Calcium/calmodulin-dependent protein kinase IV (CaMKIV) enhances osteoclast differentiation via the up-regulation of Notch1 protein stability
Calcium/calmodulin-dependent protein kinase IV (CaMKIV) enhances osteoclast differentiation via the up-regulation of Notch1 protein stability
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DOI：
10.1016/j.bbamcr.2012.10.018
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发表时间：
2013-01-01
影响因子：
5.1
通讯作者：
Park, Hee-Sae
中科院分区：
文献类型：
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作者：
Choi, Yun-Hee;Ann, Eun-Jung;Park, Hee-Sae
Notch信号通路在细胞命运决定的调控中起着至关重要的作用，也是多种情况下细胞分化（包括骨稳态）的关键调节因子。然而，Notch1信号在破骨细胞分化中的作用仍存在争议。在这项研究中，我们发现核因子κ b配体受体激活因子（RANKL）诱导的破骨细胞分化是由Notch1胞内结构域（Notch1- ic）和Ca2+/钙调蛋白依赖性蛋白激酶IV （CaMKIV）信号传导促进的。CaMKIV通过逃避泛素依赖性蛋白降解而增加Notch1-IC蛋白水平。此外，CaMKIV显著增加了Notch1- ic的稳定性，并且CaMKIV的激酶活性对于促进Notch1信号传导至关重要。CaMKIV直接与Notch1-IC相互作用并使Notch1-IC磷酸化，从而通过F-box和WD重复结构域7 （Fbw7）减少蛋白酶体蛋白降解。我们还发现Notch1-IC可以阻止KN-93对破骨细胞分化的抑制，但不能阻止Notch1-IC的磷酸化缺陷形式。这些结果表明CaMKIV磷酸化Notch1-IC增加了Notch1-IC的稳定性，从而促进了破骨细胞的分化。(c) 2012 Elsevier B.V.版权所有
The Notch signaling pathway plays a crucial role in the regulation of cell fate decision, and is also a key regulator of cell differentiation, including bone homeostasis, in a variety of contexts. However, the role of Notch1 signaling in osteoclast differentiation is still controversial. In this study, we show that Receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation is promoted by the Notch1 intracellular domain (Notch1-IC) and Ca2+/Calmodulin dependent protein kinase IV (CaMKIV) signaling. Notch1-IC protein level was augmented by CaMKIV through escape from ubiquitin dependent protein degradation. In addition, CaMKIV remarkably increased Notch1-IC stability, and the kinase activity of CaMKIV was essential for facilitating Notch1 signaling. CaMKIV directly interacted with Notch1-IC and phosphorylates Notch1-IC, thereby decreasing proteasomal protein degradation through F-box and WD repeat domain-containing 7 (Fbw7). We also found that Notch1-IC prevented inhibition of osteoclast differentiation by KN-93 but not the phosphorylation deficient form of Notch1-IC. These results suggest that phosphorylated Notch1-IC by CaMKIV increases Notch1-IC stability, which enhances osteoclast differentiation. (c) 2012 Elsevier B.V. All rights reserved.