National Research Laboratory for Regulation of Bone Metabolism and Disease, Medical Research Center for Gene Regulation, Research Institute of Medical Sciences, Brain Korea 21, Chonnam National University Medical School, Gwangju 501-746, Korea.
J Biol Chem. 2010 Feb 19;285(8):5224-31. doi: 10.1074/jbc.M109.042812. Epub 2009 Dec 26.
The regulation of NFATc1 expression is important for osteoclast differentiation and function. Herein, we demonstrate that macrophage-colony-stimulating factor induces NFATc1 degradation via Cbl proteins in a Src kinase-dependent manner. NFATc1 proteins are ubiquitinated and rapidly degraded during late stage osteoclastogenesis, and this degradation is mediated by Cbl-b and c-Cbl ubiquitin ligases in a Src-dependent manner. In addition, NFATc1 interacts endogenously with c-Src, c-Cbl, and Cbl-b in osteoclasts. Overexpression of c-Src induces down-regulation of NFATc1, and depletion of Cbl proteins blocks NFATc1 degradation during late stage osteoclastogenesis. Taken together, our data provide a negative regulatory mechanism by which macrophage-colony-stimulating factor activates Src family kinases and Cbl proteins, and subsequently, induces NFATc1 degradation during osteoclast differentiation.
NFATc1 表达的调节对于破骨细胞的分化和功能非常重要。在此，我们证明巨噬细胞集落刺激因子（M-CSF）通过Src 激酶依赖性方式诱导 Cbl 蛋白使 NFATc1 降解。在晚期破骨细胞生成过程中，NFATc1 蛋白被泛素化并迅速降解，这一降解过程由 Cbl-b 和 c-Cbl 泛素连接酶在 Src 依赖性方式下介导。此外，NFATc1 在内源性上与破骨细胞中的 c-Src、c-Cbl 和 Cbl-b 相互作用。c-Src 的过表达诱导 NFATc1 的下调，而 Cbl 蛋白的耗竭会阻止晚期破骨细胞生成过程中 NFATc1 的降解。总之，我们的数据提供了一个负调控机制，即巨噬细胞集落刺激因子激活Src 家族激酶和 Cbl 蛋白，随后诱导 NFATc1 在破骨细胞分化过程中的降解。
