TY - JOUR
T1 - Plk1-mediated phosphorylation of tsc1 enhances the efficacy of rapamycin
AU - Li, Zhiguo
AU - Kong, Yifan
AU - Song, Longzhen
AU - Luo, Qian
AU - Liu, Jinghui
AU - Shao, Chen
AU - Hou, Xianzeng
AU - Liu, Xiaoqi
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/6/1
Y1 - 2018/6/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-17-3046
DO - 10.1158/0008-5472.CAN-17-3046
M3 - Article
C2 - 29559472
AN - SCOPUS:85048034674
SN - 0008-5472
VL - 78
SP - 2864
EP - 2875
JO - Cancer Research
JF - Cancer Research
IS - 11
ER -