ArticleCirculation research2012
p90RSK targets the ERK5-CHIP ubiquitin E3 ligase activity in diabetic hearts and promotes cardiac apoptosis and dysfunction.
Article in Circulation research, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 56 citations in OpenAlex.
- Impacts of Radiation on Metabolism and Vascular Cell Senescence.Antioxidants & redox signaling · 2025Review
- E3 ubiquitin ligase CHIP alleviates H/R-induced myocardial injury by inhibiting pyroptosis.Molecular biology reports · 2025Article
- Josephin Domain Containing 2 (JOSD2) inhibition as Pan-KRAS-mutation-targeting strategy for colorectal cancer.Nature communications · 2025Article
- p90RSK modulates inter-and intracellular signaling in kidney diseases.Frontiers in cell and developmental biology · 2025Review
- RSK1 and RSK2 as therapeutic targets: an up-to-date snapshot of emerging data.Expert opinion on therapeutic targets · 2024Review
- Bone and Extracellular Signal-Related Kinase 5 (ERK5).Biomolecules · 2024Review
- An ERK5-NRF2 Axis Mediates Senescence-Associated Stemness and Atherosclerosis.Circulation research · 2023Article
- Inhibition of p90RSK Ameliorates PDGF-BB-Mediated Phenotypic Change of Vascular Smooth Muscle Cell and Subsequent Hyperplasia of Neointima.International journal of molecular sciences · 2023Article
- CHIP Haploinsufficiency Exacerbates Hepatic Steatosis via Enhanced TXNIP Expression and Endoplasmic Reticulum Stress Responses.Antioxidants (Basel, Switzerland) · 2023Article
- The significance of ERK5 catalytic-independent functions in disease pathways.Frontiers in cell and developmental biology · 2023Review
- Krüppel-Like Factor 15/Interleukin 11 Axis-Mediated Adventitial Remodeling Depends on Extracellular Signal-Regulated Kinases 1 and 2 Activation in Angiotensin II-Induced Hypertension.Journal of the American Heart Association · 2021Article
- The Role of HECT-Type E3 Ligase in the Development of Cardiac Disease.International journal of molecular sciences · 2021Review
- Conserved and Unique Roles of Chaperone-Dependent E3 Ubiquitin Ligase CHIP in Plants.Frontiers in plant science · 2021Review
- TargetingeLife · 2020Article
- FMK, an Inhibitor of p90RSK, Inhibits High Glucose-Induced TXNIP Expression via Regulation of ChREBP in Pancreatic β Cells.International journal of molecular sciences · 2019Article
- Role of p90RSK in Kidney and Other Diseases.International journal of molecular sciences · 2019Review
- Adverse Effects of Fenofibrate in Mice Deficient in the Protein Quality Control Regulator, CHIP.Journal of cardiovascular development and disease · 2018Article
- Interrelationship between diabetes mellitus and heart failure: the role of peroxisome proliferator-activated receptors in left ventricle performance.Heart failure reviews · 2018Review
- Metabolic stress-induced cardiomyopathy is caused by mitochondrial dysfunction due to attenuated Erk5 signaling.Nature communications · 2017Article
- Sub-cellular localization specific SUMOylation in the heart.Biochimica et biophysica acta. Molecular basis of disease · 2017Review
Corrections and comments
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Authors and funding
20 authors at 5 institutions in 2 countries.
Funding
Abstract
rationaleCardiomyocyte apoptosis is one of the key events in the development and progression of heart failure, and a crucial role for ICER (inducible cAMP early repressor) in this process has been previously reported. ERK5 is known to inhibit cardiac apoptosis after myocardial infarction (MI), especially in hyperglycemic states, via association with CHIP ubiquitin (Ub) ligase and subsequent upregulation of CHIP ligase activity, which induces ICER ubiquitination and subsequent protein degradation. The regulatory mechanism governing ERK5/CHIP interaction is unknown.
objectiveWe previously demonstrated increased p90RSK activation in the diabetic heart. As a logical extension of this work, we now investigate whether p90RSK activation inhibits ERK5-mediated CHIP activation, and subsequently increases ICER levels and apoptosis. METHODS AND
resultsp90RSK activation inhibits ERK5/CHIP association and CHIP Ub ligase activity. p90RSK and CHIP share a common binding site in the ERK5 C-terminal domain (aa571-807). Overexpression of either p90RSK or an ERK5 fragment (aa571-807) inhibits ERK5/CHIP association, suggesting that p90RSK and CHIP competes for ERK5 binding and that p90RSK activation is critical for inhibiting ERK5/CHIP interaction. We also identified ERK5-S496 as being directly phosphorylated by p90RSK and demonstrated that an ERK5-S496A mutant significantly impairs Angiotensin II-mediated inhibition of CHIP activity and subsequent increase in ICER levels. In vivo, either cardiac-specific depletion of ERK5 or overexpression of p90RSK inhibits CHIP activity and accelerates cardiac apoptosis after MI-a phenomenon fully reversible by activating ERK5.
conclusionsThese data suggest a role for p90RSK in inhibiting CHIP activity and promoting cardiac apoptosis through binding to and phosphorylation of ERK5-S496.
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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.