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