【7/12更新】2022年4月1日からのCiNii ArticlesのCiNii Researchへの統合について

Cot Kinase Promotes Ca 2+ Oscillation/Calcineurin-Independent Osteoclastogenesis by Stabilizing NFATc1 Protein

  • Yukiko Kuroda
    Laboratory of Cell and Tissue Biology, School of Medicine, Keio University, Tokyo, Japan
  • Chihiro Hisatsune
    Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, Wako City, Saitama, Japan
  • Akihiro Mizutani
    Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, Wako City, Saitama, Japan
  • Naoko Ogawa
    Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, Wako City, Saitama, Japan
  • Koichi Matsuo
    Laboratory of Cell and Tissue Biology, School of Medicine, Keio University, Tokyo, Japan
  • Katsuhiko Mikoshiba
    Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, Wako City, Saitama, Japan

抄録

<jats:title>ABSTRACT</jats:title> <jats:p> 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-κB ligand (RANKL) is critical for osteoclast differentiation. In our previous report (Y. Kuroda, C. Hisatsune, T. Nakamura, K. Matsuo, and K. Mikoshiba. Proc. Natl. Acad. Sci. U. S. A. 105:8643, 2008), we demonstrated that osteoblasts induce osteoclast differentiation via Ca <jats:sup>2+</jats:sup> 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 (Tpl-2), directly phosphorylates all Ca <jats:sup>2+</jats:sup> /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 Ca <jats:sup>2+</jats:sup> oscillation/calcineurin-independent osteoclastogenesis by increasing NFATc1 stability through phosphorylation. We propose that NFAT activation <jats:italic>in vivo</jats:italic> occurs via phosphorylation-induced protein stabilization, even in the absence of Ca <jats:sup>2+</jats:sup> oscillation and calcineurin activity. </jats:p>

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