1. TRAF4 promotes TGF-β receptor signaling and drives breast cancer metastasis.
- Author
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Zhang L, Zhou F, García de Vinuesa A, de Kruijf EM, Mesker WE, Hui L, Drabsch Y, Li Y, Bauer A, Rousseau A, Sheppard KA, Mickanin C, Kuppen PJ, Lu CX, and Ten Dijke P
- Subjects
- Animals, 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, Signal Transduction, Smad2 Protein metabolism, Transforming Growth Factor beta metabolism, Transforming Growth Factor beta pharmacology, Ubiquitin-Protein Ligases metabolism, Breast Neoplasms metabolism, Breast Neoplasms pathology, Receptors, Transforming Growth Factor beta metabolism, TNF Receptor-Associated Factor 4 genetics, TNF Receptor-Associated Factor 4 metabolism
- Abstract
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., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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