Abstract
Tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4) is frequently overexpressed in carcinomas, suggesting a specific role in cancer. Although TRAF4 protein is predominantly found at tight junctions (TJs) in normal mammary epithelial cells (MECs), it accumulates in the cytoplasm of malignant MECs. How TRAF4 is recruited and functions at TJs is unclear. Here we show that TRAF4 possesses a novel phosphoinositide (PIP)-binding domain crucial for its recruitment to TJs. Of interest, this property is shared by the other members of the TRAF protein family. Indeed, the TRAF domain of all TRAF proteins (TRAF1 to TRAF6) is a bona fide PIP-binding domain. Molecular and structural analyses revealed that the TRAF domain of TRAF4 exists as a trimer that binds up to three lipids using basic residues exposed at its surface. Cellular studies indicated that TRAF4 acts as a negative regulator of TJ and increases cell migration. These functions are dependent from its ability to interact with PIPs. Our results suggest that TRAF4 overexpression might contribute to breast cancer progression by destabilizing TJs and favoring cell migration.
| Original language | English |
|---|---|
| Article number | e1001726 |
| Number of pages | 21 |
| Journal | PLoS Biology |
| Volume | 11 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - 3 Dec 2013 |
Keywords
- Animals
- COS Cells
- Cell Membrane/physiology
- Cell Movement/physiology
- Cercopithecus aethiops
- Humans
- Phosphatidylinositols/physiology
- Recombinant Proteins
- TNF Receptor-Associated Factor 4/physiology
- Tight Junctions/physiology
Access to Document
- Publisher final version
2013 Rousseau et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.