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Reciprocal signaling between mTORC1 and MNK2 controls cell growth and oncogenesis

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Abstract

eIF4E plays key roles in protein synthesis and tumorigenesis. It is phosphorylated by the kinases MNK1 and MNK2. Binding of MNKs to eIF4G enhances their ability to phosphorylate eIF4E. Here, we show that mTORC1, a key regulator of mRNA translation and oncogenesis, directly phosphorylates MNK2 on Ser74. This suppresses MNK2 activity and impairs binding of MNK2 to eIF4G. These effects provide a novel mechanism by which mTORC1 signaling impairs the function of MNK2 and thereby decreases eIF4E phosphorylation. MNK2[S74A] knock-in cells show enhanced phosphorylation of eIF4E and S6K1 (i.e., increased mTORC1 signaling), enlarged cell size, and increased invasive and transformative capacities. MNK2[Ser74] phosphorylation was inversely correlated with disease progression in human prostate tumors. MNK inhibition exerted anti-proliferative effects in prostate cancer cells in vitro. These findings define a novel feedback loop whereby mTORC1 represses MNK2 activity and oncogenic signaling through eIF4E phosphorylation, allowing reciprocal regulation of these two oncogenic pathways.

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Acknowledgements

We gratefully acknowledge financial support from the South Australian Health & Medical Research Institute (SAHMRI), Australia; the Wales Gene Park, UK; the Tuberous Sclerosis Association, UK; Science Foundation for Distinguished Young Scholar of Shanghai, China (Kaikai Shen, No. 2017067) and Xinglin Scholar Talent Program from Shanghai University of Traditional Chinese Medicine, China (Kaikai Shen, No. A1-U17205010436). JX is supported by SAHMRI E/MCR seed funding Grant. LMB is supported by a Principal Cancer Research Fellowship produced with the financial and other support of Cancer Council SA's Beat Cancer Project on behalf of its donors and the State Government of South Australia through the Department of Health. LMB acknowledges Grant support from The Movember Foundation/Prostate Cancer Foundation of Australia (MRTA3) and Cancer Australia (1138766). We would also like to thank Dr Randall Grose from the Australian Cancer Research Foundation (ACRF) Cellular and Imaging Cytometry Core Facility at SAHMRI for his assistance and expertise in FACS cell sorting.

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Authors and Affiliations

  1. Lifelong Health Theme, South Australian Health and Medical Research Institute, North Terrace, Adelaide, SA, 5000, Australia

    Jianling Xie, Derick Wong, James E. Merrett, Roman V. Lenchine, Stuart De Poi, Kirk B. Jensen, Shuye Tian, Xuemin Wang & Christopher G. Proud

  2. Medical Research Council Toxicology Unit, Leicester, UK

    Kaikai Shen

  3. School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China

    Kaikai Shen & Mengyuan Yu

  4. Division of Cancer and Genetics, Cardiff University, Heath Park, Cardiff, UK

    Ashley T. Jones, Jian Yang, Andrew R. Tee & Ming Hong Shen

  5. Adelaide Medical School and Freemasons Foundation Centre for Men’s Health, University of Adelaide, Adelaide, Australia

    Swati Irani & Lisa M. Butler

  6. Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, Australia

    Swati Irani, Sally Kim Martin, Stephen Fitter, Lisa M. Butler & Andrew C. W. Zannettino

  7. Department of Molecular and Cellular Biology, University of Adelaide, Adelaide, Australia

    James E. Merrett, Roman V. Lenchine, Stuart De Poi & Kirk B. Jensen

  8. Hopwood Centre for Neurobiology, South Australian Health and Medical Research Institute, Adelaide, Australia

    Paul J. Trim, Marten F. Snel, Makoto Kamei, Xuemin Wang & Christopher G. Proud

  9. Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Science, University of Adelaide, Adelaide, Australia

    Sally Kim Martin, Stephen Fitter & Andrew C. W. Zannettino

  10. Department of Biology, Southern University of Science and Technology, Shenzhen, China

    Shuye Tian

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Contributions

JX performed most of the experiments. KS, ATJ, JY, ART, MY, MHS, SI, DW, JM, RVL, SDP, PJT, MFS, MK, SKM, ST and XW also provided data and designed the experiments. MHS, KBJ, MFS, SF, LMB, ACWZ and CGP helped designed the experiments and provided supervision. JX and CGP wrote the manuscript with help from KS, ART, MHS, SI, MFS, XW, LMB and ACWZ. All authors commented on the manuscript.

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Correspondence to Christopher G. Proud.

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Xie, J., Shen, K., Jones, A.T. et al. Reciprocal signaling between mTORC1 and MNK2 controls cell growth and oncogenesis. Cell. Mol. Life Sci. 78, 249–270 (2021). https://doi.org/10.1007/s00018-020-03491-1

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