title: Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex.
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.
authors.affiliation: Institut Necker-Enfants Malades, CS 61431, Paris, France Institut National de la Santé et de la Recherche Médicale, U1151, F-75014 Paris, France Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Ning
authors.initials: N
authors.lastname: Liang
authors.affiliation: Institut Necker-Enfants Malades, CS 61431, Paris, France Institut National de la Santé et de la Recherche Médicale, U1151, F-75014 Paris, France Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Institut Necker-Enfants Malades, CS 61431, Paris, France Institut National de la Santé et de la Recherche Médicale, U1151, F-75014 Paris, France Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France Department of Pediatric Neurology and Developmental Medicine, University Children's Hospital Basel, University of Basel, 4056 Basel, Switzerland.
authors.forename: Patricia
authors.initials: P
authors.lastname: Dill
authors.affiliation: Institut Necker-Enfants Malades, CS 61431, Paris, France Institut National de la Santé et de la Recherche Médicale, U1151, F-75014 Paris, France Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Ganna
authors.initials: G
authors.lastname: Panasyuk
authors.affiliation: Institut Necker-Enfants Malades, CS 61431, Paris, France Institut National de la Santé et de la Recherche Médicale, U1151, F-75014 Paris, France Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Pion
authors.affiliation: Institut Necker-Enfants Malades, CS 61431, Paris, France Institut National de la Santé et de la Recherche Médicale, U1151, F-75014 Paris, France Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Vonda
authors.initials: V
authors.lastname: Koka
authors.affiliation: Institut Necker-Enfants Malades, CS 61431, Paris, France Institut National de la Santé et de la Recherche Médicale, U1151, F-75014 Paris, France Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Morgan
authors.initials: M
authors.lastname: Gallazzini
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Hilaire
authors.initials: H
authors.lastname: Lam
authors.affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Henske
authors.affiliation: Department of Cellular Biology and Anatomy, Georgia Health Sciences University and Charlie Norwood VA Medical Center, Augusta, Georgia, GA 30192.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160.
authors.forename: Udayan
authors.initials: U
authors.lastname: Apte
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U775 and Université Paris Descartes, 75006 Paris, France Service de Néphrologie, Hôpital Européen Georges Pompidou, F-75015 Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pallet
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Randy L
authors.initials: RL
authors.lastname: Johnson
authors.affiliation: Institut Necker-Enfants Malades, CS 61431, Paris, France Institut National de la Santé et de la Recherche Médicale, U1151, F-75014 Paris, France Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Terzi
authors.affiliation: Translational Medicine Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
authors.affiliation: Hospices Civils de Lyon, Hôpital E. Herriot, 69437 Lyon, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.affiliation: Department of Pathology and Diagnostic, University of Verona, 37129 Verona, Italy Pederzoli Hospital, Peschiera, 37134 Verona, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Martignoni
authors.affiliation: Institut Necker-Enfants Malades, CS 61431, Paris, France Institut National de la Santé et de la Recherche Médicale, U1151, F-75014 Paris, France Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France mario.pende@inserm.fr.
authors.forename: Mario
authors.initials: M
authors.lastname: Pende
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D018207:Angiomyolipoma / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011166:Porphyrins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014402:Tuberous Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D000077362:Verteporfin; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D011166:Porphyrins; C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D000077362:Verteporfin; D058570:TOR Serine-Threonine Kinases