Journal
ONCOGENE
Volume 38, Issue 15, Pages 2778-2787Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41388-018-0609-1
Keywords
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Funding
- National Natural Science Foundation of China [81672921]
- Innovation Capacity Support Plan of Shaanxi Province [2018TD-002]
- Roswell Park Cancer Institute
- National Cancer Institute (NCI) [P30 CA016056, R01 CA207]
- Roswell Park Alliance Foundation
- American Cancer Society [RSG-14-214-01-TBE]
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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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