Translational control of ERK signaling through miRNA/4EHP-directed silencing
Abstract
MicroRNAs (miRNAs) exert a broad influence over gene expression by directing effector activities that impinge on translation and stability of mRNAs. We recently discovered that the cap-binding protein 4EHP is a key component of the mammalian miRNA-Induced Silencing Complex (miRISC), which mediates gene silencing. However, little is known about the mRNA repertoire that is controlled by the 4EHP/miRNA mechanism or its biological importance. Here, using ribosome profiling, we identify a subset of mRNAs that are translationally controlled by 4EHP. We show that the Dusp6 mRNA, which encodes an ERK1/2 phosphatase, is translationally repressed by 4EHP and a specific miRNA, miR-145. This promotes ERK1/2 phosphorylation, resulting in augmented cell growth and reduced apoptosis. Our findings thus empirically define the integral role of translational repression in miRNA-induced gene silencing and reveal a critical function for this process in the control of the ERK signalling cascade in mammalian cells.
Data availability
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Translational control of ERK signalling pathway by the mRNA cap-binding protein 4EHPPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE107826).
Article and author information
Author details
Funding
Canadian Institutes of Health Research (FDN-148423)
- Nahum Sonenberg
Fonds de la Recherche en Sante du Quebec
- Thomas F Duchaine
Natural Sciences and Engineering Research Council of Canada (RGPIN-2014-06434)
- Anne-Claude Gingras
Canadian Institutes of Health Research (FDN-143301)
- Anne-Claude Gingras
Canadian Institutes of Health Research (MOP-123352)
- Thomas F Duchaine
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- David Ron, University of Cambridge, United Kingdom
Version history
- Received: January 12, 2018
- Accepted: February 1, 2018
- Accepted Manuscript published: February 7, 2018 (version 1)
- Version of Record published: February 20, 2018 (version 2)
Copyright
© 2018, Jafarnejad et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Further reading
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- Biochemistry and Chemical Biology
Activation of the extracellular signal-regulated kinase-2 (ERK2) by phosphorylation has been shown to involve changes in protein dynamics, as determined by hydrogen-deuterium exchange mass spectrometry (HDX-MS) and NMR relaxation dispersion measurements. These can be described by a global exchange between two conformational states of the active kinase, named ‘L’ and ‘R,’ where R is associated with a catalytically productive ATP-binding mode. An ATP-competitive ERK1/2 inhibitor, Vertex-11e, has properties of conformation selection for the R-state, revealing movements of the activation loop that are allosterically coupled to the kinase active site. However, the features of inhibitors important for R-state selection are unknown. Here, we survey a panel of ATP-competitive ERK inhibitors using HDX-MS and NMR and identify 14 new molecules with properties of R-state selection. They reveal effects propagated to distal regions in the P+1 and helix αF segments surrounding the activation loop, as well as helix αL16. Crystal structures of inhibitor complexes with ERK2 reveal systematic shifts in the Gly loop and helix αC, mediated by a Tyr-Tyr ring stacking interaction and the conserved Lys-Glu salt bridge. The findings suggest a model for the R-state involving small movements in the N-lobe that promote compactness within the kinase active site and alter mobility surrounding the activation loop. Such properties of conformation selection might be exploited to modulate the protein docking interface used by ERK substrates and effectors.
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- Biochemistry and Chemical Biology
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