ArticleProceedings of the National Academy of Sciences of the United States of America2020
FGF23 contains two distinct high-affinity binding sites enabling bivalent interactions with α-Klotho.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
23 citing papers in PubMed, 34 citations in OpenAlex.
- Antiaging Properties of the Klotho Protein.Cells · 2026Review
- Mechanisms of endothelial senescence and vascular aging.Biogerontology · 2025Review
- FGF-based drug discovery: advances and challenges.Nature reviews. Drug discovery · 2025Review
- Conformational landscape of soluble α-klotho revealed by cryogenic electron microscopy.Scientific reports · 2025Article
- Emerging concepts on the FGF23 regulation and activity.Molecular and cellular biochemistry · 2025Review
- Chk2 sustains PLK1 activity in mitosis to ensure proper chromosome segregation.Nature communications · 2024Article
- Interrelationships among metabolic syndrome, bone-derived cytokines, and the most common metabolic syndrome-related diseases negatively affecting bone quality.Diabetology & metabolic syndrome · 2024Review
- Review
- Fibroblast growth factor 23 is pumping iron: C-terminal-fibroblast growth factor 23 cleaved peptide and its function in iron metabolism.Current opinion in nephrology and hypertension · 2024Review
- Overexpression and Purification of Mitogenic and Metabolic Fibroblast Growth Factors.Methods in molecular biology (Clifton, N.J.) · 2024Article
- PKC regulates αKlotho gene expression in MDCK and NRK-52E cells.Pflugers Archiv : European journal of physiology · 2024Article
- Exploring endocrine FGFs - structures, functions and biomedical applications.International journal of biochemistry and molecular biology · 2024Review
- Bone-derived C-terminal FGF23 cleaved peptides increase iron availability in acute inflammation.Blood · 2023Article
- Branched Multimeric Peptides as Affinity Reagents for the Detection of α-Klotho Protein.Angewandte Chemie (International ed. in English) · 2023Article
- Regulation of FGF23 production and phosphate metabolism by bone-kidney interactions.Nature reviews. Nephrology · 2023Review
- Heparin is essential for optimal cell signaling by FGF21 and for regulation of βKlotho cellular stability.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- The fibroblast growth factor-Klotho axis at molecular level.Open life sciences · 2023Review
- Approach to Hypophosphatemic Rickets.The Journal of clinical endocrinology and metabolism · 2022Article
- β-Klotho Promotes the Development of Intrauterine Adhesions via the PI3K/AKT Signaling Pathway.International journal of molecular sciences · 2022Article
- Identification of Small-Molecule Inhibitors of Fibroblast Growth Factor 23 Signaling via In Silico Hot Spot Prediction and Molecular Docking to α-Klotho.Journal of chemical information and modeling · 2022Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
10 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The three members of the endocrine-fibroblast growth factor (FGF) family, FGF19, 21, and 23 are circulating hormones that regulate critical metabolic processes. FGF23 stimulates the assembly of a signaling complex composed of α-Klotho (KLA) and FGF receptor (FGFR) resulting in kinase activation, regulation of phosphate homeostasis, and vitamin D levels. Here we report that the C-terminal tail of FGF23, a region responsible for KLA binding, contains two tandem repeats, repeat 1 (R1) and repeat 2 (R2) that function as two distinct ligands for KLA. FGF23 variants with a single KLA binding site, FGF23-R1, FGF23-R2, or FGF23-wild type (WT) with both R1 and R2, bind to KLA with similar binding affinity and stimulate FGFR1 activation and MAPK response. R2 is flanked by two cysteines that form a disulfide bridge in FGF23-WT; disulfide bridge formation in FGF23-WT is dispensable for KLA binding and for cell signaling via FGFRs. We show that FGF23-WT stimulates dimerization and activation of a chimeric receptor molecule composed of the extracellular domain of KLA fused to the cytoplasmic domain of FGFR and employ total internal reflection fluorescence microscopy to visualize individual KLA molecules on the cell surface. These experiments demonstrate that FGF23-WT can act as a bivalent ligand of KLA in the cell membrane. Finally, an engineered Fc-R2 protein acts as an FGF23 antagonist offering new pharmacological intervention for treating diseases caused by excessive FGF23 abundance or activity.
Indexed as
Identifiers
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.