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.

Autore Pugliese

• Specchia Valeria

Tutti gli autori

• Sorrentino G. , Ruggeri N. , Specchia V. , Cordenonsi M. , Mano M. , Dupont S. , Manfrin A. , Ingallina E. , Sommaggio R. , Piazza S. , Rosato A. , Piccolo S. , Del Sal G.

Titolo volume/Rivista

NATURE CELL BIOLOGY

Anno di pubblicazione

2014

ISSN

1465-7392

ISBN

Non Disponibile

Numero di citazioni Wos

171

Ultimo Aggiornamento Citazioni

28/04/2018

Numero di citazioni Scopus

182

Ultimo Aggiornamento Citazioni

28/04/2018

Settori ERC

Non Disponibile

Codici ASJC

Non Disponibile