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. 2008 Jul 4;283(27):18478-82. doi: 10.1074/jbc.C800055200. Epub 2008 May 12.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / metabolism*
  • Fragile X Syndrome / genetics
  • Fragile X Syndrome / metabolism
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Humans
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neuronal Plasticity* / genetics
  • Neurons / metabolism*
  • Neurons / pathology
  • Phosphorylation
  • Protein Biosynthesis* / genetics
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Protein Phosphatase 2 / genetics
  • Protein Phosphatase 2 / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Metabotropic Glutamate / genetics
  • Receptors, Metabotropic Glutamate / metabolism
  • Ribosomal Protein S6 Kinases, 70-kDa / genetics
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism*
  • Signal Transduction* / genetics
  • TOR Serine-Threonine Kinases

Substances

  • Fmr1 protein, mouse
  • Nerve Tissue Proteins
  • RNA, Messenger
  • Receptors, Metabotropic Glutamate
  • Sapap3 protein, mouse
  • metabotropic glutamate receptor type 1
  • Fragile X Mental Retardation Protein
  • Protein Kinases
  • MTOR protein, human
  • mTOR protein, mouse
  • Ribosomal Protein S6 Kinases, 70-kDa
  • TOR Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Protein Phosphatase 2