title: C-terminal domain small phosphatase 1 and MAP kinase reciprocally control REST stability and neuronal differentiation.
abstract: 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.
authors.affiliation: Vollum Institute and mandelg@ohsu.edu.
authors.forename: Edmund
authors.initials: E
authors.lastname: Nesti
authors.affiliation: Vollum Institute and.
authors.forename: Glen M
authors.initials: GM
authors.lastname: Corson
authors.affiliation: Vollum Institute and.
authors.forename: Maxwell
authors.initials: M
authors.lastname: McCleskey
authors.affiliation: Vollum Institute and.
authors.forename: Jon A
authors.initials: JA
authors.lastname: Oyer
authors.affiliation: Vollum Institute and Howard Hughes Medical Institute, Oregon Health and Science University, Portland, OR 97239 mandelg@ohsu.edu.
authors.forename: Gail
authors.initials: G
authors.lastname: Mandel
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002645:Chickens; D002843:Chromatin / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D009154:Mutation / Q000235:genetics; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D016716:PC12 Cells; D010455:Peptides / Q000378:metabolism; D019696:Peptidylprolyl Isomerase / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding; D055550:Protein Stability; D059748:Proteolysis; D051381:Rats; D012097:Repressor Proteins / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism; D000099229:RE1-Silencing Transcription Factor
chemical_list: D002843:Chromatin; D004815:Epidermal Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D049452:Green Fluorescent Proteins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009687:Nuclear Proteins; D010455:Peptides; D019696:Peptidylprolyl Isomerase; D010749:Phosphoprotein Phosphatases; D010768:Phosphoserine; D012097:Repressor Proteins; D044844:beta-Transducin Repeat-Containing Proteins; D018631:ras Proteins; D000099229:RE1-Silencing Transcription Factor; C413483:CTDSP1 protein, human; C000606846:PIN1 protein, human; C000606850:Pin1 protein, mouse