A feed forward loop enforces YAP/TAZ signaling during tumorigenesis.

Nature Communications
Mandeep K GillLiliana Attisano

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.

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Citations

Jul 1, 2020·Frontiers in Oncology·Hirohito Yamaguchi, Ghina M Taouk
Aug 28, 2020·The Journal of Experimental Medicine·Carine BonnardBruno Reversade
May 24, 2020·Acta Biochimica Et Biophysica Sinica·Xiaolei CaoBin Zhao
Jan 31, 2020·Journal of Cell Science·Arianna PocaterraSirio Dupont
Dec 29, 2020·Frontiers in Oncology·Isabel Castro-PiedrasKevin Pruitt
Feb 12, 2021·The Journal of Biological Chemistry·Jinqiu LuHai Song
May 28, 2019·Cancer Letters·Aidi TanShao Li
Feb 23, 2021·Frontiers in Oncology·Aukie HooglugtStephan Huveneers
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Apr 9, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Anh Thu Nguyen-LefebvreMamatha Bhat
Jun 12, 2021·Cancer Cell International·Jing ChenAlexander Tobias Teichmann
Jul 3, 2021·Cancers·Giampaolo MorcianoCarlotta Giorgi
Apr 15, 2021·Canadian Journal of Physiology and Pharmacology·Junjie ZhangMing-Sheng Zhou
Aug 6, 2021·Biology Direct·Eleonora MammarellaIvano Amelio
Dec 29, 2020·Journal of Medicinal Chemistry·Muhammad FaisalSo Ha Lee
Oct 1, 2021·Science·Minkyu KimNevan J Krogan
Nov 25, 2021·Molecular Carcinogenesis·Weiwei FuEverardo Macias

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Datasets Mentioned

BETA
GSE59483

Methods Mentioned

BETA
immunoprecipitation
PCR
transfection
electrophoresis
ChIP
reverse phase chromatography
RNAseq

Software Mentioned

Image J
LUMIER
Columbus
NEBuilder
Java Tree View
IN Analyzer
Cluster
Volocity

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