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TRAF4 is a novel phosphoinositide-binding protein modulating tight junctions and favoring cell migration

Adrien Rousseau1, Alastair G McEwen, Pierre Poussin-Courmontagne

  • 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), U 964, Illkirch, France ; Centre National de la Recherche Scientifique (CNRS), UMR 7104, Illkirch, France ; Université de Strasbourg, Illkirch, France.

Plos Biology
|December 7, 2013
PubMed

Insights

Tumor necrosis factor-associated factor 4 (TRAF4) protein binds to phosphoinositides at cell junctions. This interaction destabilizes tight junctions and increases cell migration, potentially driving breast cancer progression.

Area of Science:

  • Molecular and Cellular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • Tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4) is overexpressed in carcinomas.
  • TRAF4 localizes to tight junctions (TJs) in normal mammary epithelial cells (MECs) but accumulates in the cytoplasm of malignant MECs.
  • The mechanism of TRAF4 recruitment and function at TJs is not well understood.

Purpose of the Study:

  • To investigate the mechanism of TRAF4 recruitment to TJs.
  • To elucidate the function of TRAF4 at TJs and its role in cell migration.
  • To explore the potential contribution of TRAF4 to breast cancer progression.

Main Methods:

  • Identification and characterization of a novel phosphoinositide (PIP)-binding domain in TRAF4.
  • Molecular and structural analyses of the TRAF domain's interaction with PIPs.
  • Cellular studies to assess TRAF4's effect on TJ integrity and cell migration.

Main Results:

  • TRAF4 possesses a novel PIP-binding domain, shared by other TRAF proteins, crucial for TJ recruitment.
  • The TRAF domain binds lipids via exposed basic residues, forming a trimer.
  • TRAF4 negatively regulates TJs and enhances cell migration, dependent on PIP interaction.

Conclusions:

  • TRAF4's PIP-binding ability is essential for its TJ localization and function.
  • TRAF4 acts as a negative regulator of TJ integrity and promotes cell migration.
  • TRAF4 overexpression may contribute to breast cancer progression by destabilizing TJs and increasing cell motility.

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