A feed forward loop enforces YAP/TAZ signaling during tumorigenesis

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. Moran, Alexandre R. Zlotta, Theodorus H. van der Kwast, Anne-Claude Gingras, Frank Sicheri, Jeffrey L. Wrana and Liliana Attisano ()
Additional contact information
Mandeep K. Gill: University of Toronto
Tania Christova: University of Toronto
Ying Y. Zhang: University of Toronto
Alex Gregorieff: Mount Sinai Hospital
Liang Zhang: Mount Sinai Hospital
Masahiro Narimatsu: Mount Sinai Hospital
Siyuan Song: University of Toronto
Shawn Xiong: University of Toronto
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
Alexandre R. Zlotta: Mount Sinai Hospital and University Health Network
Theodorus H. van der Kwast: University Health Network
Anne-Claude Gingras: University of Toronto
Frank Sicheri: University of Toronto
Jeffrey L. Wrana: University of Toronto
Liliana Attisano: University of Toronto

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05939-2

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DOI: 10.1038/s41467-018-05939-2

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