title: TRAF4 promotes TGF-β receptor signaling and drives breast cancer metastasis.
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.
authors: Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, Postbus 9600, 2300 RC Leiden, The Netherlands; Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors: Long
authors: L
authors: Zhang
authors: Fangfang
authors: F
authors: Zhou
authors: Amaya
authors: A
authors: García de Vinuesa
authors: Esther M
authors: EM
authors: de Kruijf
authors: Wilma E
authors: WE
authors: Mesker
authors: Li
authors: L
authors: Hui
authors: Yvette
authors: Y
authors: Drabsch
authors: Yihao
authors: Y
authors: Li
authors: Andreas
authors: A
authors: Bauer
authors: Adrien
authors: A
authors: Rousseau
authors: Kelly-Ann
authors: KA
authors: Sheppard
authors: Craig
authors: C
authors: Mickanin
authors: Peter J K
authors: PJ
authors: Kuppen
authors: Chris X
authors: CX
authors: Lu
authors: Peter
authors: P
authors: Ten Dijke
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D025821:Polyubiquitin / Q000378:metabolism; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D053449:TNF Receptor-Associated Factor 4 / Q000235:genetics* / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D020930:MAP Kinase Kinase Kinases; D025821:Polyubiquitin; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D053449:TNF Receptor-Associated Factor 4; D016212:Transforming Growth Factor beta; D044767:Ubiquitin-Protein Ligases; D000099151:MAP Kinase Kinase Kinase 7; C497782:SMAD2 protein, human; C506367:TRAF4 protein, human; C471641:SMURF2 protein, human