TGF-beta 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-beta-induced SMAD and non-SMAD signaling. Upon TGF-beta stimulation, TRAF4 is recruited to the active TGF-beta receptor complex, where it antagonizes E3 ligase SMURF2 and facilitates the recruitment of deubiquitinase USP15 to the TGF-beta type I receptor (TbRI). Both processes contribute to TbRI stabilization on the plasma membrane and thereby enhance TGF-beta signaling. In addition, the TGF-beta receptor-TRAF4 interaction triggers Lys 63-linked TRAF4 polyubiquitylation and subsequent activation of the TGF-beta-activated kinase (TAK)1. TRAF4 is required for efficient TGF-beta-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-beta pathway and is a key determinant in breast cancer pathogenesis.
- INDEPENDENT ACTIVATION
- UBIQUITIN LIGASE