Metabolic control of YAP and TAZ by the mevalonate pathway
Copyright policy )Metabolic control of YAP and TAZ by the mevalonate pathway
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.
Transcription, Genetic, Transcription Factor, Pyridine, Protein-Serine-Threonine Kinase, Mice, HEK293 Cell, Drosophila Proteins, RNA, Small Interfering, Phosphorylation, Nuclear Protein, Active Transport, Cell Nucleu, Intracellular Signaling Peptides and Proteins, Nuclear Proteins, Sterol Regulatory Element Binding Protein, Drosophila melanogaster, Trans-Activator, Phosphoprotein, RNA Interference, Female, Breast Neoplasm, Human, Signal Transduction, Active Transport, Cell Nucleus, Mevalonic Acid, rho GTP-Binding Protein, Breast Neoplasms, Animals, Humans, Polyisoprenyl Phosphate, Adaptor Proteins, Signal Transducing, Cell Proliferation, YAP; TAZ; Tumor Suppressor Proteins; rho GTP-Binding Proteins, Tumor Suppressor Protein, Animal, Cell Biology, Hydroxymethylglutaryl-CoA Reductases, NAD-Dependent, HCT116 Cells, Phosphoproteins, HEK293 Cells, Intracellular Signaling Peptides and Protein, Active Transport, Cell Nucleus; Adaptor Proteins, Signal Transducing; Animals; Breast Neoplasms; Cell Proliferation; Drosophila Proteins; Drosophila melanogaster; Female; HCT116 Cells; HEK293 Cells; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hydroxymethylglutaryl-CoA Reductases, NAD-Dependent; Intracellular Signaling Peptides and Proteins; Mevalonic Acid; Mice; Nuclear Proteins; Phosphoproteins; Phosphorylation; Polyisoprenyl Phosphates; Protein-Serine-Threonine Kinases; Pyridines; RNA Interference; RNA, Small Interfering; Signal Transduction; Sterol Regulatory Element Binding Proteins; Trans-Activators; Transcription Factors; Transcription, Genetic; Tumor Suppressor Proteins; rho GTP-Binding Proteins; Cell Biology, HCT116 Cell, Drosophila Protein, Hydroxymethylglutaryl-CoA Reductase Inhibitor, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Acyltransferases
Transcription, Genetic, Transcription Factor, Pyridine, Protein-Serine-Threonine Kinase, Mice, HEK293 Cell, Drosophila Proteins, RNA, Small Interfering, Phosphorylation, Nuclear Protein, Active Transport, Cell Nucleu, Intracellular Signaling Peptides and Proteins, Nuclear Proteins, Sterol Regulatory Element Binding Protein, Drosophila melanogaster, Trans-Activator, Phosphoprotein, RNA Interference, Female, Breast Neoplasm, Human, Signal Transduction, Active Transport, Cell Nucleus, Mevalonic Acid, rho GTP-Binding Protein, Breast Neoplasms, Animals, Humans, Polyisoprenyl Phosphate, Adaptor Proteins, Signal Transducing, Cell Proliferation, YAP; TAZ; Tumor Suppressor Proteins; rho GTP-Binding Proteins, Tumor Suppressor Protein, Animal, Cell Biology, Hydroxymethylglutaryl-CoA Reductases, NAD-Dependent, HCT116 Cells, Phosphoproteins, HEK293 Cells, Intracellular Signaling Peptides and Protein, Active Transport, Cell Nucleus; Adaptor Proteins, Signal Transducing; Animals; Breast Neoplasms; Cell Proliferation; Drosophila Proteins; Drosophila melanogaster; Female; HCT116 Cells; HEK293 Cells; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hydroxymethylglutaryl-CoA Reductases, NAD-Dependent; Intracellular Signaling Peptides and Proteins; Mevalonic Acid; Mice; Nuclear Proteins; Phosphoproteins; Phosphorylation; Polyisoprenyl Phosphates; Protein-Serine-Threonine Kinases; Pyridines; RNA Interference; RNA, Small Interfering; Signal Transduction; Sterol Regulatory Element Binding Proteins; Trans-Activators; Transcription Factors; Transcription, Genetic; Tumor Suppressor Proteins; rho GTP-Binding Proteins; Cell Biology, HCT116 Cell, Drosophila Protein, Hydroxymethylglutaryl-CoA Reductase Inhibitor, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Acyltransferases
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