FMRP phosphorylation reveals an immediate-early signaling pathway triggered by group I mGluR and mediated by PP2A.
Fragile X syndrome is a common form of inherited mental retardation and is caused by loss of fragile X mental retardation protein (FMRP), a selective RNA-binding protein that influences the translation of target messages. Here, we identify protein phosphatase 2A (PP2A) as an FMRP phosphatase and report rapid FMRP dephosphorylation after immediate group I metabotropic glutamate receptor (mGluR) stimulation (<1 min) in neurons caused by enhanced PP2A enzymatic activity. In contrast, extended mGluR activation (1-5 min) resulted in mammalian target of rapamycin (mTOR)-mediated PP2A suppression and FMRP rephosphorylation. These activity-dependent changes in FMRP phosphorylation were also observed in dendrites and showed a temporal correlation with the translational profile of select FMRP target transcripts. Collectively, these data reveal an immediate-early signaling pathway linking group I mGluR activity to rapid FMRP phosphorylation dynamics mediated by mTOR and PP2A.
Narayanan
Usha
U
Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Nalavadi
Vijayalaxmi
V
Nakamoto
Mika
M
Pallas
David C
DC
Ceman
Stephanie
S
Bassell
Gary J
GJ
Warren
Stephen T
ST
D000818:Animals; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D004789:Enzyme Activation / Q000187:drug effects; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D047468:Immunoprecipitation / Q000379:methods; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D009154:Mutation / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection / Q000379:methods
D018683:Excitatory Amino Acid Agents; D051860:Fragile X Messenger Ribonucleoprotein 1; D008734:Methoxyhydroxyphenylglycol; D054648:Protein Phosphatase 2; D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; C121465:6-methyl-2-(phenylethynyl)pyridine; C010117:3,4-dihydroxyphenylglycol