S6K1 phosphorylates and regulates fragile X mental retardation protein (FMRP) with the neuronal protein synthesis-dependent mammalian target of rapamycin (mTOR) signaling cascade.
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.
Narayanan
Usha
U
Department of Human Genetics, Emory University, Atlanta, Georgia 30322, USA.
Nalavadi
Vijayalaxmi
V
Nakamoto
Mika
M
Thomas
George
G
Ceman
Stephanie
S
Bassell
Gary J
GJ
Warren
Stephen T
ST
D000818:Animals; D002478:Cells, Cultured; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D005600:Fragile X Syndrome / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009473:Neuronal Plasticity / Q000235:genetics; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases
D051860:Fragile X Messenger Ribonucleoprotein 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009419:Nerve Tissue Proteins; D011494:Protein Kinases; D054648:Protein Phosphatase 2; D012333:RNA, Messenger; D018094:Receptors, Metabotropic Glutamate; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C497684:Fmr1 protein, mouse; C523020:Sapap3 protein, mouse; C104077:metabotropic glutamate receptor type 1; C546842:MTOR protein, human; C546843:mTOR protein, mouse