ArticleThe Journal of clinical investigation2022
SCF-SKP2 E3 ubiquitin ligase links mTORC1/ER stress/ISR with YAP activation in murine renal cystogenesis.
Article in The Journal of clinical investigation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 20 citations in OpenAlex.
- SKP2 Regulates Pulmonary Inflammatory Injury Triggered by Bacterial Infection Through p27-Mediated Degradation of FOXN3.MedComm · 2026Article
- Constitutive YAP activation in distal nephron segments disrupts epithelial identity and nephron patterning.JCI insight · 2026Article
- Butyrate-producing gut bacteria restrain PBAT microplastic-triggered brain microglial lipotoxicity via a microbiota-butyrate-mTORC1-ISR relay along the gut-brain axis.Journal of neuroinflammation · 2026Article
- Targeting endoplasmic reticulum stress and YAP/TAZ-SMAD1/5 signaling to ameliorate endothelial dysfunction in diabetes.Acta pharmacologica Sinica · 2026Article
- Pellino1-mTOR/S6K1 signaling axis is a key pathogenesis for the development of polycystic kidney disease.Cell death & disease · 2026Article
- SKP2 in Cancer: From Molecular Regulation to Therapeutic Vulnerabilities and Translational Perspectives.Drug design, development and therapy · 2026Review
- Targeting ubiquitination in disease and therapy.Signal transduction and targeted therapy · 2025Review
- TIPE2 Protects Bronchial Epithelial Cells From Pyroptosis and Oxidative Stress by Interacting With the E3 Ubiquitin Ligase FBW1A in Asthmatic Mice.Journal of biochemical and molecular toxicology · 2025Article
- The ATF4-glutamine axis: a central node in cancer metabolism, stress adaptation, and therapeutic targeting.Cell death discovery · 2025Review
- Posttranslational modifications of YAP/TAZ: molecular mechanisms and therapeutic opportunities.Cellular & molecular biology letters · 2025Review
- Physiologic mechanisms underlying polycystic kidney disease.Physiological reviews · 2025Review
- Halofuginone Disrupted Collagen Deposition via mTOR-eIF2α-ATF4 Axis to Enhance Chemosensitivity in Ovarian Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Exploring the dual role of endoplasmic reticulum stress in urological cancers: Implications for tumor progression and cell death interactions.Journal of cell communication and signaling · 2024Review
- Research progress of the Hippo signaling pathway in renal cell carcinoma.Asian journal of urology · 2024Review
- Inhibition of asparagine synthetase effectively retards polycystic kidney disease progression.EMBO molecular medicine · 2024Article
- ER stress-induced YAP upregulation leads to chondrocyte phenotype loss in age-related osteoarthritis.Frontiers in pharmacology · 2024Article
- Diacylglycerol lipase alpha promotes hepatocellular carcinoma progression and induces lenvatinib resistance by enhancing YAP activity.Cell death & disease · 2023Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
The Hippo pathway nuclear effector Yes-associated protein (YAP) potentiates the progression of polycystic kidney disease (PKD) arising from ciliopathies. The mechanisms underlying the increase in YAP expression and transcriptional activity in PKD remain obscure. We observed that in kidneys from mice with juvenile cystic kidney (jck) ciliopathy, the aberrant hyperactivity of mechanistic target of rapamycin complex 1 (mTORC1), driven by ERK1/2 and PI3K/AKT cascades, induced ER proteotoxic stress. To reduce this stress by reprogramming translation, the protein kinase R-like ER kinase-eukaryotic initiation factor 2α (PERK/eIF2α) arm of the integrated stress response (ISR) was activated. PERK-mediated phosphorylation of eIF2α drove the selective translation of activating transcription factor 4 (ATF4), potentiating YAP expression. In parallel, YAP underwent K63-linked polyubiquitination by SCF S-phase kinase-associated protein 2 (SKP2) E3 ubiquitin ligase, a Hippo-independent, nonproteolytic ubiquitination that enhances YAP nuclear trafficking and transcriptional activity in cancer cells. Defective ISR cellular adaptation to ER stress in eIF2α phosphorylation-deficient jck mice further augmented YAP-mediated transcriptional activity and renal cyst growth. Conversely, pharmacological tuning down of ER stress/ISR activity and SKP2 expression in jck mice by administration of tauroursodeoxycholic acid (TUDCA) or tolvaptan impeded these processes. Restoring ER homeostasis and/or interfering with the SKP2-YAP interaction represent potential therapeutic avenues for stemming the progression of renal cystogenesis.
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