Smad6 inhibits non-canonical TGF-β1 signalling by recruiting the deubiquitinase A20 to TRAF6

Su Myung Jung, Ji Hyung Lee, Jinyoung Park, Young Sun Oh, Sung Kyun Lee, Jin Seok Park, Youn Sook Lee, Jun Hwan Kim, Jae Young Lee, Yoe Sik Bae, Seung Hoi Koo, Seong Jin Kim, Seok Hee Park

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81 Citations (Scopus)


Transforming growth factor (TGF)-β, a pivotal cytokine involved in a variety of cellular functions, transmits signals through Smad-dependent canonical and Smad-independent noncanonical pathways. In contrast to the canonical TGF-β pathway, it is unknown how noncanonical TGF-β pathways are negatively regulated. Here we demonstrate that the inhibitory Smad Smad6, but not Smad7, negatively regulates TGF-β1-induced activation of the TRAF6-TAK1-p38 MAPK/JNK pathway, a noncanonical TGF-β pathway. TGF-β1-induced Smad6 abolishes K63-linked polyubiquitination of TRAF6 by recruiting the A20 deubiquitinating enzyme in AML-12 mouse liver cells and primary hepatocytes. In addition, the knockdown of Smad6 or A20 in an animal model or cell culture system maintains TAK1 and p38 MAPK/JNK phosphorylation and increases apoptosis, emphasizing the crucial role of the Smad6-A20 axis in negative regulation of the TGF-β1-TRAF6-TAK1-p38 MAPK/JNK pathway. Therefore, our findings provide insight into the molecular mechanisms underlying negative regulation of noncanonical TGF-β pathways.

Original languageEnglish
Article number2562
JournalNature communications
Publication statusPublished - 2013 Oct 7

Bibliographical note

Funding Information:
We thank Dr Min Sung Choi for critical reading of the manuscript. We thank Sun Myung Park for technical assistance with animal experiments. This work was supported by a National Research Foundation grant of Korea (2012R1A2A2A01003850) and in part by National Research Foundation grants of Korea (2009-0081756, 2011-0019368, and ROA-2007-00020047-0) funded by the Ministry of Science, ICT & Future Planning. Y.S.L. is a recipient of a National Research Foundation grant of Korea (2012R1A6A3A04040738) funded by the Korean Government.

Publisher Copyright:
© 2013 Macmillan Publishers Limited. All rights reserved.

ASJC Scopus subject areas

  • Physics and Astronomy(all)
  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)


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