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

Abstract

Tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4), a protein localized in TJs in normal epithelial cells, is frequently overexpressed in carcinomas. We recently found that TRAF4 impedes TJ formation/stability and favors cell migration, 2 hallmarks of cancer progression. In addition TRAF4 contributes to the TGF-β-induced epithelial-mesenchymal transition (EMT), metastasis, and p53 destabilization. TRAF4 recruitment to TJs is a prerequisite for its biological function on TJ formation/stability and on cell migration. Interestingly, TRAF4 is targeted to TJs through lipid-binding. The trimeric TRAF domain of TRAF4 binds 3 phosphoinositide (PIP) molecules. These findings shed new light on the role of TRAF4 in cancer progression; they provide a novel link between lipid metabolism and cancer progression and support the notion that TRAF4 could be a relevant target for cancer therapies. TRAF4 belongs to a family of 7 human proteins involved in different biological processes, such as inflammation, immunity and embryonic development. While the lipid-binding ability of the TRAF domain is conserved among the whole TRAF protein family, its functional role remains to be established for the remaining TRAF proteins.

Keywords:

• breast cancer
• cell migration
• tight junction
• TRAF domain
• phosphoinositide

Abbreviations:

• TRAF4, tumor necrosis factor (TNF) receptor-associated factor 4
• TJ, tight junction
• PIP, phosphoinositide
• MEC, mammary epithelial cell
• TGF-β, transforming growth factor β
• EMT, epithelial-mesenchymal transition
• ZF, zinc finger

Acknowledgments

The authors wish to thank Didier Rognan for his help with the molecular graphic figures and Alastair McEwen for his critical reading of the manuscript.

Funding

This work was supported by a grant from the Ligue Contre le Cancer (Conférence de Coordination Interrégionale du Grand Est). We acknowledge funds from the Institut National de Santé et de Recherche Médicale, the Center National de la Recherche Scientifique and the Université de Strasbourg. AR received an allocation from the Ministère de l’Enseignement Supérieur et de la Recherche and a fellowship from the Ligue Nationale Contre le Cancer.