Structural feature of TRAFs, their related human diseases and therapeutic intervention

Park, Hyun Ho

doi:10.1007/s12272-021-01330-w

Cited by 12 publications

(8 citation statements)

References 109 publications

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“…The tumor necrosis factor (TNF) receptor-associated factors (TRAFs) are signaling adapter proteins that couple signals from diverse cell membrane receptor families, such as the TNF receptors and the Toll-like/interleukin-1 receptors, with intracellular downstream signaling molecules. TRAFs 2–6 encode RING and zinc finger motifs that are essential for their adapter activities [ 13 , 14 ]. The TRAF4 gene is located in the q11.2 region of chromosome 17, near the locus of HER2 oncogene.…”

Section: Introductionmentioning

confidence: 99%

TRAF4 hyperactivates HER2 signaling and contributes to Trastuzumab resistance in HER2-positive breast cancer

Gao

Zhang

et al. 2022

Oncogene

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The HER2 receptor modulates downstream signaling by forming homodimers and heterodimers with other members of the HER family. For patients with HER2-positive breast cancer, Trastuzumab, an anti-HER2 monoclonal antibody as first-line therapy has shown significant survival benefits. However, the development of acquired resistance to Trastuzumab continues to be a significant obstacle. TNF receptor-associated factor 4 (TRAF4) upregulation was discovered to be associated with a worse clinical outcome. Here we identified TRAF4 overexpression as one of the putative mechanisms for HER2-positive breast cancer cells to maintain HER2 signaling during Trastuzumab treatment, while TRAF4 knockdown reduced HER2 stability and improved Trastuzumab sensitivity. Mechanistically, TRAF4 regulates HER2 level through its impact on SMAD specific E3 ubiquitin protein ligase protein 2 (SMURF2). The development of a membrane-associated protein complex containing HER2, TRAF4, and SMURF2 has been observed. SMURF2 bound to the HER2 cytoplasmic domain, and directly ubiquitinated it leading to HER2 degradation, whereas TRAF4 stabilized HER2 by degrading SMURF2 and inhibiting the binding of SMURF2 to HER2. Moreover, downregulation of TRAF4 has decreased the AKT/mTOR signaling. In conclusion, we discovered a new HER2 signaling regulation that involves the TRAF4-SMURF2 complex, a possible mechanism that might contribute to anti-HER2 resistance, making TRAF4 a viable target for treating HER2 + breast cancer.

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Section: Introductionmentioning

confidence: 99%

TRAF4 hyperactivates HER2 signaling and contributes to Trastuzumab resistance in HER2-positive breast cancer

Gao

Zhang

et al. 2022

Oncogene

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“…53,68,69 TRAFD1 binds as homodimer or in interaction with TRAFD2, to TNF receptors, impacting pro-inflammatory cytokine production and modulating inflammatory responses in immune cells. 32,33,70 In celiac disease, TRAFD1 was recognized as an upstream regulator of IFNg signaling and thereby activating cytotoxic T-cells, an important pathomechanism. 34 The identified function of TRAFD1 as inductor of IFNg signaling aligns well with the literature and also with our findings showing increased CXCL9/MIG serum levels underlying TRAFD1 expression.…”

Section: Discussionmentioning

confidence: 99%

The Genomic Architecture of Circulating Cytokine Levels Points to Drug Targets for Immune-Related Diseases

Konieczny,

Omarov,

Malik

et al. 2024

Preprint

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Circulating cytokines orchestrate immune reactions and are promising drug targets for immune-mediated and inflammatory diseases. Exploring the genetic architecture of circulating cytokine levels could yield key insights into causal mediators of human disease. Here, we performed genome-wide association studies (GWAS) for 40 circulating cytokines in meta-analyses of 74,783 individuals. We detected 359 significant associations between cytokine levels and variants in 169 independent loci, including 150 trans- and 19 cis-acting loci. Integration with transcriptomic data point to key regulatory mechanisms, such as the buffering function of ACKR1 acting as scavenger for multiple chemokines and the role of TRAFD1 in modulating the cytokine storm triggered by TNF signaling. Applying Mendelian randomization (MR), we detected a network of complex cytokine interconnections with TNF-b, VEGF, and IL-1ra exhibiting pleiotropic downstream effects on multiple cytokines. Drug target cis-MR paired with colocalization revealed G-CSF/CSF-3 and CXCL9/MIG as potential causal mediators of asthma and Crohns disease, respectively, but also a potentially protective role of TNF-b in multiple sclerosis. Our results provide an overview of the genetic architecture of circulating cytokines and could guide the development of targeted immunotherapies.

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“… 22 This structure alteration enables TRAF4 to participate in broader processes, including neurogenesis, 23 cell polarity, 24 cell proliferation, 25 apoptosis, 26 oxidation, 27 osteogenic metabolism, 28 and repair, 29 while the majority of the TRAF family is mainly involved in immune‐related cell signaling. 30 TRAF4 has been reported to be involved in various types of cancer, ranging from solid tumors to hematological tumors 9 , 31 , 32 , 33 , 34 and inflammatory disease. 35 The present study has verified the promotive effect of TRAF4 in cardiac hypertrophy, which extends the understanding of the pathological function of TRAF4.…”

Section: Discussionmentioning

confidence: 99%

TRAF Family Member 4 Promotes Cardiac Hypertrophy Through the Activation of the AKT Pathway

Li,

Wang,

Xiao

et al. 2023

JAHA

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Background Pathological cardiac hypertrophy is a major cause of heart failure morbidity. The complex mechanism of intermolecular interactions underlying the pathogenesis of cardiac hypertrophy has led to a lack of development and application of therapeutic methods. Methods and Results Our study provides the first evidence that TRAF4, a member of the tumor necrosis factor receptor–associated factor (TRAF) family, acts as a promoter of cardiac hypertrophy. Here, Western blotting assays demonstrated that TRAF4 is upregulated in cardiac hypertrophy. Additionally, TRAF4 deletion inhibits the development of cardiac hypertrophy in a mouse model after transverse aortic constriction surgery, whereas its overexpression promotes phenylephrine stimulation‐induced cardiomyocyte hypertrophy in primary neonatal rat cardiomyocytes. Mechanistically, RNA‐seq analysis revealed that TRAF4 promoted the activation of the protein kinase B pathway during cardiac hypertrophy. Moreover, we found that inhibition of protein kinase B phosphorylation rescued the aggravated cardiomyocyte hypertrophic phenotypes caused by TRAF4 overexpression in phenylephrine‐treated neonatal rat cardiomyocytes, suggesting that TRAF4 may regulate cardiac hypertrophy in a protein kinase B–dependent manner. Conclusions Our results revealed the regulatory function of TRAF4 in cardiac hypertrophy, which may provide new insights into developing therapeutic and preventive targets for this disease.

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Structural feature of TRAFs, their related human diseases and therapeutic intervention

Cited by 12 publications

References 109 publications

TRAF4 hyperactivates HER2 signaling and contributes to Trastuzumab resistance in HER2-positive breast cancer

TRAF4 hyperactivates HER2 signaling and contributes to Trastuzumab resistance in HER2-positive breast cancer

The Genomic Architecture of Circulating Cytokine Levels Points to Drug Targets for Immune-Related Diseases

TRAF Family Member 4 Promotes Cardiac Hypertrophy Through the Activation of the AKT Pathway

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