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

Zhang, L and Zhou, F and GarciadeVinuesa, A and deKruijf, E and Mesker, W and Hui, L and Drabsch, Y and Li, Y and Bauer, A and Rousseau, A and Sheppard, K and Mickanin, C and Kuppen, P and Lu, C and tenDijke, P (2013) TRAF4 Promotes TGF-beta Receptor Signaling and Drives Breast Cancer Metastasis. MOLECULAR CELL. pp. 559-572.

Abstract

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 andnon-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 (TbetaRI). Both processes contribute to TbetaRI 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 andsubsequent 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 pathwayand is a key determinant in breast cancer pathogenesis. 2013 Elsevier Inc

Item Type: Article
Additional Information: pubid: 239 nvp_institute: NIBR contributor_address: (Zhang, Zhou, GarciadeVinuesa, Drabsch, Li, tenDijke) Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, Postbus 9600, 2300 RC Leiden, Netherlands (deKruijf, Mesker, Kuppen) Department of Surgery, Leiden University Medical Center, Postbus 9600, 2300 RC Leiden, Netherlands (Hui, Sheppard, Mickanin, Lu) Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, United States (Bauer) Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland (Rousseau) Institut de Genetique et de Biologie Moleculaire et Cellulaire, Unite Mixte de Recherche 7104, Centre Natl. de la Rech. Sci./U964 Inst. Natl. de Sante et de Rech. Med./Univ. de Strasb., 67404 Illkirch, France (Zhang) Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/22045

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