title: Cot kinase promotes Ca2+ oscillation/calcineurin-independent osteoclastogenesis by stabilizing NFATc1 protein.
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 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.
authors.affiliation: Laboratory of Cell and Tissue Biology, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kuroda
authors.forename: Chihiro
authors.initials: C
authors.lastname: Hisatsune
authors.forename: Akihiro
authors.initials: A
authors.lastname: Mizutani
authors.forename: Naoko
authors.initials: N
authors.lastname: Ogawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuo
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mikoshiba
mesh_terms: D000818:Animals; D001483:Base Sequence; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism; D019703:Calcineurin / Q000378:metabolism; D020013:Calcium Signaling; D002450:Cell Communication; D002454:Cell Differentiation; D017931:DNA Primers / Q000235:genetics; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism*; D010766:Phosphorylation; D055550:Protein Stability; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D017931:DNA Primers; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D011518:Proto-Oncogene Proteins; D053245:RANK Ligand; D011994:Recombinant Proteins; C505689:Tnfsf11 protein, mouse; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse; D019703:Calcineurin