Arkadia enhances BMP signalling through ubiquitylation and degradation of Smad6

Journal of Biochemistry
Yutaro TsubakiharaT Imamura

Abstract

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.

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Citations

Dec 7, 2016·Cold Spring Harbor Perspectives in Biology·Keiji Miyazawa, Kohei Miyazono
Jan 4, 2018·International Journal of Molecular Sciences·Blanca HerreraAránzazu Sánchez
Nov 3, 2016·Development·Yangsook Song GreenJan L Christian
Dec 30, 2017·International Journal of Molecular Medicine·Fei HouChenghong Yin
Feb 11, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Mathias BoulangerGuillaume Bossis
Sep 3, 2021·The Journal of Experimental Medicine·Hao XuDan R Littman

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