A feed forward loop enforces YAP/TAZ signaling during tumorigenesis
Open accessAbstract
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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YAP/TAZ primarily pairs with the TEAD family of TFs to induce gene expression signatures that play an important role in cancer development, progression, and metastasis.
“YAP/TAZ primarily pairs with the TEAD family of TFs to induce gene expression signatures that play an important role in cancer development, progression, and metastasis.435,436”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [435]
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References 66 · Cited by 95
- Authors
- Gill, M. K., Christova, T., Zhang, Y. Y., Gregorieff, A., Zhang, L., Narimatsu, M., Song, S., Xiong, S., Couzens, A. L., Tong, J., Krieger, J. R., Moran, M. F., Zlotta, A. R., van der Kwast, T. H., Gingras, A.-C., Sicheri, F., Wrana, J. L., & Attisano, L.
- Affiliations
- University of Toronto (CA)
- Mount Sinai Hospital (CA)
- Hospital for Sick Children (CA)
- Corresponding author
- Attisano, Liliana
- ORCID
- Venue
- Nature Communications
- Published
- 2018-08-29
- Volume
- 9
- Issue
- 1
- Pages
- 3510-3510
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6115388
- OpenAlex
- W2888407975
- Cited by
- 95
- References
- 66
- Citations by year
- 2026: 3 · 2025: 18 · 2024: 11 · 2023: 14 · 2022: 14 · 2021: 17 · 2020: 14 · 2019: 4
- FWCI
- 4.85
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- CityU Scholars (submittedVersion, cc-by)
- Funders
- Cancer Research Society
- Terry Fox Research Institute
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- Hippo signaling pathway, YAP, TAZ, NUAK2, feed-forward loop, AP-1, bladder cancer, mammary tumors, carcinogenesis, cancer therapeutics, gene expression signatures
- MeSH terms
- YAP-Signaling Proteins, Acyltransferases, Cell Transformation, Neoplastic, Female, Humans, Microscopy, Fluorescence, Phosphoproteins, Phosphorylation, Transcription Factors, Immunoblotting, Signal Transduction, Protein Serine-Threonine Kinases, Transcription Factor AP-1, Tumor Suppressor Proteins, Cell Line, Tumor, Immunoprecipitation, Adaptor Proteins, Signal Transducing, HEK293 Cells, Real-Time Polymerase Chain Reaction, Carcinogenesis
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