MNK Controls mTORC1:Substrate Association through Regulation of TELO2 Binding with mTORC1

Publication date: 7 February 2017
Source:Cell Reports, Volume 18, Issue 6
Author(s): Michael C. Brown, Matthias Gromeier
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.

Graphical abstract

Teaser

Brown and Gromeier identify MNK as a direct regulator and binding partner of mTORC1. Serendipitously, they find that MNK controls the binding of the PI3K-related kinase (PIKK) stabilizer TELO2 to mTORC1 and that this interaction modulates mTORC1:substrate binding. The endogenous mTOR inhibitor DEPTOR antagonizes TELO2-mTORC1 interaction.


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