Arkadia enhances BMP signalling through ubiquitylation and degradation of Smad6

Arkadia, a positive regulator of Smad-dependent signalling via the transforming growth factor-β (TGF-β) family, is an E3 ubiquitin ligase that induces ubiquitylation and proteasome-dependent degradation of TGF-β suppressors such as Smad7, c-Ski and SnoN. In this study, we examined the effects of Ark...

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Bibliographic Details
Published in:Journal of biochemistry (Tokyo) 2015-07, Vol.158 (1), p.61-71
Main Authors: Tsubakihara, Yutaro, Hikita, Atsuhiko, Yamamoto, Shin, Matsushita, Sachi, Matsushita, Natsuki, Oshima, Yusuke, Miyazawa, Keiji, Imamura, Takeshi
Format: Article
Language:English
Subjects:
Animals
Cells, Cultured
Cercopithecus aethiops
COS Cells
Mice
Mice, Knockout
Signal Transduction
Smad6 Protein - metabolism
Ubiquitin-Protein Ligases - deficiency
Ubiquitin-Protein Ligases - metabolism
Ubiquitination
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Summary:Arkadia, a positive regulator of Smad-dependent signalling via the transforming growth factor-β (TGF-β) family, is an E3 ubiquitin ligase that induces ubiquitylation and proteasome-dependent degradation of TGF-β suppressors such as Smad7, c-Ski and SnoN. In this study, we examined the effects of Arkadia on bone morphogenetic protein (BMP)-induced osteoblast differentiation. Knockdown of Arkadia reduced mineralization and expression of osteoblast differentiation markers. Furthermore, we showed that Smad6, a BMP-specific inhibitory Smad, is a target of Arkadia: wild-type (WT) Arkadia, but not the C937A (CA) mutant lacking E3 ubiquitin-ligase activity, induced ubiquitylation and proteasome-dependent degradation of Smad6. Accordingly, protein levels of Smad6, Smad7 and c-Ski were elevated in MEFs from Arkadia KO mice. Finally, expression of Arkadia attenuated blockade of BMP signalling by Smad6 in a transcriptional reporter assay. These results demonstrate that Smad6 is a novel target of Arkadia, and that Arkadia positively regulates BMP signalling via degradation of Smad6, Smad7 and c-Ski/SnoN.
ISSN:0021-924X
1756-2651
DOI:10.1093/jb/mvv024