Editors' ChoiceCancer

Promoting Metastasis with Ubiquitin

Sci. Signal.  24 Sep 2013:
Vol. 6, Issue 294, pp. ec225
DOI: 10.1126/scisignal.2004746

Transforming growth factor–β (TGF-β) is involved in numerous physiological and developmental processes and is implicated in cancer, epithelial-to-mesenchymal transition (EMT), and metastasis. Therapeutically targeting TGF-β is complicated by the multifunctional and context-specific nature of its actions (see Moustakas and Heldin). Zhang et al. found that tumor necrosis factor receptor–associated factor 4 (TRAF4), a ubiquitin ligase, is a central regulator of TGF-β–mediated metastasis in breast cancer. In a gain-of-function genetic screen using a TGF-β–induced transcriptional reporter (and confirmed in knockdown studies), TRAF4 was identified as a positive regulator of TGF-β–induced transcription. Mouse embryonic fibroblasts deficient in TRAF4 had decreased downstream TGF-β signaling markers, including formation of the SMAD2-SMAD4 complex and phosphorylation of SMAD2 and p38 MAPK (mitogen-activated protein kinase). In human embryonic kidney and MDA-MB-231 cells, TRAF4 bound the TGF-β receptor complex (TβRI/TβRII), the E3 ubiquitin ligase SMURF2 (which targets TβRI for degradation), the TβRI-targeting deubiquitinase USP15, or TGF-β–activated kinase 1 (TAK1, which activates p38). TGF-β treatment increased the interaction between TRAF4 and TβRI/TβRII or TAK1, and TRAF4 overexpression increased the association of TβRI with USP15 while increasing the polyubiquitylation and proteasome-mediated degradation of SMURF2. TRAF4 knockdown or SMURF2 overexpression decreased the amount of TβRI present at the plasma membrane, which indicated that TRAF4 promoted the stability of TβRI/TβRII. In breast cancer patients, TRAF4 expression correlated with TGF-β–associated metastasis, poor survival, and EMT markers. In cultured MDA-MB-231 cells, TRAF4 knockdown increased cell-cell adhesion and the expression of CDH1 (encoding E-cadherin) and impaired TGF-β–induced transcriptional activation of EMT markers, migration through transwells, and invasion into a three-dimensional collagen matrix. In mouse and zebrafish MDA-MB-231 xenograft models, TRAF4 knockdown reduced the activation of SMAD2 and TAK1 and the number of micrometastases. Together, the findings indicate that TRAF4 may be a therapeutic target to inhibit TGF-β–induced EMT and metastasis in breast cancer.

L. Zhang, F. Zhou, A. Garcia de Vinuesa, E. M. de Kruijf, W. E. Mesker, L. Hui, Y. Drabsch, Y. Li, A. Bauer, A. Rousseau, K.-A. Sheppard, C. Mickanin, P. J. K. Kuppen, C. X. Lu, P. ten Dijke, TRAF4 promotes TGF-β receptor signaling and drives breast cancer metastasis. Mol. Cell 51, 559–572 (2013).[PubMed]

A. Moustakas, C.-H. Heldin, Coordination of TGF-β signaling by ubiquitylation. Mol. Cell 51, 555–556 (2013).[PubMed]

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