title: BDNF stimulation of protein synthesis in cortical neurons requires the MAP kinase-interacting kinase MNK1.
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 m(7)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.
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton, SO17 1BJ, United Kingdom.
authors.forename: Maja
authors.initials: M
authors.lastname: Genheden
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton, SO17 1BJ, United Kingdom.
authors.forename: Justin W
authors.initials: JW
authors.lastname: Kenney
authors.affiliation: Cancer Sciences and CES Units, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, SO16 6YD, United Kingdom, and Centre for Proteomic Research, Institute for Life Sciences, University of Southampton, Highfield Campus, Southampton, SO17 1BJ, United Kingdom.
authors.forename: Harvey E
authors.identifier: http://orcid.org/0000-0001-7032-0227
authors.initials: HE
authors.lastname: Johnston
authors.affiliation: Cancer Sciences and CES Units, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, SO16 6YD, United Kingdom, and Centre for Proteomic Research, Institute for Life Sciences, University of Southampton, Highfield Campus, Southampton, SO17 1BJ, United Kingdom.
authors.forename: Antigoni
authors.initials: A
authors.lastname: Manousopoulou
authors.affiliation: Cancer Sciences and CES Units, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, SO16 6YD, United Kingdom, and Centre for Proteomic Research, Institute for Life Sciences, University of Southampton, Highfield Campus, Southampton, SO17 1BJ, United Kingdom.
authors.forename: Spiros D
authors.initials: SD
authors.lastname: Garbis
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton, SO17 1BJ, United Kingdom, Christopher.proud@sahmri.com.
authors.forename: Christopher G
authors.identifier: http://orcid.org/0000-0003-0704-6442
authors.initials: CG
authors.lastname: Proud
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019208:Brain-Derived Neurotrophic Factor; C115472:Cyfip1 protein, mouse; D039561:Eukaryotic Initiation Factor-4E; D009419:Nerve Tissue Proteins; C106281:Mknk1 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: BDNF; BONCAT; CYFIP1; MNK; SILAC; eIF4E