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

Eriko Sumiya, Takako Negishi-Koga, Yusuke Nagai, Ayako Suematsu, Tomomi Suda, Masahiro Shinohara, Kojiro Sato, Hideki Sanjo, Shizuo Akira, Hiroshi Takayanagi

Research output: Contribution to journalArticle

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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 Map3k7flox/kdCtskCre/+ 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 Map3k7flox/kdCtskCre/+ 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.

Original languageEnglish
Pages (from-to)1284-1290
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume463
Issue number4
DOIs
Publication statusPublished - Aug 7 2015

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Osteoclasts
Phosphotransferases
Osteogenesis
MAP Kinase Kinase Kinases
Transcription Factor AP-1
Chemical activation
Ligands
Phenotype
Proteins

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Phosphoproteomic analysis of kinase-deficient mice reveals multiple TAK1 targets in osteoclast differentiation. / Sumiya, Eriko; Negishi-Koga, Takako; Nagai, Yusuke; Suematsu, Ayako; Suda, Tomomi; Shinohara, Masahiro; Sato, Kojiro; Sanjo, Hideki; Akira, Shizuo; Takayanagi, Hiroshi.

In: Biochemical and Biophysical Research Communications, Vol. 463, No. 4, 07.08.2015, p. 1284-1290.

Research output: Contribution to journalArticle

Sumiya, E, Negishi-Koga, T, Nagai, Y, Suematsu, A, Suda, T, Shinohara, M, Sato, K, Sanjo, H, Akira, S & Takayanagi, H 2015, 'Phosphoproteomic analysis of kinase-deficient mice reveals multiple TAK1 targets in osteoclast differentiation', Biochemical and Biophysical Research Communications, vol. 463, no. 4, pp. 1284-1290. https://doi.org/10.1016/j.bbrc.2015.06.105
Sumiya, Eriko ; Negishi-Koga, Takako ; Nagai, Yusuke ; Suematsu, Ayako ; Suda, Tomomi ; Shinohara, Masahiro ; Sato, Kojiro ; Sanjo, Hideki ; Akira, Shizuo ; Takayanagi, Hiroshi. / Phosphoproteomic analysis of kinase-deficient mice reveals multiple TAK1 targets in osteoclast differentiation. In: Biochemical and Biophysical Research Communications. 2015 ; Vol. 463, No. 4. pp. 1284-1290.
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