C-terminal domain small phosphatase 1 and MAP kinase reciprocally control REST stability and neuronal differentiation.
The repressor element 1 (RE1) silencing transcription factor (REST) in stem cells represses hundreds of genes essential to neuronal function. During neurogenesis, REST is degraded in neural progenitors to promote subsequent elaboration of a mature neuronal phenotype. Prior studies indicate that part of the degradation mechanism involves phosphorylation of two ... sites in the C terminus of REST that require activity of beta-transducin repeat containing E3 ubiquitin protein ligase, βTrCP. We identify a proline-directed phosphorylation motif, at serines 861/864 upstream of these sites, which is a substrate for the peptidylprolyl cis/trans isomerase, Pin1, as well as the ERK1/2 kinases. Mutation at S861/864 stabilizes REST, as does inhibition of Pin1 activity. Interestingly, we find that C-terminal domain small phosphatase 1 (CTDSP1), which is recruited by REST to neuronal genes, is present in REST immunocomplexes, dephosphorylates S861/864, and stabilizes REST. Expression of a REST peptide containing S861/864 in neural progenitors inhibits terminal neuronal differentiation. Together with previous work indicating that both REST and CTDSP1 are expressed to high levels in stem cells and down-regulated during neurogenesis, our results suggest that CTDSP1 activity stabilizes REST in stem cells and that ERK-dependent phosphorylation combined with Pin1 activity promotes REST degradation in neural progenitors.
Mesh Terms:
Animals, Cell Differentiation, Chickens, Chromatin, Epidermal Growth Factor, Extracellular Signal-Regulated MAP Kinases, Green Fluorescent Proteins, HEK293 Cells, Humans, MAP Kinase Signaling System, Mice, Mutation, Neurons, Nuclear Proteins, PC12 Cells, Peptides, Peptidylprolyl Isomerase, Phosphoprotein Phosphatases, Phosphorylation, Phosphoserine, Protein Binding, Protein Stability, Proteolysis, Rats, Repressor Proteins, beta-Transducin Repeat-Containing Proteins, ras Proteins
Animals, Cell Differentiation, Chickens, Chromatin, Epidermal Growth Factor, Extracellular Signal-Regulated MAP Kinases, Green Fluorescent Proteins, HEK293 Cells, Humans, MAP Kinase Signaling System, Mice, Mutation, Neurons, Nuclear Proteins, PC12 Cells, Peptides, Peptidylprolyl Isomerase, Phosphoprotein Phosphatases, Phosphorylation, Phosphoserine, Protein Binding, Protein Stability, Proteolysis, Rats, Repressor Proteins, beta-Transducin Repeat-Containing Proteins, ras Proteins
Proc. Natl. Acad. Sci. U.S.A.
Date: Sep. 16, 2014
PubMed ID: 25197063
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