ArticleProceedings of the National Academy of Sciences of the United States of America2018
TRAF4 binds to the juxtamembrane region of EGFR directly and promotes kinase activation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 17 citations in OpenAlex.
- High-throughput characterization of 5886 HER2 variants identifies 112 new in cellulo gain-of-function mutations.Genomics · 2025Article
- New Gain-of-Function Mutations Prioritize Mechanisms of HER2 Activation.medRxiv : the preprint server for health sciences · 2025Article
- Nerve Growth Factor Signaling Promotes Nuclear Translocation of TRAF4 to Enhance Tumor Stemness and Metastatic Dormancy Via C-Jun-mediated IL-8 Autocrine.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Lnc-EST885 promotes hepatocellular carcinoma metastasis through PI3K / AKT pathway by interaction with TRAF4.Translational oncology · 2025Article
- TRAF4 is crucial for ST2+ memory Th2 cell expansion in IL-33-driven airway inflammation.JCI insight · 2023Article
- TRAF Family Member 4 Promotes Cardiac Hypertrophy Through the Activation of the AKT Pathway.Journal of the American Heart Association · 2023Article
- Overexpression of TRAF4 promotes lung cancer growth and EGFR-dependent phosphorylation of ERK5.FEBS open bio · 2022Article
- TRAF4 hyperactivates HER2 signaling and contributes to Trastuzumab resistance in HER2-positive breast cancer.Oncogene · 2022Article
- The Research Progress in Physiological and Pathological Functions of TRAF4.Frontiers in oncology · 2022Review
- Basic Amino Acids Within the Juxtamembrane Domain of the Epidermal Growth Factor Receptor Regulate Receptor Dimerization and Auto-phosphorylation.The protein journal · 2020Article
- TRAF4 acts as a fate checkpoint to regulate the adipogenic differentiation of MSCs by activating PKM2.EBioMedicine · 2020Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
The activation of the epidermal growth factor receptor (EGFR) is crucial for triggering diverse cellular functions, including cell proliferation, migration, and differentiation, and up-regulation of EGFR expression or activity is a key factor in triggering the development of cancer. Here we show that overexpression of a scaffold protein, tumor necrosis factor receptor (TNF-R)-associated factor 4 (TRAF4), promotes EGF-induced autophosphorylation of EGFR (activation) and downstream signaling, whereas TRAF4 deficiency attenuates EGFR activation and EGF-driven cell proliferation. Using structure-based sequence alignment and NMR spectroscopy, we identified a TRAF4 binding site in the C-terminal half of the juxtamembrane (JM) segment of EGFR, a region known to promote asymmetric dimerization and subsequent activation. Deletion of the TRAF4 binding site led to dramatic defects in EGFR activation and EGF-driven cell proliferation. Specific point mutations in the TRAF4 binding site also resulted in significant attenuation of EGFR activation. Detailed structural examination of the inactive versus active forms of EGFR suggests that TRAF4 binding probably induces a conformational rearrangement of the JM region to promote EGFR dimerization. These results identify a novel mechanism of TRAF4-mediated EGFR activation and signaling.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.