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Dephosphorylation-induced ubiquitination and degradation of FMRP in dendrites: a role in immediate early mGluR-stimulated translation.

Fragile X syndrome is caused by the loss of fragile X mental retardation protein (FMRP), which represses and reversibly regulates the translation of a subset of mRNAs in dendrites. Protein synthesis can be rapidly stimulated by mGluR-induced and protein phosphatase 2a (PP2A)-mediated dephosphorylation of FMRP, which is coupled to the dissociation of FMRP and target mRNAs from miRNA-induced silencing complexes. Here, we report the rapid ubiquitination and ubiquitin proteasome system (UPS)-mediated degradation of FMRP in dendrites upon DHPG (3,5-dihydroxyphenylglycine) stimulation in cultured rat neurons. Using inhibitors to PP2A and FMRP phosphomutants, degradation of FMRP was observed to depend on its prior dephosphorylation. Translational induction of an FMRP target, postsynaptic density-95 mRNA, required both PP2A and UPS. Thus, control of FMRP levels at the synapse by dephosphorylation-induced and UPS-mediated degradation provides a mode to regulate protein synthesis.

Pubmed ID: 22357842 RIS Download

Mesh terms: Analysis of Variance | Animals | Boronic Acids | Bortezomib | Cells, Cultured | Dendrites | Drosophila Proteins | Embryo, Mammalian | Enzyme Inhibitors | Female | Fragile X Mental Retardation Protein | Gene Expression Regulation | Green Fluorescent Proteins | Hippocampus | Immunoprecipitation | Intracellular Signaling Peptides and Proteins | Leupeptins | Male | Membrane Proteins | Methoxyhydroxyphenylglycol | Mutation | Neurons | Okadaic Acid | Phosphoprotein Phosphatases | Phosphorylation | Protein Biosynthesis | Pyrazines | RNA, Messenger | Rats | Rats, Sprague-Dawley | Receptors, Metabotropic Glutamate | Serine | Signal Transduction | Synapses | Transfection | Ubiquitination

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Associated grants

  • Agency: NICHD NIH HHS, Id: P30 HD001799
  • Agency: NIMH NIH HHS, Id: R01 MH085617
  • Agency: NIMH NIH HHS, Id: MH086405
  • Agency: NICHD NIH HHS, Id: P30 HD024064
  • Agency: NINDS NIH HHS, Id: R01 NS051127
  • Agency: NICHD NIH HHS, Id: 3P30HD024064
  • Agency: NINDS NIH HHS, Id: P30 NS055077

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