BDNF stimulation of protein synthesis in cortical neurons requires the map kinase-interacting kinase MNK1
BDNF stimulation of protein synthesis in cortical neurons requires the map kinase-interacting kinase MNK1
Although the MAP kinase-interacting kinases (MNKs) have been known for >15 years, their roles in the regulation of protein synthesis have remained obscure. Here, we explore the involvement of the MNKs in brain-derived neurotrophic factor (BDNF)-stimulated protein synthesis in cortical neurons from mice. Using a combination of pharmacological and genetic approaches, we show that BDNF-induced upregulation of protein synthesis requires MEK/ERK signaling and the downstream kinase, MNK1, which phosphorylates eukaryotic initiation factor (eIF) 4E. Translation initiation is mediated by the interaction of eIF4E with the m7GTP cap of mRNA and with eIF4G. The latter interaction is inhibited by the interactions of eIF4E with partner proteins, such as CYFIP1, which acts as a translational repressor. We find that BDNF induces the release of CYFIP1 from eIF4E, and that this depends on MNK1. Finally, using a novel combination of BONCAT and SILAC, we identify a subset of proteins whose synthesis is upregulated by BDNF signaling via MNK1 in neurons. Interestingly, this subset of MNK1-sensitive proteins is enriched for functions involved in neurotransmission and synaptic plasticity. Additionally, we find significant overlap between our subset of proteins whose synthesis is regulated by MNK1 and those encoded by known FMRP-binding mRNAs. Together, our data implicate MNK1 as a key component of BDNF-mediated translational regulation in neurons.
972-984
Genheden, Maja
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Kenney, Justin W.
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Johnston, Harvey E.
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Manousopoulou, Antigoni
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Garbis, Spiros D.
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Proud, Christopher G.
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21 January 2015
Genheden, Maja
5bacfa73-c67b-4a98-8d1f-7f6d45cbc388
Kenney, Justin W.
a498bbd6-750d-4778-bd72-6ea336c883e8
Johnston, Harvey E.
3c4b1bf2-a8c2-4bc3-bce7-179a379b107a
Manousopoulou, Antigoni
9a5e4e75-cea9-4d0b-91c8-0fa2af02632f
Garbis, Spiros D.
7067fd19-50c9-4d42-9611-f370289470bd
Proud, Christopher G.
59dabfc8-4b44-4be8-a17f-578a58550cb3
Genheden, Maja, Kenney, Justin W., Johnston, Harvey E., Manousopoulou, Antigoni, Garbis, Spiros D. and Proud, Christopher G.
(2015)
BDNF stimulation of protein synthesis in cortical neurons requires the map kinase-interacting kinase MNK1.
Journal of Neuroscience, 35 (3), .
(doi:10.1523/JNEUROSCI.2641-14.2015).
(PMID:25609615)
Abstract
Although the MAP kinase-interacting kinases (MNKs) have been known for >15 years, their roles in the regulation of protein synthesis have remained obscure. Here, we explore the involvement of the MNKs in brain-derived neurotrophic factor (BDNF)-stimulated protein synthesis in cortical neurons from mice. Using a combination of pharmacological and genetic approaches, we show that BDNF-induced upregulation of protein synthesis requires MEK/ERK signaling and the downstream kinase, MNK1, which phosphorylates eukaryotic initiation factor (eIF) 4E. Translation initiation is mediated by the interaction of eIF4E with the m7GTP cap of mRNA and with eIF4G. The latter interaction is inhibited by the interactions of eIF4E with partner proteins, such as CYFIP1, which acts as a translational repressor. We find that BDNF induces the release of CYFIP1 from eIF4E, and that this depends on MNK1. Finally, using a novel combination of BONCAT and SILAC, we identify a subset of proteins whose synthesis is upregulated by BDNF signaling via MNK1 in neurons. Interestingly, this subset of MNK1-sensitive proteins is enriched for functions involved in neurotransmission and synaptic plasticity. Additionally, we find significant overlap between our subset of proteins whose synthesis is regulated by MNK1 and those encoded by known FMRP-binding mRNAs. Together, our data implicate MNK1 as a key component of BDNF-mediated translational regulation in neurons.
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BDNF Stimulation of Protein Synthesis in Cortical Neurons Requires the MAP Kinase-Interacting Kinase MNK1.pdf
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Accepted/In Press date: 31 October 2014
Published date: 21 January 2015
Organisations:
Cancer Sciences
Identifiers
Local EPrints ID: 395391
URI: http://eprints.soton.ac.uk/id/eprint/395391
PURE UUID: e44ea9f2-b924-4829-a83a-69fb50b0d446
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Date deposited: 27 May 2016 14:20
Last modified: 15 Mar 2024 00:39
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Contributors
Author:
Maja Genheden
Author:
Justin W. Kenney
Author:
Harvey E. Johnston
Author:
Antigoni Manousopoulou
Author:
Spiros D. Garbis
Author:
Christopher G. Proud
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