title: Metabolic control of YAP and TAZ by the mevalonate pathway.
abstract: The YAP and TAZ mediators of the Hippo pathway (hereafter called YAP/TAZ) promote tissue proliferation and organ growth. However, how their biological properties intersect with cellular metabolism remains unexplained. Here, we show that YAP/TAZ activity is controlled by the SREBP/mevalonate pathway. Inhibition of the rate-limiting enzyme of this pathway (HMG-CoA reductase) by statins opposes YAP/TAZ nuclear localization and transcriptional responses. Mechanistically, the geranylgeranyl pyrophosphate produced by the mevalonate cascade is required for activation of Rho GTPases that, in turn, activate YAP/TAZ by inhibiting their phosphorylation and promoting their nuclear accumulation. The mevalonate-YAP/TAZ axis is required for proliferation and self-renewal of breast cancer cells. In Drosophila melanogaster, inhibition of mevalonate biosynthesis and geranylgeranylation blunts the eye overgrowth induced by Yorkie, the YAP/TAZ orthologue. In tumour cells, YAP/TAZ activation is promoted by increased levels of mevalonic acid produced by SREBP transcriptional activity, which is induced by its oncogenic cofactor mutant p53. These findings reveal an additional layer of YAP/TAZ regulation by metabolic cues.
authors.affiliation: 1] Laboratorio Nazionale CIB (LNCIB), Area Science Park, 34149 Trieste, Italy [2] Dipartimento di Scienze della Vita, Università degli Studi di Trieste, 34127 Trieste, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sorrentino
authors.affiliation: 1] Laboratorio Nazionale CIB (LNCIB), Area Science Park, 34149 Trieste, Italy [2] Dipartimento di Scienze della Vita, Università degli Studi di Trieste, 34127 Trieste, Italy.
authors.forename: Naomi
authors.initials: N
authors.lastname: Ruggeri
authors.affiliation: DiSTeBA, University of Salento, 73100 Lecce, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Specchia
authors.affiliation: Department of Molecular Medicine, University of Padua School of Medicine, 35126 Padua, Italy.
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Cordenonsi
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy.
authors.forename: Miguel
authors.initials: M
authors.lastname: Mano
authors.affiliation: Department of Molecular Medicine, University of Padua School of Medicine, 35126 Padua, Italy.
authors.forename: Sirio
authors.initials: S
authors.lastname: Dupont
authors.affiliation: Department of Molecular Medicine, University of Padua School of Medicine, 35126 Padua, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Manfrin
authors.affiliation: 1] Laboratorio Nazionale CIB (LNCIB), Area Science Park, 34149 Trieste, Italy [2] Dipartimento di Scienze della Vita, Università degli Studi di Trieste, 34127 Trieste, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Ingallina
authors.affiliation: Dipartimento di Scienze Oncologiche e Chirurgiche, Università degli Studi di Padova e Istituto Oncologico Veneto IRCCS, 35128 Padova, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Sommaggio
authors.affiliation: Laboratorio Nazionale CIB (LNCIB), Area Science Park, 34149 Trieste, Italy.
authors.forename: Silvano
authors.initials: S
authors.lastname: Piazza
authors.affiliation: Dipartimento di Scienze Oncologiche e Chirurgiche, Università degli Studi di Padova e Istituto Oncologico Veneto IRCCS, 35128 Padova, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rosato
authors.affiliation: Department of Molecular Medicine, University of Padua School of Medicine, 35126 Padua, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Piccolo
authors.affiliation: 1] Laboratorio Nazionale CIB (LNCIB), Area Science Park, 34149 Trieste, Italy [2] Dipartimento di Scienze della Vita, Università degli Studi di Trieste, 34127 Trieste, Italy.
authors.forename: Giannino
authors.initials: G
authors.lastname: Del Sal
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D049109:Cell Proliferation; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism; D005260:Female; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D025781:Hydroxymethylglutaryl-CoA Reductases, NAD-Dependent / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008798:Mevalonic Acid / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D011106:Polyisoprenyl Phosphates / Q000096:biosynthesis / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics; D000091102:YAP-Signaling Proteins; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D000099317:Hippo Kinases
chemical_list: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing; D029721:Drosophila Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D025781:Hydroxymethylglutaryl-CoA Reductases, NAD-Dependent; D047908:Intracellular Signaling Peptides and Proteins; D008798:Mevalonic Acid; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011106:Polyisoprenyl Phosphates; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines; D034741:RNA, Small Interfering; D051779:Sterol Regulatory Element Binding Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; D020741:rho GTP-Binding Proteins; C502521:Dis3 protein, Drosophila; C088374:YAP1 protein, human; C503814:Yki protein, Drosophila; C086276:cerivastatin; C108675:TAFAZZIN protein, human; C092745:LATS1 protein, human; C406449:LATS2 protein, human; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases; C002963:geranylgeranyl pyrophosphate