TRAF4 Potentiates TGFβ Oncogenic Signaling in Breast Cancer

TGFβ has been shown to function as a tumor suppressor, but can also promote invasion, epithelial–mesenchymal transition, and metastasis in advanced cancers. However, the mechanisms that specifically regulate the pro-oncogenic activity of TGFβ are poorly understood. Zhang and colleagues identified TNF receptor–associated factor 4 (TRAF4), an E3 ubiquitin ligase implicated in regulation of cell migration, as an activator of TGFβ receptor signaling. In response to TGFβ stimulation, TRAF4 transiently interacted with activated TGFβ receptor complexes and stabilized TGFβ receptor I (TβRI) at the plasma membrane. This effect was dependent on recruitment of ubiquitin specific peptidase 15 (USP15), a TβRI deubiquitinase, and TRAF4-mediated polyubiquitination and degradation of SMAD specific E3 ubiquitin protein ligase 2 (SMURF2), an E3 ligase that downregulates TGFβ/SMAD activity. In addition to this regulation of SMAD signaling, association of TRAF4 with activated TβRI induced lysine 63-linked ubiquitination of TRAF4, resulting in its interaction with TGFβ-activated kinase 1 (TAK1) and activation of downstream TAK1-regulated pathways including p38 MAPK and NF-κB, indicating that TRAF4 also potentiates non-SMAD signaling. Depletion of TRAF4 impaired TGFβ-driven cell migration and invasion and prevented induction of EMT markers and prometastatic genes by TGFβ in breast cancer cells in vitro, suggesting that TRAF4 is required for breast cancer progression and metastasis. In support of this idea, TRAF4 knockdown inhibited breast cancer metastasis in zebrafish and mouse xenograft models. Furthermore, TRAF4 was amplified in human breast and ovarian tumors, and elevated TRAF4 expression was positively correlated with activated SMAD2 and TAK1 signaling and associated with decreased relapse-free survival and poor prognosis in breast cancer. These results establish TRAF4 as a critical regulator of the pro-oncogenic activity of TGFβ and suggest TRAF4 as a potential therapeutic target in breast cancer.

Zhang L, Zhou F, García de Vinuesa A, de Kruijf EM, Mesker WE, Hui L, et al. TRAF4 promotes TGF-β receptor signaling and drives breast cancer metastasis. Mol Cell 2013;51:559–72.

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