms that regulate the autophagy machinery at various levels, from transcriptional activation to post-translational protein modification.
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                Author and article information

                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
                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
                20140341
                10.1084/jem.20140341
                4203941
                25288394
                © 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/).

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