| First Author | Kuroda Y | Year | 2012 |
| Journal | Mol Cell Biol | Volume | 32 |
| Issue | 14 | Pages | 2954-63 |
| PubMed ID | 22615493 | Mgi Jnum | J:186651 |
| Mgi Id | MGI:5432843 | Doi | 10.1128/MCB.05611-11 |
| Citation | Kuroda Y, et al. (2012) Cot kinase promotes Ca2+ oscillation/calcineurin-independent osteoclastogenesis by stabilizing NFATc1 protein. Mol Cell Biol 32(14):2954-63 |
| abstractText | 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-kappaB 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(2+) 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(2+)/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(2+) 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 Ca(2+) oscillation and calcineurin activity. |
