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

doi:10.1038/ncb2936

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^*

^*Corresponding author for this work

Cardiovascular Sciences

Research output: Contribution to journal › Article › peer-review

616 Citations (Scopus)

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 language	English
Pages (from-to)	357-366
Number of pages	10
Journal	Nature Cell Biology
Volume	16
Issue number	4
DOIs	https://doi.org/10.1038/ncb2936
Publication status	Published - Apr 2014

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@article{bf5a148497504a30999b2dd1f1d227e6,

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.",

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

note = "Funding Information: We thank A. Comel, F. Mantovani, A. Rustighi and D. Walerich for helpful discussion and reading the manuscript and A. Testa for discussions and proofreading the manuscript. This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC) and AIRC Special Program Molecular Clinical Oncology {\textquoteleft}5 per mille{\textquoteright} to S.P., A.R. and G.D.S. and the Italian Ministry of Education, University and Research (COFIN, FIRB-accordi di programma 2010 cod.RBAP10XKNC_003) to G.D.S. M.M. is supported by the FIRB RBAP11Z4Z9 project from the Italian Ministry of Education, University and Research. V.S. is supported by grant FIRB no. RBFR10V8K6 from the Italian Ministry of Education, University and Research. G.S. is a fellow of the Fondazione Italiana per la Ricerca sul Cancro (FIRC). We acknowledge G. Pastore for technical support and F. Vita for technical support with electron microscopy. The results published here are in part based on data generated by The Cancer TCGA Genome Atlas pilot project established by the NCI and NHGRI. Information about TCGA and the investigators and institutions who constitute the TCGA research network can be found at http://cancergenome.nih.gov.",

year = "2014",

month = apr,

doi = "10.1038/ncb2936",

language = "English",

volume = "16",

pages = "357--366",

journal = "Nature Cell Biology",

issn = "1465-7392",

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number = "4",

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T1 - Metabolic control of YAP and TAZ by the mevalonate pathway

AU - Sorrentino, Giovanni

AU - Ruggeri, Naomi

AU - Specchia, Valeria

AU - Cordenonsi, Michelangelo

AU - Mano, Miguel

AU - Dupont, Sirio

AU - Manfrin, Andrea

AU - Ingallina, Eleonora

AU - Sommaggio, Roberta

AU - Piazza, Silvano

AU - Rosato, Antonio

AU - Piccolo, Stefano

AU - Del Sal, Giannino

N1 - Funding Information: We thank A. Comel, F. Mantovani, A. Rustighi and D. Walerich for helpful discussion and reading the manuscript and A. Testa for discussions and proofreading the manuscript. This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC) and AIRC Special Program Molecular Clinical Oncology ‘5 per mille’ to S.P., A.R. and G.D.S. and the Italian Ministry of Education, University and Research (COFIN, FIRB-accordi di programma 2010 cod.RBAP10XKNC_003) to G.D.S. M.M. is supported by the FIRB RBAP11Z4Z9 project from the Italian Ministry of Education, University and Research. V.S. is supported by grant FIRB no. RBFR10V8K6 from the Italian Ministry of Education, University and Research. G.S. is a fellow of the Fondazione Italiana per la Ricerca sul Cancro (FIRC). We acknowledge G. Pastore for technical support and F. Vita for technical support with electron microscopy. The results published here are in part based on data generated by The Cancer TCGA Genome Atlas pilot project established by the NCI and NHGRI. Information about TCGA and the investigators and institutions who constitute the TCGA research network can be found at http://cancergenome.nih.gov.

PY - 2014/4

Y1 - 2014/4

N2 - 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.

AB - 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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U2 - 10.1038/ncb2936

DO - 10.1038/ncb2936

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AN - SCOPUS:84897579255

SN - 1465-7392

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SP - 357

EP - 366

JO - Nature Cell Biology

JF - Nature Cell Biology

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ER -

Metabolic control of YAP and TAZ by the mevalonate pathway

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