Metabolic control of YAP and TAZ by the mevalonate pathway

• Published in: Nature cell biology Vol. 16; no. 4; pp. 357 - 366
• Main Authors: Sorrentino, Giovanni, Ruggeri, Naomi, Specchia, Valeria, Cordenonsi, Michelangelo, Mano, Miguel, Dupont, Sirio, Manfrin, Andrea, Ingallina, Eleonora, Sommaggio, Roberta, Piazza, Silvano, Rosato, Antonio, Piccolo, Stefano, Del Sal, Giannino
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2014; Nature Publishing Group
• Subjects: 631/67/2327; 631/80/641/83/2360; Active Transport, Cell Nucleus - physiology; Adaptor Proteins, Signal Transducing - metabolism; Animals; Biological properties; Biosynthesis; Breast cancer; Breast Neoplasms - metabolism; Cancer Research; Cell Biology; Cell growth; Cell metabolism; Cell Proliferation; Cellular control mechanisms; Developmental Biology; Drosophila melanogaster - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; FDA approval; Federal regulation; Female; Genetic aspects; Genetic research; HCT116 Cells; HEK293 Cells; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Hydroxymethylglutaryl-CoA Reductases, NAD-Dependent - metabolism; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Life Sciences; Localization; Metabolism; Mevalonic Acid - metabolism; Mice; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Phosphoproteins - metabolism; Phosphorylation - physiology; Polyisoprenyl Phosphates - biosynthesis; Polyisoprenyl Phosphates - metabolism; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Pyridines - pharmacology; rho GTP-Binding Proteins - metabolism; RNA Interference; RNA, Small Interfering; Signal Transduction; Statins; Stem Cells; Sterol Regulatory Element Binding Proteins - genetics; Sterol Regulatory Element Binding Proteins - metabolism; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic; Tumor Suppressor Proteins - genetics; Italy
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb2936

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. Del Sal and colleagues demonstrate that the YAP and TAZ effectors of the Hippo pathway are under the control of the mevalonate pathway. They show that mutant p53 and SREBP-dependent activation of mevalonate signalling activates YAP and TAZ and promotes tumour formation in mice, a growth phenotype also conserved in Drosophila .