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A feed forward loop enforces YAP/TAZ signaling during tumorigenesis

Author

Listed:
  • Mandeep K. Gill

    (University of Toronto
    University of Toronto)

  • Tania Christova

    (University of Toronto
    University of Toronto)

  • Ying Y. Zhang

    (University of Toronto
    Mount Sinai Hospital)

  • Alex Gregorieff

    (Mount Sinai Hospital
    McGill University and Research Institute of the McGill University Health Center)

  • Liang Zhang

    (Mount Sinai Hospital
    City University of Hong Kong
    City University of Hong Kong Shenzhen Research Institute)

  • Masahiro Narimatsu

    (Mount Sinai Hospital)

  • Siyuan Song

    (University of Toronto
    University of Toronto)

  • Shawn Xiong

    (University of Toronto
    Mount Sinai Hospital)

  • Amber L. Couzens

    (Mount Sinai Hospital)

  • Jiefei Tong

    (Hospital for Sick Children)

  • Jonathan R. Krieger

    (Hospital for Sick Children)

  • Michael F. Moran

    (University of Toronto
    Hospital for Sick Children
    Hospital for Sick Children)

  • Alexandre R. Zlotta

    (Mount Sinai Hospital and University Health Network)

  • Theodorus H. van der Kwast

    (University Health Network)

  • Anne-Claude Gingras

    (University of Toronto
    Mount Sinai Hospital)

  • Frank Sicheri

    (University of Toronto
    University of Toronto
    Mount Sinai Hospital)

  • Jeffrey L. Wrana

    (University of Toronto
    Mount Sinai Hospital)

  • Liliana Attisano

    (University of Toronto
    University of Toronto)

Abstract

In most solid tumors, the Hippo pathway is inactivated through poorly understood mechanisms that result in the activation of the transcriptional regulators, YAP and TAZ. Here, we identify NUAK2 as a YAP/TAZ activator that directly inhibits LATS-mediated phosphorylation of YAP/TAZ and show that NUAK2 induction by YAP/TAZ and AP-1 is required for robust YAP/TAZ signaling. Pharmacological inhibition or loss of NUAK2 reduces the growth of cultured cancer cells and mammary tumors in mice. Moreover, in human patient samples, we show that NUAK2 expression is elevated in aggressive, high-grade bladder cancer and strongly correlates with a YAP/TAZ gene signature. These findings identify a positive feed forward loop in the Hippo pathway that establishes a key role for NUAK2 in enforcing the tumor-promoting activities of YAP/TAZ. Our results thus introduce a new opportunity for cancer therapeutics by delineating NUAK2 as a potential target for re-engaging the Hippo pathway.

Suggested Citation

  • Mandeep K. Gill & Tania Christova & Ying Y. Zhang & Alex Gregorieff & Liang Zhang & Masahiro Narimatsu & Siyuan Song & Shawn Xiong & Amber L. Couzens & Jiefei Tong & Jonathan R. Krieger & Michael F. M, 2018. "A feed forward loop enforces YAP/TAZ signaling during tumorigenesis," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05939-2
    DOI: 10.1038/s41467-018-05939-2
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    Cited by:

    1. F. A. Tucci & R. Pennisi & D. C. Rigiracciolo & M. G. Filippone & R. Bonfanti & F. Romeo & S. Freddi & E. Guerrera & C. Soriani & S. Rodighiero & R. H. Gunby & G. Jodice & F. Sanguedolce & G. Renne & , 2024. "Loss of NUMB drives aggressive bladder cancer via a RHOA/ROCK/YAP signaling axis," Nature Communications, Nature, vol. 15(1), pages 1-24, December.

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