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The phosphoinositide-binding protein TRAF4 modulates tight junction stability and migration of cancer cells

Adrien Rousseau1, Léa P Wilhelm2, Catherine Tomasetto2

  • 1Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC); Functional Genomics and Cancer Department ; Illkirch, France ; Institut National de la Santé et de la Recherche Médicale (INSERM) ; Illkirch, France ; Centre National de la Recherche Scientifique (CNRS) ; Illkirch, France ; Université de Strasbourg ; Illkirch, France ; Present address: MRC Laboratory of Molecular Biology ; Cambridge, UK.

Tissue Barriers
|January 23, 2015
PubMed

Insights

Tumor necrosis factor-associated factor 4 (TRAF4) protein overexpression in carcinomas impedes cell junctions and promotes cancer progression. TRAF4

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • Tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4) is overexpressed in carcinomas.
  • TRAF4 localizes to tight junctions (TJs) in normal epithelial cells.
  • TRAF4 impedes TJ formation/stability and promotes cell migration, key aspects of cancer progression.

Purpose of the Study:

  • To investigate the role of TRAF4 in cancer progression.
  • To elucidate the mechanism of TRAF4 recruitment to TJs.
  • To explore TRAF4 as a potential therapeutic target.

Main Methods:

  • Investigated TRAF4's function in TJ formation, stability, and cell migration.
  • Examined TRAF4's contribution to TGF-β-induced epithelial-mesenchymal transition (EMT) and metastasis.
  • Studied TRAF4 recruitment to TJs via lipid-binding and its interaction with phosphoinositides (PIPs).

Main Results:

  • TRAF4 overexpression impedes TJ formation/stability and enhances cell migration.
  • TRAF4 promotes TGF-β-induced EMT, metastasis, and p53 destabilization.
  • TRAF4 is recruited to TJs through lipid-binding, interacting with 3 PIP molecules via its trimeric TRAF domain.

Conclusions:

  • TRAF4 plays a significant role in cancer progression by disrupting TJs and promoting cell migration and metastasis.
  • TRAF4's lipid-binding ability is crucial for its function and represents a novel link between lipid metabolism and cancer.
  • TRAF4 is a potential therapeutic target for cancer treatment, and its lipid-binding function may be conserved across the TRAF protein family.
Keywords:
EMT, epithelial-mesenchymal transitionMEC, mammary epithelial cellPIP, phosphoinositideTGF-β, transforming growth factor βTJ, tight junctionTRAF domainTRAF4, tumor necrosis factor (TNF) receptor-associated factor 4ZF, zinc fingerbreast cancercell migrationphosphoinositidetight junction

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