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Author Notes:

Corresponding author at: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, 1365-C Clifton Road, C3088, Atlanta, GA 30322, USA. ssun@emory.edu

Xuerong Wang: Conceived and designed the experiments; Performed the experiments; Analyzed and interpreted the data.

Ping Yue, Hui Tao: Performed the experiments.

Shi-Yong Sun: Conceived and designed the experiments; Analyzed and interpreted the data; Wrote the paper.

We are grateful to Drs. C. R. Kahn and M. F. White for kindly providing some cell lines used in this work.

We also thank Dr. A. Hammond for editing the manuscript.

S-Y Sun is an Emory Winship Cancer Institute Halpern Research Scholar and a Georgia Research Alliance Distinguished Cancer Scientist.

The authors declare no conflict of interest.


Research Funding:

This study was supported by NIH R01s  CA118450 (S-Y. S.) and CA160522 (S-Y. S.).


  • Biochemistry
  • Biological sciences
  • Cancer research

Journal Title:



Volume 3, Number 8


, Pages e00378-e00378

Type of Work:

Article | Final Publisher PDF


It has been suggested that the mTOR complex 1 (mTORC1)/p70S6K axis represses upstream PI3K/Akt signaling through phosphorylation of IRS-1 and its subsequent degradation. One potential and current model that explains Akt activation induced by the mTOR inhibitor rapamycin is the relief of mTORC1/p70S6K-mediated feedback inhibition of IRS-1/PI3K/Akt signaling, although this has not been experimentally proven. In this study, we found that chemical inhibition of p70S6K did not increase Akt phosphorylation. Surprisingly, knockdown of p70S6K even substantially inhibited Akt phosphorylation. Hence, p70S6K inhibition clearly does not mimic the activation of Akt by rapamycin. Inhibition or enforced activation of p70S6K did not affect the ability of rapamycin to increase Akt phosphorylation. Moreover, inhibition of mTORC1 with either rapamycin or raptor knockdown did not elevate IRS-1 levels, despite potently increasing Akt phosphorylation. Critically, knockdown or knockout of IRS-1 or IRS-2 failed to abolish the ability of rapamycin to increase Akt phosphorylation. Therefore, IRS-1 and IRS-2 are not essential for mediating rapamycin-induced Akt activation. Collectively, our findings suggest that Akt activation by rapamycin or mTORC1 inhibition is unlikely due to relief of p70S6K-mediated feedback inhibition of IRS-1/PI3K/Akt signaling.

Copyright information:

© 2017 The Authors.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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