Cot Kinase Promotes Ca2+ Oscillation/Calcineurin-Independent Osteoclastogenesis by Stabilizing NFATc1 Protein
Cot Kinase Promotes Ca2+ Oscillation/Calcineurin-Independent Osteoclastogenesis by Stabilizing NFATc1 Protein
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DOI：
10.1128/mcb.05611-11
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发表时间：
2012-07-01
影响因子：
5.3
通讯作者：
Mikoshiba, Katsuhiko
中科院分区：
文献类型：
--
作者：
Kuroda, Yukiko;Hisatsune, Chihli;Mikoshiba, Katsuhiko
破骨细胞是由单核细胞/巨噬细胞谱系前体细胞融合形成的多核骨吸收细胞。 NF-κ B 配体受体激活剂 (RANKL) 激活转录因子 NFATc1（激活 T 细胞 c1 的核因子）对于破骨细胞分化至关重要。在我们之前的报告（Y. Kuroda, C. Hisatsune, T. Nakamura, K. Matsuo, and K. Mikoshiba. Proc. Nat1. Acad. Sci. U. S. A. 105:8643, 2008）中，我们证明成骨细胞通过Ca2+振荡/钙调神经磷酸酶依赖和独立的NFATc1激活途径诱导破骨细胞分化；然而，后者的机制仍不清楚。在这里，我们发现 Cot 是一种丝氨酸/苏氨酸激酶，也称为肿瘤进展位点 2 (Tp1-2)，可直接磷酸化所有 Ca2+/钙调磷酸酶调节的 NFAT 家族成员（NFATc1 至 NFATc4）并增加其蛋白质水平。此外，破骨细胞中的Cot活性通过与成骨细胞的细胞间相互作用而增强，并且Cot通过磷酸化增加NFATc1稳定性来促进Ca2+振荡/钙调神经磷酸酶独立的破骨细胞生成。我们认为，即使在没有 Ca2+ 振荡和钙调神经磷酸酶活性的情况下，体内 NFAT 激活也是通过磷酸化诱导的蛋白质稳定而发生的。
Osteoclasts are multinuclear bone-resorbing cells formed by the fusion of monocyte/macrophage-lineage precursor cells. Activation of the transcription factor NFATc1 (nuclear factor of activated T cells c1) by the receptor activator of NF-kappa B ligand (RANKL) is critical for osteoclast differentiation. In our previous report (Y. Kuroda, C. Hisatsune, T. Nakamura, K. Matsuo, and K. Mikoshiba. Proc. Nat1. Acad. Sci. U. S. A. 105:8643, 2008), we demonstrated that osteoblasts induce osteoclast differentiation via Ca2+ oscillation/calcineurin-dependent and -independent NFATc1 activation pathways; however, the mechanism underlying the latter remained unclear. Here we show that Cot, a serine/threonine kinase also known as tumor progression locus 2 (Tp1-2), directly phosphorylates all Ca2+/calcineurin-regulated NFAT family members (NFATc1 through NFATc4) and increases their protein levels. Moreover, Cot activity in osteoclasts was enhanced via cell-cell interaction with osteoblasts, and Cot promoted Ca2+ oscillation/calcineurin-independent osteoclastogenesis by increasing NFATc1 stability through phosphorylation. We propose that NFAT activation in vivo occurs via phosphorylation-induced protein stabilization, even in the absence of Ca2+ oscillation and calcineurin activity.