title: GSK-3α and GSK-3β proteins are involved in early stages of chondrocyte differentiation with functional redundancy through RelA protein phosphorylation.
abstract: Here we examine the roles of two isoforms of glycogen synthase kinase-3 (GSK-3), GSK-3α and GSK-3β, in skeletal development. Both isoforms were unphosphorylated and active in chondrocyte differentiation stages during SOX9 and type II collagen (COL2A1) expression. Although knock-out of both alleles of Gsk3a (Gsk3a(-/-)) or a single allele of Gsk3b (Gsk3b(+/-)) in mice did not significantly affect skeletal development, compound knock-out (Gsk3a(-/-);Gsk3b(+/-)) caused dwarfism with impairment of chondrocyte differentiation. GSK-3α and GSK-3β induced differentiation of cultured chondrocytes with functional redundancy in a cell-autonomous fashion, independently of the Wnt/β-catenin signal. Computational predictions followed by SOX9 and COL2A1 transcriptional assays identified RelA (NF-κB p65) as a key phosphorylation target of GSK-3. Among several phosphorylation residues in RelA, Thr-254 was identified as the critical phosphorylation site for GSK-3 that modulated chondrocyte differentiation. In conclusion, redundant functions of GSK-3α and GSK-3β through phosphorylation of RelA at Thr-254 play a crucial role in early stages of chondrocyte differentiation.
authors: Department of Sensory and Motor System Medicine, Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Tokyo 113-8655, Japan.
authors: Shozo
authors: S
authors: Itoh
authors: Taku
authors: T
authors: Saito
authors: Makoto
authors: M
authors: Hirata
authors: Masahiro
authors: M
authors: Ushita
authors: Toshiyuki
authors: T
authors: Ikeda
authors: James R
authors: JR
authors: Woodgett
authors: Hana
authors: H
authors: Algül
authors: Roland M
authors: RM
authors: Schmid
authors: Ung-Il
authors: UI
authors: Chung
authors: Hiroshi
authors: H
authors: Kawaguchi
mesh_terms: D000818:Animals; D001846:Bone Development / Q000235:genetics; D002454:Cell Differentiation; D002460:Cell Line; D019902:Chondrocytes / Q000201:enzymology* / Q000473:pathology; D024043:Collagen Type II / Q000096:biosynthesis; D004392:Dwarfism / Q000201:enzymology / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000235:genetics; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C447413:Col2a1 protein, mouse; D024043:Collagen Type II; C498144:Rela protein, mouse; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D051996:Transcription Factor RelA; D051153:Wnt Proteins; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha