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 **nglin 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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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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**e, 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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DOI: https://doi.org/10.1007/s00018-020-03491-1