ArticleNature communications2020
Paradoxical activation of the protein kinase-transcription factor ERK5 by ERK5 kinase inhibitors.
Article in Nature communications, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
33 citing papers in PubMed, 46 citations in OpenAlex.
- ML281 Does Not Function as an STK33 Inhibitor but Modulates Proliferation and Differentiation of Keratinocytes Derived from Hypertrophic Scars.International journal of molecular sciences · 2026Article
- Palbociclib targets β-catenin for degradation and synergizes with KRAS or ERK5 inhibition in colorectal cancer preclinical models.Journal of translational medicine · 2026Article
- XMD8-92 and JWG-045 exhibit anti-ferroptotic activities, independently of inhibiting ERK5.Scientific reports · 2026Article
- Development of a chaperone-mediated protein degrader targeting ERK5 that efficaciously reduces tumor growth.Cell communication and signaling : CCS · 2026Article
- Anti-cancer Effects of 1,4-Dialkoxynaphthalene-Imidazolium Salt Derivatives through ERK5 kinase activity inhibition.Scientific reports · 2025Article
- Latent allosteric control of protein interactions by ATP-competitive kinase inhibitors.Current opinion in structural biology · 2024Review
- ERK5 suppression overcomes FAK inhibitor resistance in mutant KRAS-driven non-small cell lung cancer.EMBO molecular medicine · 2024Article
- Enzyme Is the Name-Adapter Is the Game.Cells · 2024Review
- Anticancer drugs: How to select small molecule combinations?Trends in pharmacological sciences · 2024Review
- Chemical proteomics reveals the target landscape of 1,000 kinase inhibitors.Nature chemical biology · 2024Article
- An ERK5-NRF2 Axis Mediates Senescence-Associated Stemness and Atherosclerosis.Circulation research · 2023Article
- ERK1/2 inhibitors act as monovalent degraders inducing ubiquitylation and proteasome-dependent turnover of ERK2, but not ERK1.The Biochemical journal · 2023Article
- Review
- Modulation of ERK5 Activity as a Therapeutic Anti-Cancer Strategy.Journal of medicinal chemistry · 2023Review
- The significance of ERK5 catalytic-independent functions in disease pathways.Frontiers in cell and developmental biology · 2023Review
- A non-coding GWAS variant impacts anthracycline-induced cardiotoxic phenotypes in human iPSC-derived cardiomyocytes.Nature communications · 2022Article
- Acute pharmacological degradation of ERK5 does not inhibit cellular immune response or proliferation.Cell chemical biology · 2022Article
- OXTRNature communications · 2022Article
- ERK5 Is a Major Determinant of Chemical Sarcomagenesis: Implications in Human Pathology.Cancers · 2022Article
- Parallel Optimization of Potency and Pharmacokinetics Leading to the Discovery of a Pyrrole Carboxamide ERK5 Kinase Domain Inhibitor.Journal of medicinal chemistry · 2022Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
Abstract
The dual protein kinase-transcription factor, ERK5, is an emerging drug target in cancer and inflammation, and small-molecule ERK5 kinase inhibitors have been developed. However, selective ERK5 kinase inhibitors fail to recapitulate ERK5 genetic ablation phenotypes, suggesting kinase-independent functions for ERK5. Here we show that ERK5 kinase inhibitors cause paradoxical activation of ERK5 transcriptional activity mediated through its unique C-terminal transcriptional activation domain (TAD). Using the ERK5 kinase inhibitor, Compound 26 (ERK5-IN-1), as a paradigm, we have developed kinase-active, drug-resistant mutants of ERK5. With these mutants, we show that induction of ERK5 transcriptional activity requires direct binding of the inhibitor to the kinase domain. This in turn promotes conformational changes in the kinase domain that result in nuclear translocation of ERK5 and stimulation of gene transcription. This shows that both the ERK5 kinase and TAD must be considered when assessing the role of ERK5 and the effectiveness of anti-ERK5 therapeutics.
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What OpenQuestion holds
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.