Metabolic control of YAP and TAZ by the mevalonate pathway

Giovanni Sorrentino, Naomi Ruggeri, Valeria Specchia, Michelangelo Cordenonsi, Miguel Mano, Sirio Dupont, Andrea Manfrin, Eleonora Ingallina, Roberta Sommaggio, Silvano Piazza, Antonio Rosato, Stefano Piccolo, Giannino Del Sal

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)357-366
Number of pages10
JournalNature Cell Biology
Volume16
Issue number4
DOIs
Publication statusPublished - 2014

ASJC Scopus subject areas

  • Cell Biology

Fingerprint Dive into the research topics of 'Metabolic control of YAP and TAZ by the mevalonate pathway'. Together they form a unique fingerprint.

Cite this