TRAF4 Promotes TGF-β Receptor Signaling and Drives Breast Cancer Metastasis

• Published in: Molecular cell 2013-09, Vol.51 (5), p.559-572
• Main Authors: Zhang, Long, Zhou, Fangfang, García de Vinuesa, Amaya, de Kruijf, Esther M., Mesker, Wilma E., Hui, Li, Drabsch, Yvette, Li, Yihao, Bauer, Andreas, Rousseau, Adrien, Sheppard, Kelly-Ann, Mickanin, Craig, Kuppen, Peter J.K., Lu, Chris X., ten Dijke, Peter
• Format: Article
• Language: English
• Subjects: Animals; breast neoplasms; 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; metastasis; Mice; pathogenesis; patients; Phosphorylation; plasma membrane; Polyubiquitin - metabolism; Prognosis; Protein-Serine-Threonine Kinases - metabolism; 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; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta - pharmacology; tumor necrosis factors; ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2013.07.014

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. •TRAF4 mediates efficient activation of TGF-β-initiated SMAD and non-SMAD signaling•TRAF4 targets SMURF2 degradation and TAK1 activation on TGF-β receptor complex•TRAF4 is needed for efficient TGF-β-induced EMT and metastasis•TRAF4 amplification correlates with SMAD/TAK1 activation and poor prognosis