Cox AG, Hwang KL, Brown KK, Evason K, Beltz S, Tsomides A, O'Connor K, Galli GG, Yimlamai D, Chhangawala S, Yuan M, Lien EC, Wucherpfennig J, Nissim S, Minami A, Cohen DE, Camargo FD, Asara JM, Houvras Y, Stainier DYR, Goessling W. 2016. Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth. Nature cell biology. 18(8):886-896. Pubmed: 27428308 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.

Related Faculty

Photo of Fernando Camargo

The Camargo laboratory focuses on the study of adult stem cell biology, organ size regulation, and cancer.

Photo of Wolfram Goessling

Wolfram Goessling uses the zebrafish model to study regulators of liver development and to explore endodermal progenitor cell specification, organ differentiation, and growth.

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