Cited by 216Genetics and Neurodevelopmental DisordersPI3K/AKT/mTOR signaling in cancerNeuroscience and Neuropharmacology Research

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S6K1 Phosphorylates and Regulates Fragile X Mental Retardation Protein (FMRP) with the Neuronal Protein Synthesis-dependent Mammalian Target of Rapamycin (mTOR) Signaling Cascade

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Narayanan, Usha, Nalavadi, Vijayalaxmi, Nakamoto, Mika, Thomas, George, Ceman, Stephanie, Bassell, Gary J., Warren, Stephen T.·2008·Journal of Biological Chemistry

DOI 10.1074/jbc.c800055200PMC PMC2441545

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Abstract

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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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.
ORCID: Thomas, George
Ceman, Stephanie
Bassell, Gary J.
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)
DOI: 10.1074/jbc.c800055200
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: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 4483 d)
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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S6K1 Phosphorylates and Regulates Fragile X Mental Retardation Protein (FMRP) with the Neuronal Protein Synthesis-dependent Mammalian Target of Rapamycin (mTOR) Signaling Cascade

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