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YAP modifies cancer cell sensitivity to EGFR and survivin inhibitors and is negatively regulated by the non-receptor type protein tyrosine phosphatase 14

Abstract

The Yes-associated protein (YAP) is a transcriptional factor involved in tissue development and tumorigenesis. Although YAP has been recognized as a key element of the Hippo signaling pathway, the mechanisms that regulate YAP activities remain to be fully characterized. In this study, we demonstrate that the non-receptor type protein tyrosine phosphatase 14 (PTPN14) functions as a negative regulator of YAP. We show that YAP forms a protein complex with PTPN14 through the WW domains of YAP and the PPXY motifs of PTPN14. In addition, PTPN14 inhibits YAP-mediated transcriptional activities. Knockdown of YAP sensitizes cancer cells to various anti-cancer agents, such as cisplatin, the EGFR tyrosine kinase inhibitor erlotinib and the small-molecule antagonist of survivin, S12. YAP-targeted modalities may be used in combination with other cancer drugs to achieve maximal therapeutic effects.

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Acknowledgements

This work has been supported by funds from the Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute of the Cedars-Sinai Medical Center (QW), the Donna and Jesse Garber Award for Cancer Research (QW), R01CA089481and R01 CA055306 from the National Cancer Institute (MIG), the Breast Cancer Research Foundation, and the Abramson Family Cancer Research Institute at the University of Pennsylvania (MIG).We thank these investigators for providing plasmids Masato Ogata (murine PTPN14/PEZ), Joan Brugge (YAP), Kunliang Guan (Gal4-TEAD4) and Marius Sudol (LATS1). We thank Dr Chao-Xing Yuan for performing proteomics analysis at the proteomics core facility at the University of Pennsylvania. The Proteomics Core was supported by grant P30CA016520 (Abramson Cancer Center) and by grant ES013508-04 (CEET). We also thank the members of the Women’s Cancer Program (Cedars-Sinai) and the Greene laboratory (UPenn) for helpful discussion.

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Huang, JM., Nagatomo, I., Suzuki, E. et al. YAP modifies cancer cell sensitivity to EGFR and survivin inhibitors and is negatively regulated by the non-receptor type protein tyrosine phosphatase 14. Oncogene 32, 2220–2229 (2013). https://doi.org/10.1038/onc.2012.231

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