title: TRAF4 is a novel phosphoinositide-binding protein modulating tight junctions and favoring cell migration.
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.
authors: Institut 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.
authors: Adrien
authors: A
authors: Rousseau
authors: Alastair G
authors: AG
authors: McEwen
authors: Pierre
authors: P
authors: Poussin-Courmontagne
authors: Didier
authors: D
authors: Rognan
authors: Yves
authors: Y
authors: Nominé
authors: Marie-Christine
authors: MC
authors: Rio
authors: Catherine
authors: C
authors: Tomasetto
authors: Fabien
authors: F
authors: Alpy
mesh_terms: D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D002522:Chlorocebus aethiops; D006801:Humans; D010716:Phosphatidylinositols / Q000502:physiology; D011994:Recombinant Proteins; D053449:TNF Receptor-Associated Factor 4 / Q000502:physiology*; D019108:Tight Junctions / Q000502:physiology*
chemical_list: D010716:Phosphatidylinositols; D011994:Recombinant Proteins; D053449:TNF Receptor-Associated Factor 4; C506367:TRAF4 protein, human