TRAF4 Is a Novel Phosphoinositide-Binding Protein Modulating Tight Junctions and Favoring Cell Migration

Rousseau, Adrien; McEwen, A.G.; Poussin-Courmontagne, Pierre; Rognan, Didier; Nominé, Yves; Rio, Marie‐Christine; Tomasetto, Catherine; Alpy, Fabien

doi:10.1371/journal.pbio.1001726

Cited by 46 publications

(50 citation statements)

References 90 publications

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“…3D). A recent study demonstrated that TRAF4 destabilizes tight junctions (TJs) of malignant mammary epithelial cells (MECs) and increases cell migration for cancer progression via binding to phosphoinositide (PIP) on the intracellular membrane, supporting our finding that TRAF4 is attached to its proper receptor and the intracellular membrane during signaling events (22).…”

Section: Detailed Traf4-gpibβ Interaction Mode and Its Comparison Withsupporting

confidence: 85%

“…1B). Although three different groups, including ours, have recently determined the structure of the TRAF4 TRAF domain (21)(22)(23), it is not known how TRAF4 can accommodate various receptors using a limited interaction interface. Interestingly, sequence comparison with other TRAF family members revealed that receptor-interacting hot spots are not conserved in TRAF4, indicating that TRAF4 might use a novel interaction mode for binding with different receptors (Fig.…”

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confidence: 99%

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Molecular basis for unique specificity of human TRAF4 for platelets GPIbβ and GPVI

Kim

Son

Kim

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Tumor necrosis factor (TNF)-receptor associated factor 4 (TRAF4), an adaptor protein with E3-ligase activity, is involved in embryogenesis, cancer initiation and progression, and platelet receptor (GPIb-IX-V complex and GPVI)-mediated signaling for reactive oxygen species (ROS) production that initiates thrombosis at arterial shears. Disruption of platelet receptors and the TRAF4 interaction is a potential target for therapeutic intervention by antithrombotic drugs. Here, we report a crystal structure of TRAF4 (amino acid residues 290∼470) in complex with a peptide from the GPIbβ receptor (amino acid residues 177∼181). The GPIbβ peptide binds to a unique shallow surface composed of two hydrophobic pockets on TRAF4. Further studies revealed the TRAF4-binding motif Arg-Leu-X-Ala. The TRAF4-binding motif was present not only in platelet receptors but also in the TGF-β receptor. The current structure will provide a template for furthering our understanding of the receptor-binding specificity of TRAF4, TRAF4-mediated signaling, and related diseases.T he glycoprotein (GP) Ib-IX-V complex and GPVI are two major platelet receptors that mediate the initial adhesion of platelets to the injured vascular wall for initiating thrombus formation, and they are involved in thrombotic diseases such as stroke and myocardial infarction (1, 2). GPVI is known as a primary collagen receptor, while the GP Ib-IX-V complex binds to the von Willebrand factor and diverse ligands including coagulation factor XI (FXI), factor XII, thrombin, and P-selectin (3, 4). The existence of various ligands of the GP Ib-IX-V complex indicates that this receptor complex governs platelet function via multiple signaling pathways (5). The GP Ib-IX-V complex, consisting of GPIbα (the major ligand-binding subunit), GPIbβ, GPIX, and GPV, is the second most abundant receptor in platelets and is physically and functionally linked to another platelet receptor, GPVI (3).Tumor necrosis factor (TNF)-receptor associated factor 4 (TRAF4) is one of the seven identified TRAF1∼TRAF7 factors in mammals and was initially identified as a regulator of embryogenesis in mice, especially in the central and peripheral nervous system (6). TRAF4 is involved in gross tracheal, neural tube, and skeletal formation (7-9). The involvement of TRAF4 in the initiation and progression of many types of cancer has also been reported, suggesting that TRAF4 is a tentative therapeutic target for cancer treatment (10, 11). Unlike other TRAF family members, TRAF4 contains a nuclear localization signal (NLS) and does not interact with canonical TRAF-binding receptors such as TNFR2, CD30, and CD40, indicating that TRAF4 is not involved in cellular signaling that is mediated by the typical TRAF family (12, 13).Because of the critical function of the TRAF family in various signaling events, including immunity, inflammation, and apoptosis, these have been the main focus of functional, structural, and biochemical analyses of these proteins (13). Intensive study has revealed that the TRAF family, except...

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Section: Detailed Traf4-gpibβ Interaction Mode and Its Comparison Withsupporting

confidence: 85%

mentioning

confidence: 99%

Molecular basis for unique specificity of human TRAF4 for platelets GPIbβ and GPVI

Kim

Son

Kim

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Using lipid overlay assays we showed that recombinant TRAF4 binds all PIPs and phosphatidic acid (PA) through its TRAF domain. 17 Liposome flotation assays, mass spectrometry and isothermal titration calorimetry analyses confirmed this binding and showed that, in solution, the TRAF domain of TRAF4 forms a homotrimer which binds up to 3 PIP molecules. The affinity between one lipid-binding site of the TRAF trimer and one PIP molecule was around 5 mM, which is consistent with the lipid-binding affinity of other TJ-related proteins such as PAR3, Zonula Occludens-1 (ZO-1) and ZO-2.…”

Section: Introductionmentioning

confidence: 77%

“…Moreover, TRAF4 is involved in the dynamics of TJs: its expression delays TJ assembly and favors cell migration in mammary epithelial cells (MECs) documenting the important function for this protein during cancer progression. 17 The Cancer Protein TRAF4, a Dynamic Protein from TJ TRAF4 has an unusual cellular localization: it is present in many distinct cellular compartments including the cytoplasm, the nucleus and the plasma membrane. 16,18,19 We have previously documented that in normal human mammary tissues, TRAF4 is mainly localized in epithelial cell TJs and TRAF4 labeling on sections typically appears as a honeycomb pattern.…”

Section: Introductionmentioning

confidence: 99%

“…15 The RING domain of TRAF4 was shown to confer an E3-ligase activity to the protein, the 7 central ZF have an unknown function but, by analogy with other TRAF proteins, are most probably involved in protein-protein interactions, and the TRAF domain governs the trimerization of the protein. 12,17,21,22 Deletion mutants of the protein showed that the TRAF domain is necessary and sufficient for TRAF4 targeting to the plasma membrane. 16,18 The Nterminal part of TRAF4 composed of the RING and ZF domains is cytoplasmic and nuclear and often generates cytoplasmic foci of protein accumulation.…”

Section: Introductionmentioning

confidence: 99%

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

Rousseau¹,

Wilhelm²,

Tomasetto³

et al. 2014

Tissue Barriers

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Expression, correlation, and prognostic value of TRAF2 and TRAF4 expression in malignant plural effusion cells in human breast cancer

Zhao

Ren

Yang

et al. 2015

Diagnostic Cytopathology

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TRAF4 Is a Novel Phosphoinositide-Binding Protein Modulating Tight Junctions and Favoring Cell Migration

Abstract: The cancer-associated TRAF4 protein has a TRAF domain that is a bona fide phosphoinositide-binding domain and involved in the modulation of tight junctions and cell migration.

Cited by 46 publications

References 90 publications

Molecular basis for unique specificity of human TRAF4 for platelets GPIbβ and GPVI

Molecular basis for unique specificity of human TRAF4 for platelets GPIbβ and GPVI

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

Expression, correlation, and prognostic value of TRAF2 and TRAF4 expression in malignant plural effusion cells in human breast cancer

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