A feed forward loop enforces YAP/TAZ signaling during tumorigenesis
| Autor: | Michael F. Moran, Anne-Claude Gingras, Alexandre R. Zlotta, Jeffrey L. Wrana, Liliana Attisano, Jiefei Tong, Liang Zhang, Jonathan R. Krieger, Siyuan Song, Masahiro Narimatsu, Theodorus van der Kwast, Mandeep Gill, Tania Christova, Shawn Xiong, Frank Sicheri, Ying Y. Zhang, Amber L. Couzens, Alex Gregorieff |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
animal structures Carcinogenesis Science Immunoblotting General Physics and Astronomy Biology Protein Serine-Threonine Kinases medicine.disease_cause Real-Time Polymerase Chain Reaction General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Cell Line Tumor medicine Humans Immunoprecipitation Phosphorylation lcsh:Science Adaptor Proteins Signal Transducing Hippo signaling pathway Multidisciplinary Activator (genetics) Tumor Suppressor Proteins HEK 293 cells Signal transducing adaptor protein YAP-Signaling Proteins General Chemistry Gene signature Phosphoproteins Cell biology Transcription Factor AP-1 030104 developmental biology Cell Transformation Neoplastic HEK293 Cells Microscopy Fluorescence Cancer cell lcsh:Q Female Acyltransferases Signal Transduction Transcription Factors |
| Zdroj: | Nature Communications, Vol 9, Iss 1, Pp 1-13 (2018) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. The Hippo pathway is frequently dysregulated in cancer. Here, the authors identify NUAK2 as negative regulator of the Hippo pathway from a siRNA kinome screen and show that NUAK2 promotes YAP/TAZ nuclear localisation while NUAK2 is a transcriptional target of YAP/TAZ, thus providing a feed forward loop to promote tumorigenesis. |
| Databáze: | OpenAIRE |
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