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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus / physiology
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Acyltransferases
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Breast Neoplasms / metabolism
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Cell Proliferation
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism*
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Drosophila melanogaster / metabolism
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Female
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HCT116 Cells
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HEK293 Cells
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Humans
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
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Hydroxymethylglutaryl-CoA Reductases, NAD-Dependent / metabolism
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Intracellular Signaling Peptides and Proteins / metabolism
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Mevalonic Acid / metabolism*
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Mice
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Phosphoproteins / metabolism*
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Phosphorylation / physiology
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Polyisoprenyl Phosphates / biosynthesis
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Polyisoprenyl Phosphates / metabolism
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Pyridines / pharmacology
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RNA Interference
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RNA, Small Interfering
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Signal Transduction
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Sterol Regulatory Element Binding Proteins / genetics
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Sterol Regulatory Element Binding Proteins / metabolism*
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Transcription, Genetic
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Tumor Suppressor Proteins / genetics
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YAP-Signaling Proteins
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rho GTP-Binding Proteins / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Dis3 protein, Drosophila
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Drosophila Proteins
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Intracellular Signaling Peptides and Proteins
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Nuclear Proteins
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Phosphoproteins
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Polyisoprenyl Phosphates
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Pyridines
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RNA, Small Interfering
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Sterol Regulatory Element Binding Proteins
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Trans-Activators
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Transcription Factors
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Tumor Suppressor Proteins
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YAP-Signaling Proteins
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YAP1 protein, human
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Yki protein, Drosophila
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cerivastatin
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Hydroxymethylglutaryl-CoA Reductases, NAD-Dependent
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Acyltransferases
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TAFAZZIN protein, human
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LATS1 protein, human
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LATS2 protein, human
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Protein Serine-Threonine Kinases
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hpo protein, Drosophila
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rho GTP-Binding Proteins
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geranylgeranyl pyrophosphate
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Mevalonic Acid