mTORC2 tips the balance in cell survival

mTORC2 tips the balance in cell sur vival Zou et al. demonstrate that mTORC2 acts as a rheostat to regulate cell survival versus apoptosis. The protein kinase mammalian target of rapamycin (mTOR) is present in two distinct multiprotein complexes, mTORC1 and mTORC2, that regulate metabolism, cell proliferation, and survival. Cells are known to leverage microRNAs to regulate expression of proteins both upand downstream of mTORC1. However, the functions and regulation of mTORC2 are less well studied. To learn more about mTORC2 signaling, Zou et al. sought to identify its miRNA targets. miRNA expression profi ling after mTORC2 inhibition in human breast cancer cells showed that mTORC2 specifi cally down-regulated expression of miR-9-3p, a miRNA that provokes apoptosis by impairing expression of the transcription factor E2F1. mTORC2 prevented miR-9-3p expression by reducing stability of the transcription factor c-Myc. No prior studies had shown that mTORC2 can regulate c-Myc directly, but Zou et al. found that mTORC2 reduced c-Myc’s stability by inhibiting its dephosphorylation by the phosphatase PP2A. First author Zhipeng Zou aims to investigate this new pathway in more depth. Ultimately, high mTORC2 activity promoted cell survival via E2F1, whereas low mTORC2 activity caused apoptosis—explaining why mTORC2 inhibition blocks cancer cell growth. Senior author Xiaochun Bai points out that E2F1 mediates survival of cancer cells exposed to genotoxic drugs. The researchers therefore want to test whether mTORC2 inhibitors synergize with these drugs to promote cancer cell apoptosis. Zou, Z., et al. 2015. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201411128