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The Journal of Neuroscience, December 26, 2007, 27(52):14349-14357; doi:10.1523/JNEUROSCI.2969-07.2007
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Neurobiology of Disease
FMRP Phosphorylation Reveals an Immediate-Early Signaling Pathway Triggered by Group I mGluR and Mediated by PP2A
Usha Narayanan,1
Vijayalaxmi Nalavadi,2
Mika Nakamoto,1
David C. Pallas,3,5
Stephanie Ceman,6
Gary J. Bassell,2 and
Stephen T. Warren1,3,4
Departments of 1Human Genetics, 2Cell Biology, 3Biochemistry, and 4Pediatrics and 5Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, and 6Department of Cell and Developmental Biology, University of Illinois, Urbana-Champaign, Illinois 61801
Correspondence should be addressed to Stephen T. Warren at the above address. Email: swarren{at}emory.edu
Fragile X syndrome is a common form of inherited mental retardation and is caused by loss of fragile X mental retardation protein (FMRP), a selective RNA-binding protein that influences the translation of target messages. Here, we identify protein phosphatase 2A (PP2A) as an FMRP phosphatase and report rapid FMRP dephosphorylation after immediate group I metabotropic glutamate receptor (mGluR) stimulation (<1 min) in neurons caused by enhanced PP2A enzymatic activity. In contrast, extended mGluR activation (1–5 min) resulted in mammalian target of rapamycin (mTOR)-mediated PP2A suppression and FMRP rephosphorylation. These activity-dependent changes in FMRP phosphorylation were also observed in dendrites and showed a temporal correlation with the translational profile of select FMRP target transcripts. Collectively, these data reveal an immediate-early signaling pathway linking group I mGluR activity to rapid FMRP phosphorylation dynamics mediated by mTOR and PP2A.
Key words: FMRP; fragile X; phosphorylation; mGluR; synaptic plasticity; PP2A
Received June 29, 2007;
revised Nov. 2, 2007;
accepted Nov. 13, 2007.
Correspondence should be addressed to Stephen T. Warren at the above address. Email: swarren{at}emory.edu
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