Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 287, Issue 35, Pages 29227-29236Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.372086
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Funding
- Japanese Ministry of Education, Culture, Sports, Science and Technology [21390416, 22659267, 22390286]
- Grants-in-Aid for Scientific Research [21390416, 22390286, 22659267] Funding Source: KAKEN
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Here we examine the roles of two isoforms of glycogen synthase kinase-3 (GSK-3), GSK-3 alpha and GSK-3 beta, 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-3 alpha and GSK-3 beta induced differentiation of cultured chondrocytes with functional redundancy in a cell-autonomous fashion, independently of the Wnt/beta-catenin signal. Computational predictions followed by SOX9 and COL2A1 transcriptional assays identified RelA (NF-kappa B 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-3 alpha and GSK-3 beta through phosphorylation of RelA at Thr-254 play a crucial role in early stages of chondrocyte differentiation.
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