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

Author

Listed:
  • Su Myung Jung

    (Sungkyunkwan University)

  • Ji-Hyung Lee

    (Sungkyunkwan University)

  • Jinyoung Park

    (Sungkyunkwan University School of Medicine
    Korea University)

  • Young Sun Oh

    (Sungkyunkwan University
    Medical Bioconvergence Research Center, Seoul National 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)

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.

Suggested Citation

  • 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, 2013. "Smad6 inhibits non-canonical TGF-β1 signalling by recruiting the deubiquitinase A20 to TRAF6," Nature Communications, Nature, vol. 4(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3562
    DOI: 10.1038/ncomms3562
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