The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner

Nat Cell Biol. 2008 Oct;10(10):1199-207. doi: 10.1038/ncb1780. Epub 2008 Aug 31.


Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that regulates embryonic development and tissue homeostasis; however, aberrations of its activity occur in cancer. TGF-beta signals through its Type II and Type I receptors (TbetaRII and TbetaRI) causing phosphorylation of Smad proteins. TGF-beta-associated kinase 1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family, was originally identified as an effector of TGF-beta-induced p38 activation. However, the molecular mechanisms for its activation are unknown. Here we report that the ubiquitin ligase (E3) TRAF6 interacts with a consensus motif present in TbetaRI. The TbetaRI-TRAF6 interaction is required for TGF-beta-induced autoubiquitylation of TRAF6 and subsequent activation of the TAK1-p38/JNK pathway, which leads to apoptosis. TbetaRI kinase activity is required for activation of the canonical Smad pathway, whereas E3 activity of TRAF6 regulates the activation of TAK1 in a receptor kinase-independent manner. Intriguingly, TGF-beta-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-beta specifically activates TAK1 through interaction of TbetaRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Line
  • Enzyme Activation / drug effects
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Lysine / metabolism
  • MAP Kinase Kinase Kinases / metabolism*
  • Mice
  • Protein Binding / drug effects
  • Protein-Serine-Threonine Kinases / metabolism*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Smad2 Protein / metabolism
  • TNF Receptor-Associated Factor 6 / metabolism*
  • Transforming Growth Factor beta / pharmacology
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Receptors, Transforming Growth Factor beta
  • Smad2 Protein
  • TNF Receptor-Associated Factor 6
  • Transforming Growth Factor beta
  • Ubiquitin-Protein Ligases
  • Receptor Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Receptor, Transforming Growth Factor-beta Type I
  • Lysine