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 and Seok Hee Park ()
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Su Myung Jung: Sungkyunkwan University
Ji-Hyung Lee: Sungkyunkwan University
Jinyoung Park: Sungkyunkwan University School of Medicine
Young Sun Oh: Sungkyunkwan University
Sung Kyun Lee: Sungkyunkwan University
Jin Seok Park: Sungkyunkwan University
Youn Sook Lee: Sungkyunkwan University
Jun Hwan Kim: Sungkyunkwan University
Jae Young Lee: Sungkyunkwan University
Yoe-Sik Bae: Sungkyunkwan University
Seung-Hoi Koo: Korea University
Seong-Jin Kim: CHA Cancer Institute, CHA University
Seok Hee Park: Sungkyunkwan University

Nature Communications, 2013, vol. 4, issue 1, 1-16

Abstract: Abstract 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.

Date: 2013
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DOI: 10.1038/ncomms3562

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