TRAF4 promotes TGF-β receptor signaling and drives breast cancer metastasis

Mol Cell. 2013 Sep 12;51(5):559-72. doi: 10.1016/j.molcel.2013.07.014. Epub 2013 Aug 22.


TGF-β signaling is a therapeutic target in advanced cancers. We identified tumor necrosis factor receptor-associated factor 4 (TRAF4) as a key component mediating pro-oncogenic TGF-β-induced SMAD and non-SMAD signaling. Upon TGF-β stimulation, TRAF4 is recruited to the active TGF-β receptor complex, where it antagonizes E3 ligase SMURF2 and facilitates the recruitment of deubiquitinase USP15 to the TGF-β type I receptor (TβRI). Both processes contribute to TβRI stabilization on the plasma membrane and thereby enhance TGF-β signaling. In addition, the TGF-β receptor-TRAF4 interaction triggers Lys 63-linked TRAF4 polyubiquitylation and subsequent activation of the TGF-β-activated kinase (TAK)1. TRAF4 is required for efficient TGF-β-induced migration, epithelial-to-mesenchymal transition, and breast cancer metastasis. Elevated TRAF4 expression correlated with increased levels of phosphorylated SMAD2 and phosphorylated TAK1 as well as poor prognosis among breast cancer patients. Our results demonstrate that TRAF4 can regulate the TGF-β pathway and is a key determinant in breast cancer pathogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Movement
  • Epithelial-Mesenchymal Transition / drug effects
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MAP Kinase Kinase Kinases / metabolism
  • Mice
  • Phosphorylation
  • Polyubiquitin / metabolism
  • Prognosis
  • Protein Serine-Threonine Kinases / metabolism
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Signal Transduction
  • Smad2 Protein / metabolism
  • TNF Receptor-Associated Factor 4 / genetics*
  • TNF Receptor-Associated Factor 4 / metabolism*
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / pharmacology
  • Ubiquitin-Protein Ligases / metabolism


  • Receptors, Transforming Growth Factor beta
  • SMAD2 protein, human
  • Smad2 Protein
  • TNF Receptor-Associated Factor 4
  • TRAF4 protein, human
  • Transforming Growth Factor beta
  • Polyubiquitin
  • SMURF2 protein, human
  • Ubiquitin-Protein Ligases
  • Protein Serine-Threonine Kinases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Receptor, Transforming Growth Factor-beta Type I