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Biochem Biophys Res Commun. 2015 Aug 7;463(4):1284-90. doi: 10.1016/j.bbrc.2015.06.105. Epub 2015 Jun 20.

Phosphoproteomic analysis of kinase-deficient mice reveals multiple TAK1 targets in osteoclast differentiation.

Author information

1
Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-0033, Japan; Department of Cell Signaling, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo, 113-8510, Japan; Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Program, Takayanagi Osteonetwork Project, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-0033, Japan.
2
Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-0033, Japan; Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Program, Takayanagi Osteonetwork Project, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-0033, Japan.
3
Department of Cell Signaling, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo, 113-8510, Japan.
4
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, 565-0871, Japan.
5
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, 565-0871, Japan; Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, 565-0871, Japan.
6
Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-0033, Japan; Department of Cell Signaling, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo, 113-8510, Japan; Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Program, Takayanagi Osteonetwork Project, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-0033, Japan. Electronic address: takayana@m.u-tokyo.ac.jp.

Abstract

TAK1 (encoded by Map3k7) is a mitogen-activated protein kinase kinase kinase (MAP3K), which activates the transcription factors AP-1 and NF-κB in response to receptor activator of NF-κB ligand (RANKL) stimulation, thus constituting a key regulator of osteoclast differentiation. Here we report the functional relevance of the kinase activity of TAK1 in the late stage of osteoclast differentiation in vivo using Ctsk-Cre mice and TAK1 mutant mice in which the TAK1 kinase domain was flanked by loxP. The Map3k7(flox/kd)Ctsk(Cre/+) mice displayed a severe osteopetrotic phenotype due to a marked decrease in osteoclast number. RANKL-induced activation of MAPK and NF-κB was impaired in the late stage of osteoclast differentiation. The absence of suppressive effect of an administered NF-κB inhibitor on the late stage of osteoclastogenesis led us to investigate unknown TAK1 targets in osteoclast differentiation. We performed a phosphoproteomic analysis of RANKL-stimulated osteoclast precursor cells from Map3k7(flox/kd)Ctsk(Cre/+) mice, revealing multiple targets regulated by TAK1 during osteoclastogenesis. Thus, TAK1 functions as a critical regulator of the phosophorylation status of various cellular proteins that govern osteoclastogenesis.

KEYWORDS:

Osteoclast; Osteopetrosis; Phosphoproteome; RANKL; TAK1

PMID:
26102028
DOI:
10.1016/j.bbrc.2015.06.105
[Indexed for MEDLINE]

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