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J. Biol. Chem., Vol. 283, Issue 27, 18478-18482, July 4, 2008

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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^*

Usha Narayanan¹, Vijayalaxmi Nalavadi, Mika Nakamoto, George Thomas^¶, Stephanie Ceman^||, Gary J. Bassell, and Stephen T. Warren^**2

From the Departments of Human Genetics, Cell Biology, ^**Biochemistry, the Pediatrics, Emory University, Atlanta, Georgia 30322, and the ^¶Genome Research Institute, Cincinnati, Ohio 45215, the ^||Department of Cell and Developmental Biology, University of Illinois, Urbana-Champaign, Illinois 61801

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.

Received for publication, March 11, 2008 , and in revised form, May 7, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HD020521 and HD24064 (to S. T. W.), NS051127 (to G. J. B.), and HD41591 (to S. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains eight supplemental figures and supplemental methods.

¹ Recipient of a Fragile X Research Foundation post-doctoral fellowship.

² To whom correspondence should be addressed: Dept. of Human Genetics, Emory University School of Medicine, 615 Michael St., Ste. 305E, Atlanta, GA 30322. Tel.: 404-727-5979; Fax: 404-727-3949; E-mail: swarren{at}genetics.emory.edu.

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