TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-beta

Mol Cell. 2008 Sep 26;31(6):918-24. doi: 10.1016/j.molcel.2008.09.002.


In many physiological and disease processes, TGF-beta usurps branches of MAP kinase pathways in conjunction with Smads to induce apoptosis and epithelial-to-mesenchymal transition, but the detailed mechanism of how a MAP kinase cascade is activated by TGF-beta receptors is not clear. We report here that TRAF6 is specifically required for the Smad-independent activation of JNK and p38, and its carboxyl TRAF homology domain physically interacts with TGF-beta receptors. TGF-beta induces K63-linked ubiquitination of TRAF6 and promotes association between TRAF6 and TAK1. Our results indicate that TGF-beta activates JNK and p38 through a mechanism similar to that operating in the interleukin-1beta/Toll-like receptor pathway.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Line
  • Enzyme Activation / drug effects
  • Epithelium / drug effects
  • Epithelium / metabolism
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Lysine / metabolism
  • MAP Kinase Kinase Kinases / metabolism
  • Mesoderm / drug effects
  • Mesoderm / metabolism
  • Mice
  • Protein Binding / drug effects
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction / drug effects
  • Smad Proteins / metabolism
  • TNF Receptor-Associated Factor 6 / metabolism*
  • Transforming Growth Factor beta / pharmacology*
  • Ubiquitination / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Receptors, Transforming Growth Factor beta
  • Smad Proteins
  • TNF Receptor-Associated Factor 6
  • Transforming Growth Factor beta
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Lysine