The AKT/TSC/mTOR axis is an important pathway controlling cell growth, survival, and proliferation in response to extracellular cues. Recently, it was reported that AKT activity fluctuates across the cell cycle. However, it remains unclear whether downstream targets of AKT are also regulated by the cell cycle. Here, we report that mTORC1 activity inversely correlates with AKT activity during the cell cycle. Mechanistically, Plk1 phosphorylation of TSC1 at S467 and S578 interfered with TSC1/TSC2 binding, destabilized TSC1, promoted dissociation of the TSC complex from the lysosome, and eventually led to mTORC1 activation. Tumors derived from cancer cells expressing the TSC1-S467E/S578E mutant exhibited greater sensitivity to rapamycin than those expressing WT TSC1. Collectively, our data support a model in which Plk1, instead of AKT, regulates the TSC/mTORC1 pathway during mitosis, eventually regulating the efficacy of rapamycin. Significance: This seminal report shows that activation of mTORC1 can be independent of AKT during mitosis.
|Number of pages||12|
|State||Published - Jun 1 2018|
Bibliographical noteFunding Information:
This work was supported by NIH grants R01 CA157429 (to X. Liu), R01 CA192894 (to X. Liu), R01 CA196835 (to X. Liu), R01 CA196634 (to X. Liu), and P30 CA023168 (Purdue Center for Cancer Research).
© 2018 American Association for Cancer Research.
ASJC Scopus subject areas
- Cancer Research