Affinage

TRAF4

TNF receptor-associated factor 4 · UniProt Q9BUZ4

Length
470 aa
Mass
53.5 kDa
Annotated
2026-04-28
100 papers in source corpus 47 papers cited in narrative 47 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRAF4 is a RING-domain E3 ubiquitin ligase and scaffold protein that integrates multiple receptor-proximal signaling pathways—including TGF-β, EGFR, IGF, IL-17/IL-25, TLR, and mTORC1—by catalyzing non-proteolytic (K27, K29, K63) ubiquitination of substrates such as TrkA, AR, IRS-1, CHK1, JNK, Akt, and LAMTOR1, and proteolytic (K48) ubiquitination of Smurf1, Smurf2, and PPARγ (PMID:29715200, PMID:37155905, PMID:33991522, PMID:32357935, PMID:38229144, PMID:31076633, PMID:35731212). Independent of its ligase activity, TRAF4 scaffolds deubiquitinases USP15 and USP7 to stabilize TβRI and Caveolin-1, and competitively sequesters USP7/USP10 from p53 to promote p53 destabilization (PMID:23973329, PMID:35895752, PMID:23388826, PMID:30940456). TRAF4 also scaffolds NADPH oxidase by binding phosphorylated p47phox, coupling TNF-α and radiation stimuli to ROS production and downstream MAPK/NF-κB activation in endothelial cells (PMID:15743827, PMID:28827764). TRAF4-deficient mice exhibit neural tube closure defects, tracheal malformations, and CNS demyelination, and TRAF4 is required for tight junction localization—dependent on Smurf1-mediated K190 ubiquitination and phosphoinositide binding of its trimeric TRAF domain—linking its molecular activities to epithelial integrity, cell migration, and embryonic development (PMID:11943846, PMID:22363515, PMID:23760265, PMID:24311986).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1995 Medium

    Cloning of TRAF4 (CART1) established its domain architecture—RING finger, zinc-finger repeats, and C-terminal TRAF domain—providing the structural framework for all subsequent mechanistic studies.

    Evidence Molecular cloning and domain analysis from breast carcinoma cells

    PMID:7592751

    Open questions at the time
    • No enzymatic activity demonstrated
    • Receptor partners unknown
    • In vivo function uncharacterized
  2. 2002 High

    Knockout mice revealed that TRAF4 is essential for embryonic neural tube closure, tracheal ring formation, and axial skeleton development, establishing its non-redundant developmental role and distinguishing it from other TRAF family members.

    Evidence Two independent TRAF4-knockout mouse studies with histopathology

    PMID:10934170 PMID:11943846

    Open questions at the time
    • Molecular targets in developing tissues unknown
    • Cell-autonomous vs. non-autonomous role not resolved
  3. 2002 Medium

    Identification of p47phox as a TRAF4 binding partner established TRAF4 as a scaffold linking NADPH oxidase to JNK signaling and ROS production, revealing its first defined molecular mechanism.

    Evidence Library screen, co-expression assays, dominant-negative inhibition in endothelial cells

    PMID:12023963

    Open questions at the time
    • Endogenous complex stoichiometry not determined
    • Upstream signals triggering the interaction unclear
  4. 2005 High

    TNF-α-stimulated membrane co-translocation of phosphorylated p47phox with TRAF4 was shown to drive NADPH oxidase activation and ROS-dependent ERK/p38 signaling, mechanistically dissecting how TRAF4 scaffolding couples receptor stimulation to oxidase activity.

    Evidence siRNA knockdown, membrane fractionation, p47phox−/− mouse endothelial cells, NADPH oxidase activity assay

    PMID:15743827

    Open questions at the time
    • Direct structural basis for phospho-p47phox selectivity not resolved
    • Whether TRAF4 ubiquitin ligase activity contributes to NOX complex regulation was unknown
  5. 2005 High

    TRAF4 was found to activate MEKK4 through oligomerization to stimulate JNK, and separately to counteract TRAF6/TRIF-mediated TLR signaling, establishing its dual role as both a kinase activator and a negative regulator of innate immune pathways.

    Evidence Endogenous co-IP from cells and embryos, kinase-dead mutant, chemical dimerization (MEKK4); co-IP and NF-κB/IFN-β reporter assays (TLR suppression)

    PMID:16052631 PMID:16157600

    Open questions at the time
    • How TRAF4 selectively suppresses TRAF6 while activating MEKK4 not mechanistically explained
  6. 2012 High

    IKKα phosphorylation of TRAF4 at S426—within a unique β-bulge absent in other TRAFs—was shown to be required for TRAF4-mediated inhibition of NOD2/NF-κB signaling, providing a structural explanation for TRAF4's atypical inhibitory function among TRAF family members.

    Evidence Peptide array, mutagenesis, structural analysis, co-IP, NF-κB reporter assays

    PMID:21097508 PMID:22547678

    Open questions at the time
    • Whether S426 phosphorylation affects other TRAF4 functions not tested
    • In vivo validation in NOD2-driven inflammation lacking
  7. 2013 High

    A cluster of 2013 studies established TRAF4 as a multifunctional node in TGF-β signaling (stabilizing TβRI via USP15 recruitment and antagonizing SMURF2), a competitor that sequesters USP7 from p53 to promote p53 degradation, and a tight-junction-localized regulator of cell migration dependent on Smurf1-mediated K190 ubiquitination and phosphoinositide binding of its trimeric TRAF domain.

    Evidence Crystal structures of TRAF domain and PIP-binding site, co-IP/ubiquitination assays, K190R mutagenesis, breast cancer metastasis model, p53 stability assays

    PMID:23388826 PMID:23760265 PMID:23973329 PMID:24311986 PMID:24419373

    Open questions at the time
    • Whether USP15 recruitment requires TRAF4 ubiquitin ligase activity unknown
    • Structural basis of Smurf2 antagonism not resolved
    • Relative contribution of PIP-binding vs. Smurf1 ubiquitination to tight junction targeting unclear
  8. 2015 High

    TRAF4 was placed in the IL-17R–Act1–TRAF4–MEKK3–ERK5 signaling axis driving keratinocyte proliferation and in the IL-25R pathway where it recruits SMURF2 to degrade inhibitor DAZAP2, revealing TRAF4 as a required adaptor in two distinct interleukin signaling cascades.

    Evidence TRAF4−/− cells and mice, genetic epistasis, promoter analysis, co-IP/degradation assays, airway eosinophilia model

    PMID:25681341 PMID:26347473

    Open questions at the time
    • How Act1 selectively engages TRAF4 vs. TRAF6 not determined
    • Whether TRAF4 E3 activity is required in the IL-17 axis not tested
  9. 2017 High

    TRAF4 was demonstrated to function as a bona fide E3 ligase catalyzing K27/K29-linked non-proteolytic ubiquitination of TrkA to enhance its kinase activity, and structural studies defined a GPIbβ-binding motif (RLXA) on TRAF4 also present in TGF-β receptors, unifying receptor engagement mechanisms.

    Evidence Site-directed mutagenesis of TrkA ubiquitination sites, kinase activity assays, crystal structure of TRAF4–GPIbβ complex, NMR of TRAF4–EGFR JM interaction

    PMID:29073066 PMID:29715200 PMID:30352854

    Open questions at the time
    • Whether K27/K29 linkages on TrkA are recognized by specific readers unknown
    • Generality of RLXA motif for all TRAF4 substrates not validated
  10. 2020 High

    TRAF4-catalyzed K63-linked ubiquitination of CHK1 at K132 was shown to be required for ATR-mediated CHK1 phosphorylation in the DNA damage response, extending TRAF4's E3 ligase activity to the DNA repair pathway.

    Evidence Mass spectrometry, site-specific K132R mutagenesis, in vitro and in vivo ubiquitination assays, xenograft chemosensitivity model

    PMID:32357935

    Open questions at the time
    • How TRAF4 is recruited to DNA damage sites unknown
    • Whether other DNA damage substrates exist not explored
  11. 2022 Medium

    Multiple studies showed TRAF4 stabilizes diverse substrates (CAV1, HER2, Eg5) by targeting their negative regulators Smurf1/Smurf2 for K48-linked ubiquitination and degradation, and independently recruits USP7 to deubiquitinate CAV1, establishing a generalizable dual mechanism of substrate stabilization.

    Evidence Co-IP with domain mapping, ubiquitination/degradation assays for Smurf1/Smurf2/Eg5/CAV1, USP7 co-IP, in vivo GBM stemness model

    PMID:35692762 PMID:35731212 PMID:35864174 PMID:35895752

    Open questions at the time
    • Whether Smurf degradation and DUB recruitment are coordinated or independent is unclear
    • In vivo validation for Eg5 and HER2 stabilization limited
  12. 2023 High

    TRAF4-mediated K27-linked ubiquitination of the androgen receptor C-terminal tail was found to redirect AR genomic binding toward FOXA1/HOXB13-enriched loci and drive olfactory receptor gene transcription and proliferation under androgen deprivation, revealing a chromatin-level consequence of TRAF4 E3 activity.

    Evidence Linkage-specific ubiquitination assays, AR site mutagenesis, ChIP-seq, transcriptomics, in vivo CRPC models

    PMID:37155905

    Open questions at the time
    • Whether K27-ubiquitinated AR is recognized by a specific reader protein unknown
    • Structural basis for TRAF4-AR interaction not determined
  13. 2024 High

    TRAF4 was shown to directly ubiquitinate LAMTOR1 at K151 with K63-linked chains, promoting Ragulator-Rag GTPase interaction and mTORC1 activation in response to amino acids, connecting TRAF4 to nutrient sensing.

    Evidence Co-IP, K151R knock-in cells, TRAF4-KO mice, mTORC1 activity assays, colon cancer model

    PMID:38229144

    Open questions at the time
    • How amino acid signals activate TRAF4 E3 activity toward LAMTOR1 unknown
    • Whether TRAF4 participates in lysosomal recruitment or only ubiquitination not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: (1) how TRAF4 achieves substrate selectivity across its many signaling contexts, (2) whether its RING-domain ligase and scaffold/adaptor functions are coordinated or mutually exclusive in specific complexes, and (3) what upstream signals regulate TRAF4 activity beyond IKKα phosphorylation and Smurf1-mediated ubiquitination.
  • No systematic substrate-selectivity or structure-activity study across substrates
  • No comprehensive TRAF4 interactome under defined signaling states
  • Regulation of TRAF4 protein turnover incompletely characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10 GO:0016874 ligase activity 8 GO:0098772 molecular function regulator activity 5 GO:0060090 molecular adaptor activity 4 GO:0008289 lipid binding 1
Localization
GO:0005829 cytosol 3 GO:0005886 plasma membrane 3 GO:0005634 nucleus 2
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-168256 Immune System 5 R-HSA-392499 Metabolism of proteins 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1500931 Cell-Cell communication 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 1
Partners
ACT1LAMTOR1MEKK4P47PHOXSMURF2TRAF6USP15USP7
Complex memberships
NADPH oxidase (p47phox/NOX2/NOX4)PACSIN1-TRAF4-TRAF6 complexRagulator (LAMTOR1-Rag GTPase)TβRI-TRAF4-USP15 receptor complex

Evidence

Reading pass · 47 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 TRAF4 (initially named CART1) encodes a protein with three structural domains: an N-terminal RING finger motif, a central CART motif (HC3HC3 repeats), and a C-terminal TRAF domain involved in protein-protein interactions; in breast carcinoma cells, the protein localizes to the nucleus. Molecular cloning, domain analysis, subcellular localization by immunofluorescence The Journal of biological chemistry Medium 7592751
1998 TRAF4 binds the cytosolic domain of the lymphotoxin-beta receptor (LTβR) and weakly with p75 NGFR in vitro, but not with TNFR1, TNFR2, Fas, or CD40; TRAF4 localizes to the cytoplasm in transfected cells. In vitro binding assays, immunofluorescence in transfected cells The American journal of pathology Medium 9626059
2002 TRAF4 interacts with p47phox (NADPH oxidase subunit) via a tail-to-tail interaction between the C-terminus of p47phox and the conserved TRAF domain of TRAF4; coexpression of p47phox and TRAF4 increases oxidant production and JNK activation, and overexpression of the p47phox-binding domain of TRAF4 blocks TNFα- and HIV-1 Tat-induced JNK activation in endothelial cells. Library screen, domain analysis, co-expression in cells, dominant-negative inhibition, antioxidant rescue The Journal of biological chemistry Medium 12023963
2002 TRAF4 is required during embryogenesis for tracheal ring formation, axial skeleton development, and neural tube closure, as shown by traf4 knockout mice that exhibit tracheal ring disruption, axial skeleton malformations, and high incidence of spina bifida. Gene disruption (knockout mice), histopathology Proceedings of the National Academy of Sciences of the United States of America High 11943846
2000 TRAF4-deficient mice develop a constricted upper trachea at the laryngotracheal junction, causing respiratory airflow abnormalities and increased pulmonary inflammation, demonstrating that TRAF4 is required for proper anastomosis of upper and lower respiratory systems during development. Gene targeting (knockout mice), histopathology, pulmonary function analysis The American journal of pathology High 10934170
2002 Full-length TRAF4 localizes to the cytoplasm, but the isolated TRAF domain (T4(259-470)) localizes to the nucleus and can recruit full-length TRAF4 into the nucleus; TRAF4 is recruited to cell-cell contact sites via its C-TRAF domain. TRAF4 mRNA is up-regulated by TNF or PMA through the NF-κB pathway (IKKγ/NEMO-dependent), and TNF-induced upregulation requires RIP. GFP chimeras and deletion mutants, confocal microscopy, NF-κB pathway inhibition using IKKγ- and RIP-deficient cells European journal of biochemistry Medium 12354113
2003 TRAF4 is identified as a p53-regulated proapoptotic gene; TRAF4 expression is specifically induced by p53 in response to temperature-sensitive p53 activation, p53 adenoviral overexpression, and DNA damage. The murine TRAF4 promoter contains a functional p53 DNA-binding site ~1 kb upstream of the start codon. Overexpression of TRAF4 induces apoptosis and suppresses colony formation; TRAF4 localizes to the cytoplasm. Microarray screen, reporter assay with p53 binding site, adenoviral overexpression, colony formation, subcellular fractionation The Journal of biological chemistry Medium 12788948
2004 TRAF4 functions as an intermediate in GITR-induced NF-κB activation; TRAF4-mediated NF-κB activation downstream of GITR depends on a previously mapped TRAF-binding site in the cytoplasmic domain of GITR and is inhibited by A20. Functional reporter assays, receptor cytoplasmic domain mapping, dominant-negative inhibition Cellular and molecular life sciences : CMLS Medium 15583869
2005 TRAF4 physically interacts with p47phox (NADPH oxidase subunit) and with TRAF6 and TRIF, functionally counteracting TRAF6- and TRIF-mediated TLR signaling to suppress NF-κB and IFN-β promoter activation. Co-immunoprecipitation, functional NF-κB and IFN-β reporter assays European journal of immunology Medium 16052631
2005 Upon TNF-α stimulation of microvascular endothelial cells, p47phox is phosphorylated in a PKC-dependent manner; TRAF4 preferentially binds phosphorylated p47phox, resulting in membrane co-translocation of p47phox-TRAF4, NADPH oxidase activation, ROS-dependent ERK1/2 and p38 MAPK activation, and ICAM-1 expression. siRNA knockdown of TRAF4 inhibited TNF-α-induced ERK1/2 activation but not p47phox phosphorylation or p22phox binding. Co-immunoprecipitation, siRNA knockdown, membrane fractionation, NADPH oxidase activity assay, p47phox-/- mouse ECs Molecular and cellular biology High 15743827
2005 TRAF4 interacts with and activates MEKK4 to stimulate JNK; endogenous TRAF4 and MEKK4 associate in human K562 cells and mouse E10.5 embryos. TRAF4 binds the kinase domain of MEKK4, promotes MEKK4 oligomerization, and coexpression of TRAF4 and MEKK4 synergistically activates JNK in a MEKK4 kinase-dependent manner. Chemical induction of MEKK4 dimerization activates JNK. Co-immunoprecipitation in cells and embryos, co-localization, kinase-inactive mutant, chemical-induced dimerization The Journal of biological chemistry High 16157600
2010 TRAF4 binds directly to NOD2 at two consecutive glutamate residues in NOD2; this interaction is required for TRAF4-mediated inhibition of NOD2-induced NF-κB activation and bacterial killing. Mutation of these glutamate residues abolished both TRAF4 binding and inhibition. Co-immunoprecipitation, mutational analysis, NF-κB reporter assays, bacterial killing assay The Journal of biological chemistry High 21097508
2011 TRAF4 is a novel binding partner of platelet glycoprotein GPIbβ and GPVI, as demonstrated by protein array analysis and affinity-binding assays; TRAF4, p47phox, and Hic-5 co-immunoprecipitate with GPIb/GPVI from human platelet lysates. GPIb- or GPVI-selective agonists induce phosphorylation of TRAF4-associated proteins Hic-5 and Pyk2, attenuated by Nox2 inhibition. Protein array analysis, affinity pulldown, co-immunoprecipitation from human platelets, phosphorylation assays Journal of thrombosis and haemostasis : JTH Medium 20946164
2012 IKKα phosphorylates TRAF4 at serine-426, which is required for TRAF4-mediated negative regulation of NOD2 signaling. NOD2 binding is required for TRAF4 phosphorylation. Serine-426 resides within an exaggerated β-bulge in TRAF4 not present in other TRAF proteins, providing a structural basis for TRAF4's atypical inhibitory function. Peptide substrate array, bioinformatic screening, mutagenesis, structural analysis, co-immunoprecipitation, NF-κB reporter assays Molecular and cellular biology High 22547678
2012 TRAF4-deficient mice exhibit ataxia, CNS myelin perturbation with disorganized myelin layers and paranode disorganization, Purkinje cell degeneration, and activation of the NgR/p75NTR/RhoA/Rock2 signaling pathway. TRAF4 is expressed by oligodendrocytes at all differentiation stages, demonstrating a role in CNS myelination and cerebellar homeostasis. TRAF4-KO mice, behavioral analysis, electron microscopy, primary cell culture, immunofluorescence, TUNEL, western blotting, Q-RT-PCR PloS one High 22363515
2013 Upon TGF-β stimulation, TRAF4 is recruited to the active TGF-β receptor complex where it: (1) antagonizes E3 ligase SMURF2 and facilitates recruitment of deubiquitinase USP15 to TβRI, stabilizing TβRI on the plasma membrane; (2) undergoes K63-linked polyubiquitylation, leading to TAK1 activation. TRAF4 is required for TGF-β-induced migration, epithelial-to-mesenchymal transition, and breast cancer metastasis. Co-immunoprecipitation, ubiquitination assays, receptor stability assays, siRNA knockdown, breast cancer metastasis mouse model Molecular cell High 23973329
2013 TRAF4 is required for Akt activation through ubiquitination in lung cancer cells; TRAF4 attenuation by RNAi inhibited Akt activity and downstream glucose metabolism (Glut1 and HK2 expression). RNAi knockdown, Akt ubiquitination assay, glucose metabolism assay, xenograft tumor model Cancer research Medium 24154876
2013 TRAF4 binds the N-terminal TRAF-like region of the deubiquitinase HAUSP/USP7 via its TRAF domain, blocking p53 access to USP7, thereby preventing p53 deubiquitination and stabilization in response to cellular stress, leading to p53 destabilization and resistance to cytotoxic stress. Co-immunoprecipitation, domain mapping, p53 stability assays, cDNA library rescue screening Genes & development High 23388826
2013 Smurf1 ubiquitinates TRAF4 at K190, which is required for proper TRAF4 localization to tight junctions in confluent epithelial cells, Rac1 activation by TRAF4, and TRAF4-dependent cell migration in mammary epithelial and breast cancer cells. Co-immunoprecipitation, ubiquitination assays, K190R mutant, tight junction localization by microscopy, Rac1 activation assay, migration assays The Journal of biological chemistry High 23760265
2013 TRAF4 possesses a phosphoinositide (PIP)-binding domain within its TRAF domain that exists as a trimer binding up to three lipid molecules via basic surface residues; this PIP-binding is required for TRAF4 recruitment to tight junctions, its function as a negative regulator of tight junction integrity, and its promotion of cell migration. Structural analysis (molecular/crystal), NMR, lipid-binding assays, mutagenesis, tight junction stability assay, migration assay PLoS biology High 24311986
2013 TRAF2 interacts with TRAF4 and regulates its cytoplasmic/nuclear distribution in breast cancer cells; TRAF2 depletion reduces cytoplasmic TRAF4 and increases nuclear TRAF4, while TRAF2 overexpression augments cytoplasmic TRAF4 and promotes cell proliferation and NF-κB activation. Co-immunoprecipitation, immunofluorescence, siRNA knockdown, western blotting Biochemical and biophysical research communications Medium 23743189
2013 Crystal structure of the human TRAF4 TRAF domain with coiled-coil domain determined at 2.3 Å resolution, revealing the structural basis for TRAF4 signaling interactions. X-ray crystallography Acta crystallographica. Section D, Biological crystallography High 24419373
2015 IL-17 activates keratinocyte proliferation and tumor formation through the IL-17R-Act1-TRAF4-MEKK3-ERK5 signaling axis, inducing Steap4 and p63 expression. p63 transcriptionally induces TRAF4 expression, forming a positive feedback loop driving sustained ERK5 activation. Genetic epistasis in IL-17 signaling, TRAF4-/- cells, pathway inhibition, promoter analysis, reporter assays The Journal of experimental medicine High 26347473
2015 IL-25R (IL-17RB) recruits TRAF4, which is required for ACT1/IL-25R interaction. TRAF4 recruits the E3 ligase SMURF2 to degrade the IL-25R-inhibitory molecule DAZAP2, enabling IL-25 signaling. TRAF4-/- mice show blunted IL-25-induced airway eosinophilia and Th2 cytokine production. TRAF4 knockout mice, co-immunoprecipitation, ubiquitination/degradation assays, in vivo allergic airway challenge Journal of immunology High 25681341
2017 TRAF4 acts as an E3 ubiquitin ligase that promotes K27- and K29-linked non-proteolytic ubiquitination of the TrkA kinase domain, increasing TrkA kinase activity and autophosphorylation, interaction with downstream proteins, and cancer cell invasion. TRAF4 also mediates NGF-stimulated p38 MAPK activation downstream of TrkA. Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis of TrkA ubiquitination sites, kinase activity assay, cell invasion assay, siRNA knockdown The Journal of clinical investigation High 29715200
2017 TRAF4 binds MEKK3 downstream of Act1 in IL-17 signaling to drive ERK5 activation in keratinocytes; also radiation induces K63-linked poly-ubiquitination of TRAF4 in lung fibroblasts, and K63-ubiquitinated TRAF4 forms complexes with NOX2/NOX4 via phosphorylated p47phox, stabilizing NOX complexes by reducing lysosomal degradation of NOX2/NOX4, increasing endosomal ROS and NF-κB-mediated ICAM1 upregulation. Co-immunoprecipitation, ubiquitination assays, lysosomal inhibition, ROS measurement, ICAM1 expression, conditioned media experiments Scientific reports Medium 28827764
2017 TRAF4 binds the juxtamembrane (JM) segment C-terminal half of EGFR (identified by NMR spectroscopy) and promotes EGF-induced EGFR autophosphorylation and downstream signaling; deletion or point mutations of the TRAF4 binding site impair EGFR activation and EGF-driven cell proliferation. NMR spectroscopy, structure-based sequence alignment, mutagenesis, EGFR phosphorylation assays, cell proliferation assay Proceedings of the National Academy of Sciences of the United States of America High 30352854
2017 Crystal structure of TRAF4 in complex with a GPIbβ receptor peptide reveals that GPIbβ binds a unique shallow surface with two hydrophobic pockets on TRAF4; the TRAF4-binding motif Arg-Leu-X-Ala is present in platelet receptors and the TGF-β receptor. X-ray crystallography of TRAF4-GPIbβ peptide complex, mutational analysis Proceedings of the National Academy of Sciences of the United States of America High 29073066
2017 In Drosophila, TRAF4 (Traf4) is a novel Draper binding partner required for JNK signaling in glia following axonal injury; TRAF4 and misshapen (MSN) act downstream of Draper to activate JNK, resulting in AP-1 and STAT92E-dependent transcriptional responses and phagocytosis of axonal debris. Co-immunoprecipitation, Drosophila genetic epistasis, reporter assays, phagocytosis assays Nature communications Medium 28165006
2019 TRAF4 positively regulates osteogenic differentiation of mesenchymal stem cells by acting as an E3 ubiquitin ligase mediating K48-linked ubiquitination of Smurf2 at K119, leading to Smurf2 degradation and thereby enhancing BMP/SMAD signaling. Co-immunoprecipitation, ubiquitination assays, site-specific mutagenesis (K119 of Smurf2), lentiviral KD/OE, in vivo MSC implantation Cell death and differentiation High 31076633
2019 TRAF4 interacts with deubiquitinase USP10 and blocks p53 access to USP10, resulting in p53 destabilization and promotion of keloid fibroblast proliferation; this occurs independently of TRAF4's E3 ubiquitin ligase activity. Co-immunoprecipitation, p53 stability assays, siRNA knockdown rescue experiments, patient sample correlation The Journal of investigative dermatology Medium 30940456
2019 TRAF4 interacts with copper chaperone Atox1 in a Cu-dependent manner in TNF-α-stimulated endothelial cells; TRAF4 depletion by siRNA inhibits Atox1 nuclear translocation, p47phox expression, ROS production, and downstream VCAM1/ICAM1 expression and monocyte adhesion. Co-immunoprecipitation, siRNA knockdown, nuclear fractionation, ROS measurement, adhesion molecule expression, confocal colocalization American journal of physiology. Cell physiology Medium 31553645
2020 TRAF4 binds PKM2 and activates its kinase activity; TRAF4-activated PKM2 subsequently activates β-catenin signaling to inhibit adipogenesis of mesenchymal stem cells. TRAF4 downregulation during adipogenesis is regulated by ALKBH5-mediated N6-methyladenosine RNA demethylation. Co-immunoprecipitation (domain mapping), PKM2 kinase activity assay, inhibitor/agonist experiments, m6A RIP assay, lentiviral KD/OE, in vivo MSC implantation EBioMedicine Medium 32268273
2020 TRAF4-mediated K63-linked ubiquitination of CHK1 at K132 is required for ATR-mediated CHK1 phosphorylation and activation following DNA damage; TRAF4 depletion impairs CHK1 activity and sensitizes colorectal cancer cells to chemotherapy. Mass spectrometry identification, co-immunoprecipitation, ubiquitination assays in vitro and in vivo, site-specific mutagenesis (K132R), CHK1 phosphorylation assay, cell viability and xenograft assays Journal of hematology & oncology High 32357935
2020 TRAF4 inhibits TRAF4's interaction with AKT to block K63-ubiquitination of AKT; COX-2 knockdown prevents TGF-β-induced K63-ubiquitination of AKT by blocking TRAF4 recruitment to AKT in fibroblasts. Co-immunoprecipitation, ubiquitination assays, siRNA, pharmacological inhibition Redox biology Medium 33152664
2021 Curcumin inhibits adipogenesis by reducing ALKBH5 (m6A demethylase) expression, leading to higher m6A modification of TRAF4 mRNA recognized by YTHDF1, enhancing TRAF4 translation. TRAF4, acting as an E3 RING ubiquitin ligase, promotes K48-linked ubiquitination and proteasomal degradation of PPARγ, thereby inhibiting adipogenesis. m6A sequencing, RIP assay, ubiquitination assay, proteasome inhibition, lentiviral overexpression/KD, adipogenesis assay EMBO reports Medium 33880847
2021 The E3 ligase TRAF4 promotes K29-linked non-proteolytic ubiquitination of IRS-1 at its C-terminal end, enhancing IGFR-IRS-1 interaction, IRS-1 tyrosine phosphorylation, and downstream AKT and ERK activation in response to IGF-1; mutation of IRS-1 ubiquitination sites abolishes these effects. Site-directed mutagenesis, ubiquitination assays (linkage-specific), co-immunoprecipitation, AKT/ERK phosphorylation assay, cell proliferation assay The Journal of biological chemistry High 33991522
2022 TRAF4 specifically interacts with the N-terminal tail of Caveolin-1 (CAV1); TRAF4 prevents ZNRF1-mediated ubiquitination and facilitates USP7-mediated deubiquitination of CAV1, independently of TRAF4's E3 ubiquitin ligase activity, thereby stabilizing CAV1 and activating AKT/ERK1/2 signaling to promote GBM stemness and TMZ resistance. Co-immunoprecipitation (N-terminal domain mapping), ubiquitination assays, USP7 interaction, in vitro and in vivo stemness/tumorigenicity assays, risperidone drug screen Cancer research High 35895752
2022 TRAF4 regulates HER2 stability through a membrane-associated TRAF4-SMURF2-HER2 complex: SMURF2 binds HER2 cytoplasmic domain and ubiquitinates it for degradation, while TRAF4 stabilizes HER2 by degrading SMURF2 and inhibiting SMURF2-HER2 binding. Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, protein stability assays Oncogene Medium 35864174
2022 TRAF4 mediates atypical ubiquitination of SETDB1 (through its Tudor domain interaction) to maintain SETDB1 stability, thereby promoting AKT pathway activation in glioblastoma cells. Co-immunoprecipitation (domain mapping), ubiquitination assay, SETDB1 stability assay, AKT pathway readouts, KD/OE functional assays International journal of molecular sciences Medium 36077559
2022 TRAF4 stabilizes Eg5 by inhibiting its ubiquitination via SMURF2: TRAF4 interacts with Eg5 through its Zinc fingers domain, promotes Smurf2 ubiquitination and degradation via its RING domain, and the resulting reduction of Smurf2 inhibits Smurf2-catalyzed ubiquitination of Eg5, stabilizing Eg5 protein during mitosis. Co-immunoprecipitation (domain mapping), ubiquitination assays, proteasome inhibition, Eg5 protein stability assay, spindle assembly microscopy Frontiers in oncology Medium 35692762
2022 TRAF4 inhibits bladder cancer EMT and invasion by acting as an E3 ubiquitin ligase targeting SMURF1 for proteasomal degradation, thereby relieving SMURF1's suppression of BMP/SMAD signaling and enhancing phospho-SMAD1/5 levels; ERK-mediated phosphorylation of TRAF4 leads to lower TRAF4 protein levels in bladder cancer. Gene expression manipulation, transcriptomic analysis, ubiquitination/degradation assays, phospho-SMAD assays, patient sample correlation Molecular cancer research : MCR Medium 35731212
2022 TRAF4 promotes K63-linked ubiquitination of Akt upon irradiation, activating Akt/GSK3β signaling, which phosphorylates MCL-1 at S159, disrupting MCL-1 interaction with JOSD1 deubiquitinase and preventing MCL-1 degradation, thereby conferring radioresistance in oral squamous cell carcinoma. Co-immunoprecipitation, ubiquitination assays, phosphorylation assays, TRAF4 KO, xenograft model Cell death & disease Medium 36535926
2023 TRAF4 mediates K27-linked non-proteolytic ubiquitination at the C-terminal tail of the androgen receptor (AR), increasing AR association with pioneer factor FOXA1 and directing AR binding to distinct genomic loci enriched with FOXA1- and HOXB13-binding motifs, driving olfactory receptor gene transcription, increased intracellular cAMP, E2F activity, and cell proliferation under androgen deprivation. Ubiquitination assays with linkage-specific antibodies, site-directed mutagenesis of AR ubiquitination sites, ChIP-seq, transcriptomic analysis, cAMP assays, in vivo CRPC models Proceedings of the National Academy of Sciences of the United States of America High 37155905
2023 TRAF4 mediates K63-linked ubiquitination of JNK/JNKs upon irradiation, promoting JNK phosphorylation and activation, which drives c-Jun-mediated Bcl-xL transcription and radioresistance in colorectal cancer cells. Co-immunoprecipitation, ubiquitination assays (K63-specific), JNK phosphorylation assays, Bcl-xL inhibitor treatment, xenograft model Cell death & disease Medium 36765039
2023 PACSIN1 forms a trimolecular complex with TRAF4 and TRAF6 that is important for regulation of type I IFN; the PACSIN1 Q59K SLE-associated mutation decreases binding to TRAF4, leading to unrestrained TRAF6-mediated TLR-7 signaling and elevated IFNβ/IFN-inducible gene expression. Co-immunoprecipitation, CRISPR/Cas9 editing in human cell line and mice, luciferase reporter, RNA interference, immunofluorescence Arthritis & rheumatology Medium 36622335
2024 TRAF4 directly interacts with LAMTOR1 and catalyzes K63-linked polyubiquitination of LAMTOR1 at K151; this ubiquitination promotes LAMTOR1 binding to Rag GTPases and enhances mTORC1 activation. K151R knock-in or TRAF4 knockout blocks amino acid-induced mTORC1 activation. Co-immunoprecipitation, ubiquitination assays, site-specific mutagenesis (K151R knock-in), mTORC1 activity assays, TRAF4 KO mouse model, colon cancer progression model Advanced science High 38229144

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 TRAF4 promotes TGF-β receptor signaling and drives breast cancer metastasis. Molecular cell 211 23973329
1995 Presence of a new conserved domain in CART1, a novel member of the tumor necrosis factor receptor-associated protein family, which is expressed in breast carcinoma. The Journal of biological chemistry 210 7592751
1996 Prenatal folic acid treatment suppresses acrania and meroanencephaly in mice mutant for the Cart1 homeobox gene. Nature genetics 204 8673125
2015 A novel IL-17 signaling pathway controlling keratinocyte proliferation and tumorigenesis via the TRAF4-ERK5 axis. The Journal of experimental medicine 190 26347473
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2018 Circular RNA‑MTO1 suppresses breast cancer cell viability and reverses monastrol resistance through regulating the TRAF4/Eg5 axis. International journal of oncology 112 30015883
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2005 TRAF4 acts as a silencer in TLR-mediated signaling through the association with TRAF6 and TRIF. European journal of immunology 85 16052631
2021 Curcumin prevents obesity by targeting TRAF4-induced ubiquitylation in m6 A-dependent manner. EMBO reports 81 33880847
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2018 TRAF4-mediated ubiquitination of NGF receptor TrkA regulates prostate cancer metastasis. The Journal of clinical investigation 69 29715200
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2011 TNF receptor-associated factor 4 (TRAF4) is a novel binding partner of glycoprotein Ib and glycoprotein VI in human platelets. Journal of thrombosis and haemostasis : JTH 60 20946164
2019 TRAF4 positively regulates the osteogenic differentiation of mesenchymal stem cells by acting as an E3 ubiquitin ligase to degrade Smurf2. Cell death and differentiation 59 31076633
2016 Leptin and insulin up-regulate miR-4443 to suppress NCOA1 and TRAF4, and decrease the invasiveness of human colon cancer cells. BMC cancer 58 27842582
2021 miR-29 modulates CD40 signaling in chronic lymphocytic leukemia by targeting TRAF4: an axis affected by BCR inhibitors. Blood 57 33171493
2010 A novel motif in the Crohn's disease susceptibility protein, NOD2, allows TRAF4 to down-regulate innate immune responses. The Journal of biological chemistry 56 21097508
2003 Identification and characterization of the cytoplasmic protein TRAF4 as a p53-regulated proapoptotic gene. The Journal of biological chemistry 55 12788948
2020 MIR210HG promotes cell proliferation and invasion by regulating miR-503-5p/TRAF4 axis in cervical cancer. Aging 54 32087604
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2001 Pim-1 translocates sorting nexin 6/TRAF4-associated factor 2 from cytoplasm to nucleus. FEBS letters 48 11591366
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2013 SRC-3 coactivator regulates cell resistance to cytotoxic stress via TRAF4-mediated p53 destabilization. Genes & development 43 23388826
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2022 TRAF4 Maintains Deubiquitination of Caveolin-1 to Drive Glioblastoma Stemness and Temozolomide Resistance. Cancer research 36 35895752
2015 Proliferative role of TRAF4 in breast cancer by upregulating PRMT5 nuclear expression. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 35 25704480
2015 TRAF4 enhances oral squamous cell carcinoma cell growth, invasion and migration by Wnt-β-catenin signaling pathway. International journal of clinical and experimental pathology 35 26617938
2020 Nonenzymatic function of Aldolase A downregulates miR-145 to promote the Oct4/DUSP4/TRAF4 axis and the acquisition of lung cancer stemness. Cell death & disease 34 32188842
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2020 Ubiquitination of the DNA-damage checkpoint kinase CHK1 by TRAF4 is required for CHK1 activation. Journal of hematology & oncology 28 32357935
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2022 TRAF4 hyperactivates HER2 signaling and contributes to Trastuzumab resistance in HER2-positive breast cancer. Oncogene 24 35864174
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2024 TRAF4-Mediated LAMTOR1 Ubiquitination Promotes mTORC1 Activation and Inhibits the Inflammation-Induced Colorectal Cancer Progression. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 19 38229144
2022 TRAF4 Inhibits Bladder Cancer Progression by Promoting BMP/SMAD Signaling. Molecular cancer research : MCR 19 35731212
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2023 TRAF4-mediated nonproteolytic ubiquitination of androgen receptor promotes castration-resistant prostate cancer. Proceedings of the National Academy of Sciences of the United States of America 16 37155905
2014 TRAF4 promotes tumorigenesis of breast cancer through activation of Akt. Oncology reports 16 24993240
2014 TRAF4 mediates activation of TGF-β signaling and is a biomarker for oncogenesis in breast cancer. Science China. Life sciences 16 25249198
2024 TRAF4 regulates ubiquitination-modulated survivin turnover and confers radioresistance. International journal of biological sciences 15 38164179
2023 De Novo PACSIN1 Gene Variant Found in Childhood Lupus and a Role for PACSIN1/TRAF4 Complex in Toll-like Receptor 7 Activation. Arthritis & rheumatology (Hoboken, N.J.) 15 36622335
2021 Grouper TRAF4, a Novel, CP-Interacting Protein That Promotes Red-Spotted Grouper Nervous Necrosis Virus Replication. International journal of molecular sciences 15 34200212
2017 Elevated TRAF4 expression impaired LPS-induced autophagy in mesenchymal stem cells from ankylosing spondylitis patients. Experimental & molecular medicine 15 28604663
2023 SRC-3/TRAF4 facilitates ovarian cancer development by activating the PI3K/AKT signaling pathway. Medical oncology (Northwood, London, England) 13 36625999
2020 TRAF4, a new substrate of SIAH1, participates in chemotherapy resistance of breast cancer cell by counteracting SIAH1-mediated downregulation of β-catenin. Breast cancer research and treatment 13 32671611
2019 RETRACTED: TRAF4 promotes endometrial cancer cell growth and migration by activation of PI3K/AKT/Oct4 signaling. Experimental and molecular pathology 13 30853613
2017 Molecular basis for unique specificity of human TRAF4 for platelets GPIbβ and GPVI. Proceedings of the National Academy of Sciences of the United States of America 13 29073066
2015 Cytoplasmic TRAF4 contributes to the activation of p70s6k signaling pathway in breast cancer. Oncotarget 13 25738361
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2022 TRAF4 Promotes the Proliferation of Glioblastoma by Stabilizing SETDB1 to Activate the AKT Pathway. International journal of molecular sciences 12 36077559
2021 The E3 ligase TRAF4 promotes IGF signaling by mediating atypical ubiquitination of IRS-1. The Journal of biological chemistry 11 33991522
2023 USP7 mediates TRAF4 deubiquitination to facilitate the malignant phenotype of ovarian cancer via the RSK4/PI3K/AKT axis. Journal of cancer research and therapeutics 10 37006049
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