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NTRK1 is a positive regulator of YAP oncogenic function

Oncogene volume 38, pages 2778–2787 (2019)Cite this article

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Abstract

Multiple cancer signalling networks take part in regulatory crosstalks with the Hippo tumour suppressor pathway through the transcriptional cofactor Yes-associated protein (YAP). Nevertheless, how YAP is controlled by pathway crosstalks in tumourigenesis remains poorly understood. Here, we performed a targeted kinase inhibitor screen in human cancer cells to identify novel Hippo pathway regulators. Notably, we identified the nerve growth factor (NGF) receptor tyrosine kinase (NTRK1), a molecule not previously associated with Hippo signalling. NTRK1 inhibition decreased YAP-driven transcription, cancer cell proliferation and migration. Furthermore, using a complementary functional genomics approach and mouse xenograft models, we show that NTRK1 regulates YAP oncogenic activity in vivo. Mechanistically, NTRK1 inhibition was found to induce large suppressor kinase 1 (LATS1) phosphorylation and to control YAP subcellular localization. Taken together, these results provide compelling evidence of crosstalks between the NGF-NTRK1 and Hippo cancer pathways.

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Acknowledgements

We would like to thank Dr. Haber who kindly provided us 293AD cells and Dr. Camargo who kindly provided us the CTGF promoter luciferase reporter construct. Also, we thank the Small Molecule Screen, Flow and Image Cytometry, Laboratory Animal and Experimental Tumour Models Shared Resources/Facilities of RPCI. This work was supported by the National Natural Science Foundation of China 81672921; Innovation Capacity Support Plan of Shaanxi Province, Grant/Award Number:2018TD-002 (to SH). This work was supported by the Roswell Park Cancer Institute and National Cancer Institute (NCI) Grant #P30 CA016056, Roswell Park Alliance Foundation, National Cancer Institute (NCI) R01 CA207504 and the American Cancer Society Research Scholar Grant RSG-14-214-01-TBE (to JZ).

Author contributions

XY, HS, CF and JZ designed the experiments. XY, HS, BB, YC, NY, AM, MC, CF, SH and JZ carried out the experiments and analysed the data. CF, LK and JZ wrote the paper.

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  1. These authors contributed equally: Xinyuan Yang, He Shen

Authors and Affiliations

  1. Department of Oncology, The First Affiliated Hospital of Xi’an Jiaotong University Medical College, Xi’an, 710061, Shannxi, P. R. China

    Xinyuan Yang & Su-Xia Han

  2. Department of Cancer Genetics & Genomics, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA

    Xinyuan Yang, He Shen, Yanmin Chen, Ashley L. Mussell & Jianmin Zhang

  3. Small Molecule Core, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA

    Brian Buckley & Mikhail Chernov

  4. Department of Anesthesiology, Jacobs School of Medicine & Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, 14214, USA

    Nuo Yang

  5. Harvard TH Chan School of Public Health, Molecular and Integrative Physiological Sciences, 665 Huntington Avenue, Boston, MA, 02115, USA

    Lester Kobzik & Costa Frangou

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  1. Xinyuan Yang
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Correspondence to Su-Xia Han or Jianmin Zhang.

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Yang, X., Shen, H., Buckley, B. et al. NTRK1 is a positive regulator of YAP oncogenic function. Oncogene 38, 2778–2787 (2019). https://doi.org/10.1038/s41388-018-0609-1

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