| RRC ID |
10834
|
| 著者 |
Kobayashi Y, Mizoguchi T, Take I, Kurihara S, Udagawa N, Takahashi N.
|
| タイトル |
Prostaglandin E2 enhances osteoclastic differentiation of precursor cells through protein kinase A-dependent phosphorylation of TAK1.
|
| ジャーナル |
J Biol Chem
|
| Abstract |
Prostaglandin E2 (PGE2) synergistically enhances the receptor activator for NF-kappa B ligand (RANKL)-induced osteoclastic differentiation of the precursor cells. Here we investigated the mechanisms of the stimulatory effect of PGE2 on osteoclast differentiation. PGE2 enhanced osteoclastic differentiation of RAW264.7 cells in the presence of RANKL through EP2 and EP4 prostanoid receptors. RANKL-induced degradation of I kappa B alpha and phosphorylation of p38 MAPK and c-Jun N-terminal kinase in RAW264.7 cells were up-regulated by PGE2 in a cAMP-dependent protein kinase A (PKA)-dependent manner, suggesting that EP2 and EP4 signals cross-talk with RANK signals. Transforming growth factor beta-activated kinase 1 (TAK1), an important MAPK kinase kinase in several cytokine signals, possesses a PKA recognition site at amino acids 409-412. PKA directly phosphorylated TAK1 in RAW264.7 cells transfected with wild-type TAK1 but not with the Ser412 --> Ala mutant TAK1. Ser412 --> Ala TAK1 served as a dominant-negative mutant in PKA-enhanced degradation of I kappa B alpha, phosphorylation of p38 MAPK, and PGE2-enhanced osteoclastic differentiation in RAW264.7 cells. Furthermore, forskolin enhanced tumor necrosis factor alpha-induced I kappa B alpha degradation, p38 MAPK phosphorylation, and osteoclastic differentiation in RAW264.7 cells. Ser412 --> Ala TAK1 abolished the stimulatory effects of forskolin on those cellular events induced by tumor necrosis factor alpha. Ser412 --> Ala TAK1 also inhibited the forskolin-induced up-regulation of interleukin 6 production in RAW264.7 cells treated with lipopolysaccharide. These results suggest that the phosphorylation of the Ser412 residue in TAK1 by PKA is essential for cAMP/PKA-induced up-regulation of osteoclastic differentiation and cytokine production in the precursor cells.
|
| 巻・号 |
280(12)
|
| ページ |
11395-403
|
| 公開日 |
2005-3-25
|
| DOI |
10.1074/jbc.M411189200
|
| PII |
S0021-9258(20)80841-2
|
| PMID |
15647289
|
| MeSH |
Animals
Carrier Proteins / pharmacology
Cell Differentiation / drug effects
Cells, Cultured
Cyclic AMP / physiology
Cyclic AMP-Dependent Protein Kinases / physiology*
Dinoprostone / pharmacology*
Humans
Interleukin-6 / biosynthesis
MAP Kinase Kinase Kinases / physiology*
Membrane Glycoproteins / pharmacology
Mice
Osteoclasts / cytology
Osteoclasts / drug effects*
Phosphorylation
RANK Ligand
Receptor Activator of Nuclear Factor-kappa B
Receptors, Prostaglandin E / analysis
Receptors, Prostaglandin E / physiology
Receptors, Prostaglandin E, EP2 Subtype
Receptors, Prostaglandin E, EP4 Subtype
Stem Cells / cytology
Stem Cells / drug effects*
Tumor Necrosis Factor-alpha / pharmacology
p38 Mitogen-Activated Protein Kinases / metabolism
|
| IF |
4.238
|
| 引用数 |
93
|
|
WOS 分野
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
RAW 264(RCB0535) |
