title: Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth.
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 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.
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Cox
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA.|Harvard/MIT MD-PhD Program, Harvard Medical School, Boston, MA.
authors.forename: Katie L
authors.initials: KL
authors.lastname: Hwang
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Kristin K
authors.initials: KK
authors.lastname: Brown
authors.affiliation: University of Utah, Salt Lake City, UT.
authors.forename: Kimberley
authors.initials: K
authors.lastname: Evason
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Beltz
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Allison
authors.initials: A
authors.lastname: Tsomides
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Keelin
authors.initials: K
authors.lastname: O'Connor
authors.affiliation: Boston Children's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Giorgio G
authors.initials: GG
authors.lastname: Galli
authors.affiliation: Boston Children's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Dean
authors.initials: D
authors.lastname: Yimlamai
authors.affiliation: Weill Cornell Medical College and New York Presbyterian Hospital, NY.
authors.forename: Sagar
authors.initials: S
authors.lastname: Chhangawala
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Min
authors.initials: M
authors.lastname: Yuan
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Evan C
authors.initials: EC
authors.lastname: Lien
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Julia
authors.initials: J
authors.lastname: Wucherpfennig
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Sahar
authors.initials: S
authors.lastname: Nissim
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Minami
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: David E
authors.initials: DE
authors.lastname: Cohen
authors.affiliation: Boston Children's Hospital, Harvard Medical School, Boston, MA.|Harvard Stem Cell Institute, Cambridge, MA.
authors.forename: Fernando D
authors.initials: FD
authors.lastname: Camargo
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Weill Cornell Medical College and New York Presbyterian Hospital, NY.
authors.forename: Yariv
authors.initials: Y
authors.lastname: Houvras
authors.affiliation: Max Planck Institute, Bad Nauheim, Germany.
authors.forename: Didier Y R
authors.initials: DYR
authors.lastname: Stainier
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA.|Harvard Stem Cell Institute, Cambridge, MA.|Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.|Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Goessling
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D030801:Animals, Genetically Modified; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000254:growth & development*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D015534:Trans-Activators; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C583457:Yes-associated protein (yap), zebrafish; D029961:Zebrafish Proteins; D005973:Glutamine