ArticleThe Journal of biological chemistry2010
Metabolic regulator betaKlotho interacts with fibroblast growth factor receptor 4 (FGFR4) to induce apoptosis and inhibit tumor cell proliferation.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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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
34 citing papers in PubMed, 53 citations in OpenAlex.
- Review
- FGF19 in Solid Tumors: Molecular Mechanisms, Metabolic Reprogramming, and Emerging Therapeutic Opportunities.Theranostics · 2026Review
- Unveiling CTRB2, RSPO3, KLOTB, and ROR1 as obesity-pancreatic disease association proteins: a comprehensive Mendelian randomization study.Gastroenterology report · 2025Article
- Three Dimensional Bioprinting for Hepatic Tissue Engineering: From In Vitro Models to Clinical Applications.Tissue engineering and regenerative medicine · 2024Review
- Recent progress in understanding mitokines as diagnostic and therapeutic targets in hepatocellular carcinoma.World journal of clinical cases · 2023Review
- β-Klotho Promotes the Development of Intrauterine Adhesions via the PI3K/AKT Signaling Pathway.International journal of molecular sciences · 2022Article
- Review
- Role of FGF15 in Hepatic Surgery in the Presence of Tumorigenesis: Dr. Jekyll or Mr. Hyde?Cells · 2021Review
- Serum β-klotho is a potential biomarker in the prediction of clinical outcomes among patients with NSCLC.Journal of thoracic disease · 2021Article
- Liver regeneration: biological and pathological mechanisms and implications.Nature reviews. Gastroenterology & hepatology · 2021Review
- βKlotho, a direct target of miR-206, contributes to the growth of hepatoblastoma through augmenting PI3K/Akt/mTOR signaling.American journal of cancer research · 2021Article
- FGFR4: A promising therapeutic target for breast cancer and other solid tumors.Pharmacology & therapeutics · 2020Review
- Bile Acid Diarrhea and NAFLD: Shared Pathways for Distinct Phenotypes.Hepatology communications · 2020Review
- Editorial: Resident and Ectopic FGF Signaling in Development and Disease.Frontiers in cell and developmental biology · 2020Article
- The FGF metabolic axis.Frontiers of medicine · 2019Review
- βKlotho is identified as a target for theranostics in non-small cell lung cancer.Theranostics · 2019Article
- βKlotho inhibits androgen/androgen receptor‑associated epithelial‑mesenchymal transition in prostate cancer through inactivation of ERK1/2 signaling.Oncology reports · 2018Article
- Downregulation of klotho β is associated with invasive ductal carcinoma progression.Oncology letters · 2017Article
- Novel transcriptome assembly and comparative toxicity pathway analysis in mahi-mahi (Coryphaena hippurus) embryos and larvae exposed to Deepwater Horizon oil.Scientific reports · 2017Article
- Fibroblast growth factors, old kids on the new block.Seminars in cell & developmental biology · 2016Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
In organs involved in metabolic homeostasis, transmembrane α and βklothos direct FGFR signaling to control of metabolic pathways. Coordinate expression of βklotho and FGFR4 is a property of mature hepatocytes. Genetic deletion of FGFR4 or βklotho in mice disrupts hepatic cholesterol/bile acid and lipid metabolism. The deletion of FGFR4 has no effect on the proliferative response of hepatocytes after liver injury. However, its absence results in accelerated progression of dimethynitrosamine-initiated hepatocellular carcinomas, indicating that FGFR4 suppresses hepatoma proliferation. The mechanism underlying the FGFR4-mediated hepatoma suppression has not been addressed. Here we show that βklotho expression is more consistently down-regulated in human and mouse hepatomas than FGFR4. Co-expression and activation by either endocrine FGF19 or cellular FGF1 of the FGFR4 kinase in a complex with βklotho restricts cell population growth through induction of apoptotic cell death in both hepatic and nonhepatic cells. The βklotho-FGFR4 partnership caused a depression of activated AKT and mammalian target of rapamycin while activating ERK1/2 that may underlie the pro-apoptotic effect. Our results show that βklotho not only interacts with heparan sulfate-FGFR4 to form a complex with high affinity for endocrine FGF19 but also impacts the quality of downstream signaling and biological end points activated by either FGF19 or canonical FGF1. Thus the same βklotho-heparan sulfate-FGFR4 partnership that mediates endocrine control of hepatic metabolism plays a role in cellular homeostasis and hepatoma suppression through negative control of cell population growth mediated by pro-apoptotic 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.