Cot Kinase Promotes Ca2+ Oscillation/Calcineurin-Independent Osteoclastogenesis by Stabilizing nfatc1 Protein

Yukiko Kuroda, Chihiro Hisatsune, Akihiro Mizutani, Naoko Ogawa, Koichi Matsuo, Katsuhiko Mikoshiba

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

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 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 (Tpl-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.

Original languageEnglish
Pages (from-to)2954-2963
Number of pages10
JournalMolecular and cellular biology
Volume32
Issue number14
DOIs
Publication statusPublished - 2012 Jul

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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