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Nat Cell Biol. 2014 Apr;16(4):357-66. doi: 10.1038/ncb2936. Epub 2014 Mar 23.

Metabolic control of YAP and TAZ by the mevalonate pathway.

Author information

1
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.
2
DiSTeBA, University of Salento, 73100 Lecce, Italy.
3
Department of Molecular Medicine, University of Padua School of Medicine, 35126 Padua, Italy.
4
International Centre for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy.
5
Dipartimento di Scienze Oncologiche e Chirurgiche, Università degli Studi di Padova e Istituto Oncologico Veneto IRCCS, 35128 Padova, Italy.
6
Laboratorio Nazionale CIB (LNCIB), Area Science Park, 34149 Trieste, Italy.

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.

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PMID:
24658687
DOI:
10.1038/ncb2936
[Indexed for MEDLINE]

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