Reciprocal signaling between mTORC1 and MNK2 controls cell growth and oncogenesis

Xie, Jianling, Shen, Kaikai ORCID: https://orcid.org/0000-0002-3891-7231, Jones, Ashley T., Yang, Jian ORCID: https://orcid.org/0000-0003-2631-4553, Tee, Andrew R. ORCID: https://orcid.org/0000-0002-5577-4631, Shen, Ming Hong ORCID: https://orcid.org/0000-0002-3891-7231, Yu, Mengyuan, Irani, Swati, Wong, Derick, Merrett, James E., Lenchine, Roman V., De Poi, Stuart, Jensen, Kirk B., Trim, Paul J., Snel, Marten F., Kamei, Makoto, Martin, Sally Kim, Fitter, Stephen, Tian, Shuye, Wang, Xuemin, Butler, Lisa M., Zannettino, Andrew C. W. and Proud, Christopher G. 2021. Reciprocal signaling between mTORC1 and MNK2 controls cell growth and oncogenesis. Cellular and Molecular Life Sciences 78 (1) , 249–270. 10.1007/s00018-020-03491-1

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Springer Verlag
ISSN:	1420-682X
Date of First Compliant Deposit:	19 March 2021
Date of Acceptance:	17 February 2020
Last Modified:	13 Nov 2024 05:45
URI:	https://orca.cardiff.ac.uk/id/eprint/139957

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