Department of Sensory and Motor System Medicine, Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Tokyo 113-8655, Japan.
J Biol Chem. 2012 Aug 24;287(35):29227-36. doi: 10.1074/jbc.M112.372086. Epub 2012 Jul 3.
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.
在这里，我们研究了糖原合酶激酶-3（GSK-3）的两种同工型（GSK-3α和 GSK-3β）在骨骼发育中的作用。在 SOX9 和 II 型胶原（COL2A1）表达的软骨细胞分化阶段，两种同工型均未磷酸化且具有活性。尽管敲除小鼠的 Gsk3a（Gsk3a(-/-)）或 Gsk3b 的单个等位基因（Gsk3b(+/-)）都不会显著影响骨骼发育，但复合敲除（Gsk3a(-/-);Gsk3b(+/-)）会导致矮小症，并损害软骨细胞分化。GSK-3α 和 GSK-3β 以细胞自主的方式诱导培养的软骨细胞分化，具有功能冗余性，独立于 Wnt/β-连环蛋白信号。SOX9 和 COL2A1 转录分析的计算预测随后确定 RelA（NF-κB p65）是 GSK-3 的关键磷酸化靶标。在 RelA 的几个磷酸化残基中，鉴定出 Thr-254 是调节软骨细胞分化的 GSK-3 的关键磷酸化位点。总之，通过 RelA 的 Thr-254 磷酸化，GSK-3α 和 GSK-3β 的冗余功能在软骨细胞分化的早期阶段发挥着关键作用。
