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Control of mTOR signaling by ubiquitin

Oncogene volume 38, pages 3989–4001 (2019)Cite this article

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Abstract

The evolutionarily conserved mTOR signaling pathway plays essential roles in cell growth, proliferation, metabolism and responses to cellular stresses. Hyperactivation of the mTOR signaling is observed in virtually all solid tumors and has been an attractive drug target. In addition to changes at genetic levels, aberrant activation of the mTOR signaling is also a result from dysregulated posttranslational modifications on key pathway members, such as phosphorylation that has been extensively studied. Emerging evidence also supports a critical role for ubiquitin-mediated modifications in dynamically regulating the mTOR signaling pathway, while a comprehensive review for relevant studies is missing. In this review, we will summarize characterized ubiquitination events on major mTOR signaling components, their modifying E3 ubiquitin ligases, deubiquitinases and corresponding pathophysiological functions. We will also reveal methodologies that have been used to identify E3 ligases or DUBs to facilitate the search for yet-to-be discovered ubiquitin-mediated regulatory mechanisms in mTOR signaling. We hope that our review and perspectives provide rationales and strategies to target ubiquitination for inhibiting mTOR signaling to treat human diseases.

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Acknowledgements

The authors sincerely apologize to all those colleagues whose important work were not cited in this review owing to space limitations, especially many prominent and pioneer work in the mTOR field. We thank other Liu members for critical reading of the manuscript and helpful discussions. This work was supported by the NIH grants (R00CA181342 to PL), a V Foundation Research Scholar Grant (V2018-009 to PL), a UNC IBM Junior Faculty Development Award (PL) and the UNC University Cancer Research Fund (PL).

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Authors and Affiliations

  1. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China

    Yao Jiang

  2. Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Yao Jiang, Siyuan Su, Yanqiong Zhang, Jiayi Qian & Pengda Liu

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  1. Yao Jiang
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  2. Siyuan Su
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  3. Yanqiong Zhang
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  4. Jiayi Qian
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  5. Pengda Liu
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Correspondence to Pengda Liu.

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Jiang, Y., Su, S., Zhang, Y. et al. Control of mTOR signaling by ubiquitin. Oncogene 38, 3989–4001 (2019). https://doi.org/10.1038/s41388-019-0713-x

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