Abstract
Protein geranylgeranylation (GGylation) is an important biochemical process for many cellular signaling molecules. Previous studies have shown that GGylation is essential for cell survival in many types of cancer. However, the molecular mechanism mediating the cell survival effect remains elusive. In this report, we show that the Hippo pathway mediates GGylation-dependent cell proliferation and migration in breast cancer cells. Blockade of GGylation enhanced phosphorylation of Mst1/2 and Lats1, and inhibited YAP and TAZ activity and the Hippo-YAP/TAZ pathway-dependent transcription. The effect of GGylation blockade on inhibition of breast cancer cell proliferation and migration is dependent on the Hippo-YAP/TAZ signaling, in which YAP appears to regulate cell proliferation and TAZ to regulate cell migration. Furthermore, GGylation-dependent cell proliferation is correlated with the activity of YAP/TAZ in breast cancer cells. Finally, Gγ and RhoA are the GGylated proteins that may transduce GGylation signals to the Hippo-YAP/TAZ pathway. Taken together, our studies have demonstrated that the Hippo-YAP/TAZ pathway is essential for GGylation-dependent cancer cell proliferation and migration.
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Acknowledgements
We thank Dr Pradines of the Département Innovation Thérapeutique et Oncologie Moléculaire, Centre de Physiopathologie, Institut Claudius Regaud for sending us wild-type and the farnesylated RhoA plasmids, Dr Steyger of Oregon Hearing Research Center for the retroviral plasmid pBabe-TRPV4 and Dr Kunliang Guan of University of California at San Diego for HEK293A cell line. This research was supported by Geisinger Research Large Grant (SRC-081, to WY) and NIH R01GM050369 (to CHB).
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Mi, W., Lin, Q., Childress, C. et al. Geranylgeranylation signals to the Hippo pathway for breast cancer cell proliferation and migration. Oncogene 34, 3095–3106 (2015). https://doi.org/10.1038/onc.2014.251
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DOI: https://doi.org/10.1038/onc.2014.251
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