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; Liliana Attisano

doi:10.1038/s41467-018-05939-2

A feed forward loop enforces YAP/TAZ signaling during tumorigenesis

Nat Commun. 2018 Aug 29;9(1):3510. doi: 10.1038/s41467-018-05939-2.

Authors

Mandeep K Gill^{1

2}, Tania Christova^{1

2}, Ying Y Zhang^{3

4}, Alex Gregorieff^{4

5}, Liang Zhang^{4

6

7}, Masahiro Narimatsu⁴, Siyuan Song^{1

2}, Shawn Xiong^{1

4}, Amber L Couzens⁴, Jiefei Tong⁸, Jonathan R Krieger⁹, Michael F Moran^{3

8

9}, Alexandre R Zlotta¹⁰, Theodorus H van der Kwast¹¹, Anne-Claude Gingras^{3

4}, Frank Sicheri^{1

3

4}, Jeffrey L Wrana^{3

4}, Liliana Attisano^{12

13}

Affiliations

¹ Department of Biochemistry, University of Toronto, Toronto, ON, M5S 1A8, Canada.
² Donnelly Centre, University of Toronto, Toronto, ON, M5S 3E1, Canada.
³ Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
⁴ Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.
⁵ Department of Pathology, McGill University and Research Institute of the McGill University Health Center, Montreal, H4A 3J1, QC, Canada.
⁶ Department of Biomedical Sciences, College of Veterinary Medicine and Life Sciences, City University of Hong Kong, 999077, Hong Kong, China.
⁷ City University of Hong Kong Shenzhen Research Institute, Shenzhen, Guangdong, 518057, China.
⁸ Program in Cell Biology, Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada.
⁹ SPARC BioCentre, Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada.
¹⁰ Department of Surgery, Division of Urology, University of Toronto, Mount Sinai Hospital and University Health Network, Toronto, M5G 1X5, ON, Canada.
¹¹ Department of Pathology, Toronto General Hospital, University Health Network, Toronto, ON, M5G 2C4, Canada.
¹² Department of Biochemistry, University of Toronto, Toronto, ON, M5S 1A8, Canada. [email protected].
¹³ Donnelly Centre, University of Toronto, Toronto, ON, M5S 3E1, Canada. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acyltransferases
Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism*
Carcinogenesis / genetics
Carcinogenesis / metabolism*
Cell Line, Tumor
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism
Female
HEK293 Cells
Humans
Immunoblotting
Immunoprecipitation
Microscopy, Fluorescence
Phosphoproteins / genetics
Phosphoproteins / metabolism*
Phosphorylation
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism
Real-Time Polymerase Chain Reaction
Signal Transduction / genetics
Signal Transduction / physiology
Transcription Factor AP-1 / genetics
Transcription Factor AP-1 / metabolism
Transcription Factors / genetics
Transcription Factors / metabolism*
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism
YAP-Signaling Proteins

Substances

Adaptor Proteins, Signal Transducing
Phosphoproteins
Transcription Factor AP-1
Transcription Factors
Tumor Suppressor Proteins
YAP-Signaling Proteins
YAP1 protein, human
Acyltransferases
TAFAZZIN protein, human
LATS1 protein, human
LATS2 protein, human
NUAK2 protein, human
Protein Serine-Threonine Kinases