The DOI matches its Crossref record; 46 of the 46 references it cites were found in a registry or an index.
S6K1 Phosphorylates and Regulates Fragile X Mental Retardation Protein (FMRP) with the Neuronal Protein Synthesis-dependent Mammalian Target of Rapamycin (mTOR) Signaling Cascade
Open accessAbstract
Fragile X syndrome is a common form of cognitive deficit caused by the functional absence of fragile X mental retardation protein (FMRP), a dendritic RNA-binding protein that represses translation of specific messages. Although FMRP is phosphorylated in a group I metabotropic glutamate receptor (mGluR) activity-dependent manner following brief protein phosphatase 2A (PP2A)-mediated dephosphorylation, the kinase regulating FMRP function in neuronal protein synthesis is unclear. Here we identify ribosomal protein S6 kinase (S6K1) as a major FMRP kinase in the mouse hippocampus, finding that activity-dependent phosphorylation of FMRP by S6K1 requires signaling inputs from mammalian target of rapamycin (mTOR), ERK1/2, and PP2A. Further, the loss of hippocampal S6K1 and the subsequent absence of phospho-FMRP mimic FMRP loss in the increased expression of SAPAP3, a synapse-associated FMRP target mRNA. Together these data reveal a S6K1-PP2A signaling module regulating FMRP function and place FMRP phosphorylation in the mGluR-triggered signaling cascade required for protein-synthesis-dependent synaptic plasticity.
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“The molecular signaling pathways orchestrating protein synthesis, spine shape, and synaptic plasticity, such as mTOR and ERK (Figure 2), are also impaired in FXS (72,(87)(88)(89), possibly because some FMRP target mRNAs encode members of second messenger cascades converging on ERK (88,89).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [72]
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Cites
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mTOR signaling: At the crossroads of plasticity, memory and disease
Hoeffer, C. A., & Klann, E. (2010) · Trends in Neurosciences · doi:10.1016/j.tins.2009.11.003 · Cited by 1,128
Fragile X Syndrome: Loss of Local mRNA Regulation Alters Synaptic Development and Function
Bassell, G. J., & Warren, S. T. (2008) · Neuron · doi:10.1016/j.neuron.2008.10.004 · Cited by 1,051
Self-citationRegulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks
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Metadata
- Authors
- Narayanan, U., Nalavadi, V., Nakamoto, M., Thomas, G., Ceman, S., Bassell, G. J., & Warren, S. T.
- Affiliations
- Emory University (US)
- University of Illinois Urbana-Champaign (US)
- Corresponding author
- Warren, Stephen T.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-07
- Volume
- 283
- Issue
- 27
- Pages
- 18478-18482
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2441545
- OpenAlex
- W2063704147
- Cited by
- 216
- References
- 46
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 2 · 2023: 6 · 2022: 7 · 2021: 5 · 2020: 10 · 2019: 10 · 2018: 13 · 2017: 14 · 2016: 10 · 2015: 11 · 2014: 13 · 2013: 20 · 2012: 23
- FWCI
- 12.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship@UMassChan (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS-051127, R01NS051127)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 24064, HD020521, R01HD041591, P30HD024064, HD41591)
- Topics
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- S6K1, FMRP, mTOR signaling, protein synthesis, fragile X syndrome, protein phosphatase 2A, ERK1/2, metabotropic glutamate receptors, hippocampus, synaptic plasticity, RNA-binding proteins, translational regulation
- MeSH terms
- Animals, Cells, Cultured, Fragile X Syndrome, Hippocampus, Humans, Nerve Tissue Proteins, Neuronal Plasticity, Neurons, Phosphorylation, Protein Kinases, RNA, Messenger, Protein Biosynthesis, Signal Transduction, Receptors, Metabotropic Glutamate, Mice, Knockout, Mitogen-Activated Protein Kinase 1, Ribosomal Protein S6 Kinases, 70-kDa, Mitogen-Activated Protein Kinase 3, Mice, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1, Protein Phosphatase 2, TOR Serine-Threonine Kinases
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