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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. Warren^1,3,4

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

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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

This article has been cited by other articles:

				U. Narayanan, V. Nalavadi, M. Nakamoto, G. Thomas, S. Ceman, G. J. Bassell, and S. T. Warren S6K1 Phosphorylates and Regulates Fragile X Mental Retardation Protein (FMRP) with the Neuronal Protein Synthesis-dependent Mammalian Target of Rapamycin (mTOR) Signaling Cascade J. Biol. Chem., July 4, 2008; 283(27): 18478 - 18482. [Abstract] [Full Text] [PDF]

				J. A. Ronesi and K. M. Huber Metabotropic Glutamate Receptors and Fragile X Mental Retardation Protein: Partners in Translational Regulation at the Synapse Sci. Signal., February 5, 2008; 1(5): pe6 - pe6. [Abstract] [Full Text] [PDF]

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