Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth

• Published in: Nature cell biology Vol. 18; no. 8; pp. 886 - 896
• Main Authors: Cox, Andrew G., Hwang, Katie L., Brown, Kristin K., Evason, Kimberley J., Beltz, Sebastian, Tsomides, Allison, O’Connor, Keelin, Galli, Giorgio G., Yimlamai, Dean, Chhangawala, Sagar, Yuan, Min, Lien, Evan C., Wucherpfennig, Julia, Nissim, Sahar, Minami, Akihiro, Cohen, David E., Camargo, Fernando D., Asara, John M., Houvras, Yariv, Stainier, Didier Y. R., Goessling, Wolfram
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-08-2016; Nature Publishing Group
• Subjects: 45/91; 631/136/334/1874/763; 631/443/319; 631/67; 631/80/83/2360; 64; 64/116; 96; 96/63; 96/95; Adaptor Proteins, Signal Transducing - genetics; Animals; Animals, Genetically Modified; Biosynthesis; Cancer Research; Carcinoma, Hepatocellular - metabolism; Cell Biology; Cell division; Cell growth; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - pathology; Danio rerio; Developmental Biology; Disease susceptibility; Gene expression; Genes; Genetic aspects; Glutamine - metabolism; Health aspects; Humans; Hyperplasia; Isotopic enrichment; Kinases; Life Sciences; Liver - growth & development; Liver cancer; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Medical schools; Metabolism; Nitrogen; Phosphoproteins - genetics; Phosphoproteins - metabolism; Stem Cells; Trans-Activators - genetics; Transcription Factors; Tumorigenesis; YAP-Signaling Proteins; Zebrafish; Zebrafish Proteins - genetics; United States > US; Massachusetts; Utah
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb3389

The Hippo pathway is an important regulator of organ size and tumorigenesis. It is unclear, however, how Hippo signalling provides the cellular building blocks required for rapid growth. Here, we demonstrate that transgenic zebrafish expressing an activated form of the Hippo pathway effector Yap1 (also known as YAP) develop enlarged livers and are prone to liver tumour formation. Transcriptomic and metabolomic profiling identify that Yap1 reprograms glutamine metabolism. Yap1 directly enhances
glutamine synthetase
(
glul
) expression and activity, elevating steady-state levels of glutamine and enhancing the relative isotopic enrichment of nitrogen during
de novo
purine and pyrimidine biosynthesis. Genetic or pharmacological inhibition of GLUL diminishes the isotopic enrichment of nitrogen into nucleotides, suppressing hepatomegaly and the growth of liver cancer cells. Consequently, Yap-driven liver growth is susceptible to nucleotide inhibition. Together, our findings demonstrate that Yap1 integrates the anabolic demands of tissue growth during development and tumorigenesis by reprogramming nitrogen metabolism to stimulate nucleotide biosynthesis.
Cox
et al.
 report that Yap induces the expression of glutamine synthetase, thereby elevating glutamine and nitrogen levels for
de novo
nucleotide synthesis. They show that this promotes hepatomegaly and growth of liver cancer cells in zebrafish.