The mechanistic target of rapamycin (mTOR) integrates numerous stimuli and coordinates the adaptive response of many cellular processes. To accomplish this, mTOR associates with distinct co-factors that determine its signaling output. While many of these co-factors are known, in many cases their function and regulation remain opaque. The MAPK-interacting kinase (MNK) contributes to rapamycin resistance in cancer cells. Here, we demonstrate that MNK sustains mTORC1 activity following rapamycin treatment and contributes to mTORC1 signaling following T cell activation and growth stimuli in cancer cells. We determine that MNK engages with mTORC1, promotes mTORC1 association with the phosphatidyl inositol 3' kinase-related kinase (PIKK) stabilizer, TELO2, and facilitates mTORC1:substrate binding. Moreover, our data suggest that DEPTOR, the endogenous inhibitor of mTOR, opposes mTORC1:substrate association by preventing TELO2:mTORC1 binding. Thus, MNK orchestrates counterbalancing forces that regulate mTORC1 enzymatic activity. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
Michael C Brown, Matthias Gromeier. MNK Controls mTORC1:Substrate Association through Regulation of TELO2 Binding with mTORC1. Cell reports. 2017 Feb 07;18(6):1444-1457
PMID: 28178522
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