TRAF4 promotes TGF-β receptor signaling and drives breast cancer metastasis

Long Zhang, Fangfang Zhou, Amaya García de Vinuesa, Esther M de Kruijf, Wilma E Mesker, Li Hui, Yvette Drabsch, Yihao Li, Andreas Bauer, Adrien Rousseau, Kelly-Ann Sheppard, Craig Mickanin, Peter J K Kuppen, Chris X Lu, Peter Ten Dijke

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)559-72
Number of pages14
JournalMolecular Cell
Volume51
Issue number5
DOIs
Publication statusPublished - 12 Sep 2013

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Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
Breast Neoplasms
Neoplasm Metastasis
Ubiquitin-Protein Ligases
Epithelial-Mesenchymal Transition
Phosphotransferases
Cell Membrane

Keywords

  • Animals
  • Breast Neoplasms/metabolism
  • Cell Line, Tumor
  • Cell Movement
  • Epithelial-Mesenchymal Transition/drug effects
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MAP Kinase Kinase Kinases/metabolism
  • Mice
  • Phosphorylation
  • Polyubiquitin/metabolism
  • Prognosis
  • Protein-Serine-Threonine Kinases/metabolism
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta/metabolism
  • Signal Transduction
  • Smad2 Protein/metabolism
  • TNF Receptor-Associated Factor 4/genetics
  • Transforming Growth Factor beta/metabolism
  • Ubiquitin-Protein Ligases/metabolism

Cite this

Zhang, L., Zhou, F., García de Vinuesa, A., de Kruijf, E. M., Mesker, W. E., Hui, L., ... Ten Dijke, P. (2013). TRAF4 promotes TGF-β receptor signaling and drives breast cancer metastasis. Molecular Cell, 51(5), 559-72. https://doi.org/10.1016/j.molcel.2013.07.014
Zhang, Long ; Zhou, Fangfang ; García de Vinuesa, Amaya ; de Kruijf, Esther M ; Mesker, Wilma E ; Hui, Li ; Drabsch, Yvette ; Li, Yihao ; Bauer, Andreas ; Rousseau, Adrien ; Sheppard, Kelly-Ann ; Mickanin, Craig ; Kuppen, Peter J K ; Lu, Chris X ; Ten Dijke, Peter. / TRAF4 promotes TGF-β receptor signaling and drives breast cancer metastasis. In: Molecular Cell. 2013 ; Vol. 51, No. 5. pp. 559-72.
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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.",
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author = "Long Zhang and Fangfang Zhou and {Garc{\'i}a de Vinuesa}, Amaya and {de Kruijf}, {Esther M} and Mesker, {Wilma E} and Li Hui and Yvette Drabsch and Yihao Li and Andreas Bauer and Adrien Rousseau and Kelly-Ann Sheppard and Craig Mickanin and Kuppen, {Peter J K} and Lu, {Chris X} and {Ten Dijke}, Peter",
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Zhang, L, Zhou, F, García de Vinuesa, A, de Kruijf, EM, Mesker, WE, Hui, L, Drabsch, Y, Li, Y, Bauer, A, Rousseau, A, Sheppard, K-A, Mickanin, C, Kuppen, PJK, Lu, CX & Ten Dijke, P 2013, 'TRAF4 promotes TGF-β receptor signaling and drives breast cancer metastasis', Molecular Cell, vol. 51, no. 5, pp. 559-72. https://doi.org/10.1016/j.molcel.2013.07.014

TRAF4 promotes TGF-β receptor signaling and drives breast cancer metastasis. / Zhang, Long; Zhou, Fangfang; García de Vinuesa, Amaya; de Kruijf, Esther M; Mesker, Wilma E; Hui, Li; Drabsch, Yvette; Li, Yihao; Bauer, Andreas; Rousseau, Adrien; Sheppard, Kelly-Ann; Mickanin, Craig; Kuppen, Peter J K; Lu, Chris X; Ten Dijke, Peter.

In: Molecular Cell, Vol. 51, No. 5, 12.09.2013, p. 559-72.

Research output: Contribution to journalArticle

TY - JOUR

T1 - TRAF4 promotes TGF-β receptor signaling and drives breast cancer metastasis

AU - Zhang, Long

AU - Zhou, Fangfang

AU - García de Vinuesa, Amaya

AU - de Kruijf, Esther M

AU - Mesker, Wilma E

AU - Hui, Li

AU - Drabsch, Yvette

AU - Li, Yihao

AU - Bauer, Andreas

AU - Rousseau, Adrien

AU - Sheppard, Kelly-Ann

AU - Mickanin, Craig

AU - Kuppen, Peter J K

AU - Lu, Chris X

AU - Ten Dijke, Peter

N1 - Copyright © 2013 Elsevier Inc. All rights reserved.

PY - 2013/9/12

Y1 - 2013/9/12

N2 - 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.

AB - 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.

KW - Animals

KW - Breast Neoplasms/metabolism

KW - Cell Line, Tumor

KW - Cell Movement

KW - Epithelial-Mesenchymal Transition/drug effects

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - MAP Kinase Kinase Kinases/metabolism

KW - Mice

KW - Phosphorylation

KW - Polyubiquitin/metabolism

KW - Prognosis

KW - Protein-Serine-Threonine Kinases/metabolism

KW - Receptor, Transforming Growth Factor-beta Type I

KW - Receptors, Transforming Growth Factor beta/metabolism

KW - Signal Transduction

KW - Smad2 Protein/metabolism

KW - TNF Receptor-Associated Factor 4/genetics

KW - Transforming Growth Factor beta/metabolism

KW - Ubiquitin-Protein Ligases/metabolism

U2 - 10.1016/j.molcel.2013.07.014

DO - 10.1016/j.molcel.2013.07.014

M3 - Article

VL - 51

SP - 559

EP - 572

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 5

ER -

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. Molecular Cell. 2013 Sep 12;51(5):559-72. https://doi.org/10.1016/j.molcel.2013.07.014