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Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
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TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-beta

Motozo Yamashita1, Karoly Fatyol, Chaoyang Jin

  • 1Laboratory of Cellular and Molecular Biology, National Cancer Institute, Bethesda, MD 20892, USA.

Molecular Cell
|October 17, 2008
PubMed

Insights

Tumor growth factor-beta (TGF-beta) activates JNK and p38 pathways via TRAF6, independent of Smads. This mechanism, involving TRAF6 ubiquitination and TAK1 association, mirrors the interleukin-1beta/Toll-like receptor pathway.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Signal transduction

Background:

  • Transforming growth factor-beta (TGF-beta) is implicated in apoptosis and epithelial-to-mesenchymal transition (EMT).
  • TGF-beta utilizes MAP kinase pathways and Smads, but the precise activation mechanism remains unclear.
  • Understanding TGF-beta signaling is crucial for physiological and disease process research.

Purpose of the Study:

  • To elucidate the mechanism of MAP kinase cascade activation by TGF-beta receptors.
  • To identify key molecules involved in the Smad-independent activation of JNK and p38 by TGF-beta.
  • To compare the TGF-beta signaling pathway with other known inflammatory pathways.

Main Methods:

  • Investigated the role of TRAF6 in TGF-beta-induced signaling.
  • Examined the physical interaction between TRAF6 and TGF-beta receptors.
  • Analyzed TGF-beta-induced ubiquitination of TRAF6 and its association with TAK1.
  • Compared the activation of JNK and p38 by TGF-beta to the interleukin-1beta/Toll-like receptor pathway.

Main Results:

  • TRAF6 is essential for the Smad-independent activation of JNK and p38 by TGF-beta.
  • The carboxyl TRAF homology domain of TRAF6 directly interacts with TGF-beta receptors.
  • TGF-beta stimulation leads to K63-linked ubiquitination of TRAF6.
  • TRAF6 ubiquitination promotes its association with TAK1, a key kinase in the MAP kinase cascade.
  • The activation mechanism of JNK and p38 by TGF-beta is analogous to that in the IL-1beta/TLR pathway.

Conclusions:

  • TRAF6 acts as a critical mediator in TGF-beta signaling, linking TGF-beta receptors to JNK and p38 activation.
  • The findings reveal a novel Smad-independent pathway for TGF-beta-induced cellular responses.
  • This study provides new insights into the crosstalk between TGF-beta and inflammatory signaling pathways.

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