Protein geranylgeranylation (GGylation) is an important biochemical process for cellular localization of many signaling molecules including Rho and Rab small GTPases and heterotrimeric GTPase gamma subunits. Previous studies have shown that GGylation is essential for cancer cell survival. However, the molecular mechanism mediating the cell survival effect remains elusive. Here we show that the hippo pathway is the downstream pathway of GGylation in breast cancer cells. Inhibition of GGylation enhanced phosphorylation of Mst1, Mst2 and Lats1 kinases, and eliminated LPA-induced activation of Yap and Taz and the hippo pathway-dependent transcription of Cyr61 and CTGF. We have demonstrated that the inhibitory effects of atorvastatin, an inhibitor of the biosynthesis of geranylgeranyl pyrophosphate (GGPP), and GGTI-298, an inhibitor of geranylgeranyltransferase I (GGTase I), on cell proliferation and migration are dependent on the hippo pathway in the breast cancer cells. In addition, knockdown of Yap and Taz produced the similar inhibitory effect on the cell proliferation and migration to that of atorvastatin and GGTI-298, suggesting the functional correlation between GGylation and the hippo signaling. Thus, our studies have demonstrated that the hippo pathway mediates the GGylation-dependent cancer cell survival and migration.

Citation Format: Wenyi Mi, Qiong Lin, Chandra Childress, Wannian Yang. Geranylgeranylation signals to the hippo pathway for breast cancer cell proliferation and migration. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3291. doi:10.1158/1538-7445.AM2014-3291