S6K1 phosphorylates and regulates fragile X mental retardation protein (FMRP) with the neuronal protein synthesis-dependent mammalian target of rapamycin (mTOR) signaling cascade
Graduate School of Biomedical Sciences; Department of Human Genetics; Department of Cell Biology
Medical Subject Headings
Animals; Cells, Cultured; Fragile X Mental Retardation Protein; Fragile X Syndrome; Hippocampus; Humans; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Nerve Tissue Proteins; *Neuronal Plasticity; Neurons; Phosphorylation; *Protein Biosynthesis; Protein Kinases; Protein Phosphatase 2; RNA, Messenger; Receptors, Metabotropic Glutamate; Ribosomal Protein S6 Kinases, 70-kDa; *Signal Transduction
Life Sciences | Medicine and Health Sciences
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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Citation: J Biol Chem. 2008 Jul 4;283(27):18478-82. Epub 2008 May 12. Link to article on publisher's site
The Journal of biological chemistry
Narayanan, Usha; Nalavadi, Vijayalaxmi; Nakamoto, Mika; Thomas, George; Ceman, Stephanie; Bassell, Gary J.; and Warren, Stephen T., "S6K1 phosphorylates and regulates fragile X mental retardation protein (FMRP) with the neuronal protein synthesis-dependent mammalian target of rapamycin (mTOR) signaling cascade" (2008). GSBS Student Publications. 1501.