title: Delta-catenin/NPRAP: A new member of the glycogen synthase kinase-3beta signaling complex that promotes beta-catenin turnover in neurons.
abstract: Through a multiprotein complex, glycogen synthase kinase-3beta (GSK-3beta) phosphorylates and destabilizes beta-catenin, an important signaling event for neuronal growth and proper synaptic function. delta-Catenin, or NPRAP (CTNND2), is a neural enriched member of the beta-catenin superfamily and is also known to modulate neurite outgrowth and synaptic activity. In this study, we investigated the possibility that delta-catenin expression is also affected by GSK-3beta signaling and participates in the molecular complex regulating beta-catenin turnover in neurons. Immunofluorescent light microscopy revealed colocalization of delta-catenin with members of the molecular destruction complex: GSK-3beta, beta-catenin, and adenomatous polyposis coli proteins in rat primary neurons. GSK-3beta formed a complex with delta-catenin, and its inhibition resulted in increased delta-catenin and beta-catenin expression levels. LY294002 and amyloid peptide, known activators of GSK-3beta signaling, reduced delta-catenin expression levels. Furthermore, delta-catenin immunoreactivity increased and protein turnover decreased when neurons were treated with proteasome inhibitors, suggesting that the stability of delta-catenin, like that of beta-catenin, is regulated by proteasome-mediated degradation. Coimmunoprecipitation experiments showed that delta-catenin overexpression promoted GSK-3beta and beta-catenin interactions. Primary cortical neurons and PC12 cells expressing delta-catenin treated with proteasome inhibitors showed increased ubiquitinated beta-catenin forms. Consistent with the hypothesis that delta-catenin promotes the interaction of the destruction complex molecules, cycloheximide treatment of cells overexpressing delta-catenin showed enhanced beta-catenin turnover. These studies identify delta-catenin as a new member of the GSK-3beta signaling pathway and further suggest that delta-catenin is potentially involved in facilitating the interaction, ubiquitination, and subsequent turnover of beta-catenin in neuronal cells.
authors.affiliation: Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, North Carolina 27834, USA.
authors.forename: Sonja
authors.initials: S
authors.lastname: Bareiss
authors.forename: Kwonseop
authors.initials: K
authors.lastname: Kim
authors.forename: Qun
authors.initials: Q
authors.lastname: Lu
mesh_terms: D016475:3T3 Cells; D000818:Animals; D015153:Blotting, Western; D051177:Catenins / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006207:Half-Life; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D054875:Ubiquitination / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism*; D000095002:Delta Catenin
chemical_list: D051177:Catenins; D004791:Enzyme Inhibitors; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D000095002:Delta Catenin