BDNF stimulation of protein synthesis in cortical neurons requires the MAP kinase-interacting kinase MNK1
Open accessAbstract
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.
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In Mnk1-null neurons, altered expression of a subset of proteins was observed, including 26 proteins whose encoding mRNAs are bound by FMRP in translating ribosomes.
“In particular, in Mnk1-null neurons, altered expression of a subset of proteins was observed, including 26 proteins whose encoding mRNAs are bound by FMRP in translating ribosomes (Genheden et al., 2016; Darnell et al., 2011).”
From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Genheden et al., 2016
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Global quantification of mammalian gene expression control
Schwanhäusser, B., Busse, D., Li, N., Dittmar, G., Schuchhardt, J., Wolf, J., Chen, W., & Selbach, M. (2011) · Nature · doi:10.1038/nature10098 · Cited by 6,566 · cited 1× · see citing works
“Regulation of mRNA translation is crucial in determining the proteome (Schwanhausser et al., 2011).”
BackgroundFMRP Stalls Ribosomal Translocation on mRNAs Linked to Synaptic Function and Autism
Darnell, J. C., Van Driesche, S. J., Zhang, C., Hung, K. Y. S., Mele, A., Fraser, C. E., Stone, E. F., Chen, C., Fak, J. J., Chi, S. W., et al. (2011) · Cell · doi:10.1016/j.cell.2011.06.013 · Cited by 2,072 · see citing works
Autism-related deficits via dysregulated eIF4E-dependent translational control
Gkogkas, C. G., Khoutorsky, A., Ran, I., Rampakakis, E., Nevarko, T., Weatherill, D. B., Vasuta, C., Yee, S., Truitt, M., Dallaire, P., et al. (2013) · Nature · doi:10.1038/nature11628 · Cited by 522 · see citing works
De Rubeis, S., Pasciuto, E., Li, K. W., Fernández, E., Di Marino, D., Buzzi, A., Ostroff, L. E., Klann, E., Zwartkruis, F. J. T., Komiyama, N. H., et al. (2013) · Neuron · doi:10.1016/j.neuron.2013.06.039 · Cited by 296 · see citing works
ERK1/2 Phosphorylate Raptor to Promote Ras-dependent Activation of mTOR Complex 1 (mTORC1)
Carriere, A., Romeo, Y., Acosta-Jaquez, H. A., Moreau, J., Bonneil, E., Thibault, P., Fingar, D. C., & Roux, P. P. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.159046 · Cited by 268 · see citing works
Narayanan, U., Nalavadi, V., Nakamoto, M., Pallas, D. C., Ceman, S., Bassell, G. J., & Warren, S. T. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.2969-07.2007 · Cited by 228 · see citing works
Narayanan, U., Nalavadi, V., Nakamoto, M., Thomas, G., Ceman, S., Bassell, G. J., & Warren, S. T. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.c800055200 · Cited by 216 · see citing works
Role of BDNF epigenetics in activity-dependent neuronal plasticity
Karpova, N. N. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.04.002 · Cited by 200 · see citing works
Pathania, M., Davenport, E. C., Muir, J., Sheehan, D. F., López-Doménech, G., & Kittler, J. T. (2014) · Translational Psychiatry · doi:10.1038/tp.2014.16 · Cited by 189 · cited 2× · see citing works
“CYFIP1 has also been implicated in maintenance of dendritic complexity (Pathania et al., 2014) and coordinating BDNFinduced cytoskeletal remodeling (De Rubeis et al.”
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- Leal G, Comprido D, Duarte CB (2014) BDNF-induced local protein syn- thesis and synaptic plasticity. Neuropharmacology 76:639 -656. CrossRef Medline
- Pop AS, Gomez-Mancilla B, Neri G, Willemsen R, Gasparini F (2014) Frag- ile X syndrome: a preclinical review on metabotropic glutamate receptor 5 (mGluR5) antagonists and drug development. Psychopharmacology (Berl) 231:1217-1226. CrossRef Medline
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Leal, G., Bramham, C. R., & Duarte, C. B. (2017) · Vitamins and Hormones · doi:10.1016/bs.vh.2016.10.004 · Cited by 425 · see citing works
Dysregulation and restoration of translational homeostasis in fragile X syndrome
Richter, J. D., Bassell, G. J., & Klann, E. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn4001 · Cited by 275 · see citing works
Role of p38/MAPKs in Alzheimer's Disease: Implications for Amyloid Beta Toxicity Targeted Therapy
Kheiri, G., Dolatshahi, M., Rahmani, F., & Rezaei, N. (2018) · Reviews in the Neurosciences · doi:10.1515/revneuro-2018-0008 · Cited by 211 · see citing works
Abekhoukh, S., Sahin, H. B., Grossi, M., Zongaro, S., Maurin, T., Madrigal, I., Kazue-Sugioka, D., Raas-Rothschild, A., Doulazmi, M., Carrera, P., et al. (2017) · Disease Models & Mechanisms · doi:10.1242/dmm.025809 · Cited by 59 · see citing works
“In particular, in Mnk1 -null neurons, altered expression of a subset of proteins was observed, including 26 proteins whose encoding mRNAs are bound by FMRP in translating ribosomes (Genheden et al., 2016; Darnell et al., 2011).”
- Authors
- Genheden, M., Kenney, J. W., Johnston, H. E., Manousopoulou, A., Garbis, S. D., & Proud, C. G.
- Affiliations
- University of Southampton (GB)
- Southampton General Hospital (GB)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2015-01-21
- Volume
- 35
- Issue
- 3
- Pages
- 972-984
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4300335
- OpenAlex
- W2050998615
- Cited by
- 78
- References
- 9
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 6 · 2023: 2 · 2022: 8 · 2021: 3 · 2020: 5 · 2019: 8 · 2018: 9 · 2017: 9 · 2016: 13 · 2015: 7
- FWCI
- 5.50
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (086688)
- University of Southampton
- Biotechnology and Biological Sciences Research Council (BB/I004483/1, BB/I004483)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- brain-derived neurotrophic factor, MNK1, protein synthesis, cortical neurons, MEK/ERK signaling, eIF4E phosphorylation, CYFIP1, eIF4G, translational regulation, FMRP, synaptic plasticity, neurotransmission, BONCAT, SILAC
- MeSH terms
- Animals, Cerebral Cortex, Nerve Tissue Proteins, Neurons, Phosphorylation, Protein Biosynthesis, Signal Transduction, Up-Regulation, Protein Serine-Threonine Kinases, Brain-Derived Neurotrophic Factor, Eukaryotic Initiation Factor-4E, Adaptor Proteins, Signal Transducing, Mice
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