Phosphoproteomic analysis of kinase-deficient mice reveals multiple TAK1 targets in osteoclast differentiation
| Autor: | Shizuo Akira, Kojiro Sato, Masahiro Shinohara, Yusuke Nagai, Tomomi Suda, Hideki Sanjo, Takako Negishi-Koga, Ayako Suematsu, Hiroshi Takayanagi, Eriko Sumiya |
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| Rok vydání: | 2015 |
| Předmět: |
musculoskeletal diseases
Proteome MAP Kinase Signaling System Molecular Sequence Data Biophysics Osteoclasts MAP3K7 Biochemistry Mice Osteoclast medicine Animals Amino Acid Sequence Kinase activity Protein kinase A Molecular Biology biology MAP kinase kinase kinase Kinase NF-kappa B Cell Differentiation Cell Biology MAP Kinase Kinase Kinases Phosphoproteins Mice Inbred C57BL medicine.anatomical_structure Protein kinase domain RANKL biology.protein Cancer research |
| Zdroj: | Biochemical and biophysical research communications. 463(4) |
| ISSN: | 1090-2104 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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