ArticleCancer research2013
Proteomic analysis of ubiquitin ligase KEAP1 reveals associated proteins that inhibit NRF2 ubiquitination.
Article in Cancer research, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 153 papers.
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Who cites it
153 citing papers in PubMed, 248 citations in OpenAlex.
- Association between Locoregional Failure and NFE2L2/KEAP1/CUL3 Mutations in NRG/RTOG 9512: A Randomized Trial of Radiation Fractionation in T2N0 Glottic Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Trial
- Article
- Bidirectional crosstalk between the catalytic and moonlighting functions of human dipeptidyl peptidase 3: potential physiological implications.RSC advances · 2026Article
- The Discovery of GSK3227634: A Potent Inhaled Inhibitor of the KEAP1/NRF2 Protein-Protein Interaction for the Treatment of Chronic Obstructive Pulmonary Disease.Journal of medicinal chemistry · 2026Article
- Nrf2 signaling pathway and its molecular regulatory mechanism.Journal of Zhejiang University. Science. B · 2026Review
- Beyond KEAP1: The Context-Specific NRF2 Partner Code in Disease and Therapy.Antioxidants (Basel, Switzerland) · 2026Review
- TSC22D4 drives clear cell renal cell carcinoma progression and therapy resistance by stabilizing NRF2 through KEAP1 disruption.Cell death & disease · 2026Article
- A Covalent Allosteric Molecular Glue Suppresses NRF2-Dependent Cancer Growth.Cancer discovery · 2026Article
- Proteome-wide prediction of interactions between structured domains and peptide motifs reveals functionally coherent subnetworks.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Keap1 Deficiency Promotes Macrophage M2 Polarization and Protects β Cells.Journal of diabetes research · 2026Article
- The PI3K pathway is a downstream effector of NRF2 activation in the esophagus.Translational oncology · 2026Article
- One Enzyme, Many Faces: The Expanding Role of DPP3 in Cardiovascular and Critical Care.Journal of clinical medicine · 2025Review
- Ellagic acid mediates cardioprotection against adrenaline-induced toxicity via PI3K/AKT and Keap1-NRF2 axes.Scientific reports · 2025Article
- NRF2 activation in cancer and overview of NRF2 small molecule inhibitors.Archives of pharmacal research · 2025Review
- PIP5K1A Suppresses Ferroptosis and Induces Sorafenib Resistance by Stabilizing NRF2 in Hepatocellular Carcinoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- New Amidino-Substituted Benzimidazole Derivatives as Human Dipeptidyl Peptidase III Inhibitors: Synthesis, In Vitro Evaluation, QSAR, and Molecular Docking Studies.International journal of molecular sciences · 2025Article
- KEAP1-NRF2 Interaction in Cancer: Competitive Interactors and Their Role in Carcinogenesis.Cancers · 2025Review
- The serine protease DPP9 and the redox sensor KEAP1 form a mutually inhibitory complex.The Journal of biological chemistry · 2025Article
- RoseTTAFold diffusion-guided short peptide design: a case study of binders against Keap1/Nrf2.Computational and structural biotechnology journal · 2025Article
- Mechanistic Insights and Potential Therapeutic Implications of NRF2 in Diabetic Encephalopathy.Molecular neurobiology · 2024Review
93 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Somatic mutations in the KEAP1 ubiquitin ligase or its substrate NRF2 (NFE2L2) commonly occur in human cancer, resulting in constitutive NRF2-mediated transcription of cytoprotective genes. However, many tumors display high NRF2 activity in the absence of mutation, supporting the hypothesis that alternative mechanisms of pathway activation exist. Previously, we and others discovered that via a competitive binding mechanism, the proteins WTX (AMER1), PALB2, and SQSTM1 bind KEAP1 to activate NRF2. Proteomic analysis of the KEAP1 protein interaction network revealed a significant enrichment of associated proteins containing an ETGE amino acid motif, which matches the KEAP1 interaction motif found in NRF2. Like WTX, PALB2, and SQSTM1, we found that the dipeptidyl peptidase 3 (DPP3) protein binds KEAP1 via an "ETGE" motif to displace NRF2, thus inhibiting NRF2 ubiquitination and driving NRF2-dependent transcription. Comparing the spectrum of KEAP1-interacting proteins with the genomic profile of 178 squamous cell lung carcinomas characterized by The Cancer Genome Atlas revealed amplification and mRNA overexpression of the DPP3 gene in tumors with high NRF2 activity but lacking NRF2 stabilizing mutations. We further show that tumor-derived mutations in KEAP1 are hypomorphic with respect to NRF2 inhibition and that DPP3 overexpression in the presence of these mutants further promotes NRF2 activation. Collectively, our findings further support the competition model of NRF2 activation and suggest that "ETGE"-containing proteins such as DPP3 contribute to NRF2 activity in cancer.
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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.