Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth Academic Article uri icon

Overview

MeSH Major

  • Adaptor Proteins, Signal Transducing
  • Cell Transformation, Neoplastic
  • Liver
  • Phosphoproteins
  • Trans-Activators
  • Zebrafish Proteins

abstract

  • 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┬ásynthetase (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.

publication date

  • August 2016

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4990146

Digital Object Identifier (DOI)

  • 10.1038/ncb3389

PubMed ID

  • 27428308

Additional Document Info

start page

  • 886

end page

  • 96

volume

  • 18

number

  • 8