BDNF stimulation of protein synthesis in cortical neurons requires the MAP kinase-interacting kinase MNK1

Maja Genheden, Justin W. Kenney, Harvey E. Johnston, Antigoni Manousopoulou, Spiros D. Garbis, Christopher G. Proud

Research output: Contribution to journalArticle

40 Citations (Scopus)

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 (elF) 4E. Translation initiation is mediated by the interaction of eIF4E with the m7 GTP 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.

LanguageEnglish
Pages972-984
Number of pages13
JournalJournal of Neuroscience
Volume35
Issue number3
DOIs
Publication statusPublished - 21 Jan 2015

Keywords

  • BDNF
  • BONCAT
  • CYFIP1
  • MNK
  • SILAC
  • eIF4E

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Genheden, Maja ; Kenney, Justin W. ; Johnston, Harvey E. ; Manousopoulou, Antigoni ; Garbis, Spiros D. ; Proud, Christopher G. / BDNF stimulation of protein synthesis in cortical neurons requires the MAP kinase-interacting kinase MNK1. In: Journal of Neuroscience. 2015 ; Vol. 35, No. 3. pp. 972-984.
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BDNF stimulation of protein synthesis in cortical neurons requires the MAP kinase-interacting kinase MNK1. / Genheden, Maja; Kenney, Justin W.; Johnston, Harvey E.; Manousopoulou, Antigoni; Garbis, Spiros D.; Proud, Christopher G.

In: Journal of Neuroscience, Vol. 35, No. 3, 21.01.2015, p. 972-984.

Research output: Contribution to journalArticle

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AU - Kenney, Justin W.

AU - Johnston, Harvey E.

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