Calcium/calmodulin-dependent protein kinase IV (CaMKIV) enhances osteoclast differentiation via the up-regulation of Notch1 protein stability

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• 作者：Yun-Hee Choi ; Eun-Jung Ann ; Ji-Hye Yoon ; Jung-Soon Mo ; Mi-Yeon Kim ; ^{mykim31002@jnu.ac.kr} ; Hee-Sae Park ; ^{proteome@jnu.ac.kr}
• 关键词：CaMKIV ; Notch1-IC ; Osteoclastogenesis ; Phosphorylation ; Fbw7 ; Ubiquitylation
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Cell Research
• 出版年：2013
• 出版时间：January, 2013
• 年：2013
• 卷：1833
• 期：1
• 页码：69-79
• 全文大小：1333 K

文摘

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 Ca^2 +/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.